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Old 04-16-2009, 05:54 PM   #1
Rich66
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Cancer stem cells: The root of all evil?

University of Michigan (home of Dr. Max Wicha)
cancer stem cell website: http://www.mcancer.org/stemcells/





Cancer stem cells
The root of all evil?
Sep 11th 2008
From The Economist print edition

Cancer may be caused by stem cells gone bad. If that proves to be correct, it should revolutionise treatment
Get article background
MUCH of medical research is a hard slog for small reward. But, just occasionally, a finding revolutionises the field and cracks open a whole range of diseases. The discovery in the 19th century that many illnesses are caused by bacteria was one such. The unravelling of Mendelian genetics was another. It now seems likely that medical science is on the brink of a finding of equal significance. The underlying biology of that scourge of modern humanity, cancer, looks as though it is about to yield its main secret. If it does, it is possible that the headline-writer’s cliché, “a cure for cancer”, will come true over the years, just as the antibiotics that followed from the discovery of bacteria swept away previously lethal infectious diseases.
The discovery—or, rather, the hypothesis that is now being tested—is that cancers grow from stem cells in the way that healthy organs do. A stem cell is one that, when it divides, produces two unequal daughters. One remains a stem cell while the other multiplies into the sorts of cells required by its organ. This matters for cancer because, at the moment, all the cells of a tumour are seen as more or less equivalent. Therapies designed to kill them do not distinguish between them. Success is defined as eliminating as many of them as possible, so those therapies have been refined to do just that. However, if all that the therapies are doing is killing the descendants of the non-stem-cell daughters, the problem has not been eliminated. Instead of attacking the many, you have to attack the few. That means aiming at the stem cells themselves.
Not all investigators support the cancer-stem-cell hypothesis, but the share who do so is growing rapidly. A mere five years ago, few research papers on the subject were presented at big academic meetings. This year there were hundreds at one such meeting alone. Moreover, data from clinical trials based on the hypothesis suggest that it has real value for patients. As a result, drug companies have taken notice and are trying to develop substances that will kill cancer stem cells.

The virtues of self-restraint
The root cause of both cancer and stem cells is multicellularity. In the distant past, when all living things had only one cell, that cell’s reproduction was at a premium. In the body of an animal, however, most cells have taken a vow of self-denial. Reproduction is delegated to the sex cells. The rest, called somatic cells, are merely supporting actors, specialised for the tasks needed to give the sex cells a chance to get into the next generation. For this to happen required the evolution of genes that were able to curb several billion years’ worth of instinct to proliferate without killing that instinct entirely. Only then could somatic cells do their job, and be present in appropriate numbers.
The standard model of tumour formation was based on the fact that somatic cells slowly accumulate mutations. Sometimes these disable the anti-proliferation genes. If enough of the brakes come off in a somatic cell, so the theory went, it will recover its ancestral vigour and start growing into a tumour. Cancer, then, is an inevitable cost of being multicellular.
The discovery of stem cells changed this picture subtly, but importantly. Blood stem cells were found a long time ago, but only recently has it become apparent that all tissues have stem cells. The instincts of stem cells lie halfway between those of sex cells and ordinary body cells. They never stop reproducing, but they cannot look forward to making the generational leap. When the body dies, so do they. However, they are few in number, and because at cell division only one daughter continues to be a stem cell, that number does not grow.
This division of labour may even be another type of anti-cancer mechanism. It allows stringent locks to be put on somatic cells (which, for example, strictly limit the number of times they can divide), yet it permits tissue to be renewed. Without stem cells, such tissue-renewal would be the province of any and every somatic cell—a recipe, as the traditional model observes, for tumorous disaster. The obverse of this, however, is that if a stem cell does mutate into something bad, it is likely to be very bad indeed. That, in essence, is the stem-cell hypothesis of cancer.

One obvious prediction of this hypothesis is that tumours will have at least two sorts of cell in them: a dominant population of daughter cells and a minority one of stem cells. The first person to show that to be true was John Dick, a molecular biologist at the University of Toronto. In 1997 he isolated what looked like stem cells from a blood cancer called acute myeloid leukaemia (AML). Blood cancers are easier to deal with in this context than solid tumours because their cells do not have to be separated from one another before they are examined. One characteristic of AML cells is that they have two sorts of a protein, called CD34 and CD38, on their surfaces. Dr Dick thus used two sets of special antibodies for his experiment. One sort stuck only to the CD34 molecule, the other only to CD38. Each sort was also attached to a fluorescent tag.
By mixing the AML cells from his patients with the two antibodies and running them through a machine that sorted them according to how they fluoresced, he showed that most were positive for both proteins. However, a small fraction (as low as 0.2%) were positive only for CD34. These, he suspected, were the stem cells.
He was able to confirm this by injecting the minority cells into mice. The resulting tumours had the same mix of cells as those from human patients. However, when he injected mice with samples from the majority cells, with both sorts of the protein, no tumours resulted. The CD34-only cells thus acted as cancer stem cells.
Moreover, this phenomenon was not confined to leukaemia. In 2003 a group of researchers at the University of Michigan in Ann Arbor, led by Max Wicha and Michael Clarke, used a similar trick on breast-cancer cells. In this case the surface proteins were known as CD24 and CD44, and the minority were those positive only for CD44. As with AML, these minority cells produced cancers in mice, whereas the majority cells did not.
Since these two pieces of work, the list of cancer stem cells has multiplied. It now includes tumours of the breast, brain, prostate, colon, pancreas, ovary, lung, bladder, head and neck, as well as melanoma, sarcoma, AML, chronic myelogenous leukaemia, Hodgkin’s lymphoma and myeloma.
That is quite a list. The question is, what can be done with it? Jeremy Rich, a neurologist at Duke University in Durham, North Carolina, has one idea. He created mice that had human glioblastoma tumours, a form of brain cancer, growing in them. Then he treated these mice with radiation (the standard therapy for such cancer in people). He found that the cancer stem cells were more likely to survive this treatment than the other cells in the tumour. That turned out to be because, although all the tumour cells suffered equal amounts of DNA damage from the radiation, the stem cells were better able to repair this damage. When he treated the mice simultaneously with radiation and with a drug that interferes with DNA repair, however, the stem cells no longer had an advantage. They were killed by the radiation along with the other cells.
If that result applies to people as well as rodents, it opens up a whole avenue of possibility. In fact, Dr Rich is now in negotiations with several companies, with a view to testing the idea in humans. That “if” is a real one, though. A mouse is not a human being.
Indeed, the stem-cell hypothesis is often criticised for its reliance on animal models of disease. Some researchers worry that the experiments used to identify putative cancer stem cells are too far removed from reality—human tumour cells do not naturally need to survive in mice—and thus may not reflect human cancer biology at all.
Proponents of the hypothesis are alive to that concern, but they think that the same pattern has been seen so often in so many different cancers that it is unlikely to be completely wrong. The practical test, though, will be whether the hypothesis and ideas that emanate from it, such as Dr Rich’s combination therapy, actually help patients survive.

Searching for the suspects
As a step towards discovering whether they do, William Matsui, an oncologist at Johns Hopkins University School of Medicine in Baltimore, looked for cancer stem cells in pancreatic-tumour samples taken from nearly 300 patients. His team found that patients whose tumours did contain such stem cells survived for an average of 14 months. Those whose tumours lacked them survived for 18 months.
That finding is consistent with the idea that cancer stem cells contribute to the most aggressive forms of the disease, though it does not prove they cause tumours in the first place. And although the absence of detectable stem cells in some tumours may be seen as casting doubt on the whole idea, it may instead be that they are too rare to be easily detected. If the stem-cell idea is confirmed, it may help doctors and patients choose how to treat different tumours. Those with detectable stem cells might be candidates for aggressive chemical and radiation therapies, while those without might best be treated with the surgeon’s knife alone.
Breast-cancer researchers are also testing the stem-cell hypothesisin the clinic. Jenny Chang’s group at Baylor College of Medicine, in Texas, took samples of tumours from women before and after standard chemotherapy. When they counted the cells in the tissue they found that the proportion of stem cells in a tumour increased after treatment. That suggests the chemotherapy was killing the non-stem tumour cells and leaving the stem cells behind. When the group repeated the experiment using a modern drug called Tykerb that blocks what is known as the HER2 pathway, they got a different result. HER2 is a gene which encodes a protein that acts as a receptor for molecules called growth factors which, as their name suggests, encourage cell growth and proliferation. After the HER2-blocking treatment, cancer stem cells formed the same proportion of the residual tumour as beforehand. That suggests they, too, were being clobbered by the new treatment. It is probably no coincidence that another drug, Herceptin, which also goes after HER2, is one of the few medicines that is able to prolong the lives of people with advanced cancer.
The stem-cell hypothesis has also changed the way people do basic research. For example, over the past few years cancer researchers have been grinding up pieces of tumour and using what are known as gene-expression microarrays to work out which genes are active in them. However, if the hypothesis is correct, this approach will probably yield the wrong result, because the crucial cells make up but a small part of a tumour’s bulk and the activity of their genes will be swamped by that of the genes of the more common non-stem cells. The answer is to isolate the stem cells before the grinding starts.
This approach has already yielded one important finding. When Dr Chang used microarrays to study gene expression in the CD44-positive cells from breast tumours, she noticed that they did not look like those of the epithelial cells that make up the bulk of such a tumour. Epithelial cells are immobile, grow in “cobblestone” patterns and produce proteins that help them stick together. The gene expression of the putative stem cells, however, resembled that of a mesenchymal cell. Mesenchymal cells rarely stick together. Indeed, they are mobile and are able to slip through the matrix of proteins that holds epithelial cells together.
That finding is important because mobile cells are more likely to escape from a tumour and form secondary cancers elsewhere in the body. Once such secondaries are established, successful treatment is much harder. And the CD44-positive cells also expressed genes that are important for stem-cell self-renewal, particularly one called Notch that controls the flow of chemical signals within a cell.
Researchers at OSI Pharmaceuticals, a firm that makes a drug called Tarceva, found a similar pattern in lung cancer. Several years ago, they started looking for gene-expression patterns that correlated with response to Tarceva. They found that tumours with a pattern that resembled epithelial cells were sensitive to the drug. By contrast, those that had a mesenchymal pattern were not. They hypothesised that as tumours develop, some of their cells actually switch from a sticky, epithelial state to a mobile, mesenchymal one. This epithelial-to-mesenchymal transition, or EMT, is well known to biologists who study embryonic development, but OSI’s results, and those of other researchers, suggest that cancers may have hijacked it for their own use.
Robert Weinberg, a molecular biologist at the Massachusetts Institute of Technology, and his colleagues have come to the same conclusion but they have taken the hypothesis one step further. They think that tumour cells which have undergone EMT have acquired many of the characteristics of cancer stem cells. Experiments in his laboratory, employing a variety of animal models of breast cancer, suggest that communication between tumour cells and surrounding non-cancerous support cells can lead some of the cancer cells to undergo EMT.
That is intriguing. If this transition really can be induced in tumour cells, then any of them might be able to become a cancer stem cell. So it may be that the fundamentalist version of the stem-cell hypothesis is wrong, and the stem cells are a result of a cancer, rather than its cause. That could be another reason why Dr Matsui found that pancreatic cancers do not always seem to contain stem cells.
Dr Weinberg is sensitive to this point, and is cautious when talking about these experiments. He refers to the cells that have undergone EMT as “having the qualities of stem cells” but avoids actually calling them cancer stem cells. If his idea is correct, though, it means that finding drugs which block the signals that induce EMT could reduce the stem-cell population and prolong the survival of the patient. It also means that both the epithelial cells and the mesenchymal ones will have to be attacked. And OSI is now testing a drug that does just that.

Notch up a victory?
Breast-cancer researchers, too, are testing drugs that hit molecular targets highlighted by cancer-stem-cell studies. Merck, for example, has turned to a drug it originally developed to treat Alzheimer’s disease. Although this drug, code-named MK0752, did not slow that disease, it does block activity of Notch, the stem-cell self-renewal gene, and might thus be an appropriate weapon against breast-cancer stem cells. Dr Chang and Dr Wicha have started a clinical trial which uses MK0752 in combination with standard chemotherapy. By the end of the year they hope to have some idea of whether the combination kills cancer cells in human tumours.
Attacking Notch is a high-risk approach, because this gene is used by healthy stem cells as well as cancerous ones; healthy organs as well as tumours could be damaged. Some researchers are therefore taking a different tack and looking for drugs that hit only the unhealthy stem cells. Craig Jordan, a biologist at the University of Rochester Medical Centre, in New York state, is one such. He has discovered that a chemical called parthenolide, found in feverfew, a medicinal plant, kills AML stem cells. Normal stem cells, however, seem to be able to tolerate the drug without difficulty. The reason is that the leukaemia cells are reliant on a biochemical pathway that parthenolide blocks, whereas normal stem cells are not. If all goes well, a trial to test the safety of a modified form of parthenolide will start in a few months.
If the safety issues can be dealt with—and most researchers think they can—then attacking cancer stem cells really could help patients survive. If, that is, the stem-cell hypothesis is correct.
At the moment, scientists being scientists, few are willing to be anything other than cautious. They have seen too many past cures for cancer vanish in a puff of smoke. The proof needs to come from patients—preferably with them living longer. But if the stem-cell hypothesis is indeed shown to be correct, it will have the great virtue of unifying and simplifying the understanding of what cancer is. And that alone is reason for hope.

Comments from article readers:
http://www.economist.com/science/dis...ry_id=12202589



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Old 04-16-2009, 06:38 PM   #2
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Since I've read about cancer stem cells I've felt that killing them is the key to curing or managing the disease.
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Old 04-16-2009, 06:42 PM   #3
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Cancer stem cells

On the move
Jun 5th 2008 | CHICAGO
From The Economist print edition


Organ-transplant data provide more evidence that stem cells cause cancer
DOCTORS track the long-term health of organ-transplant patients in registries. Such registries make it possible to uncover trends or long-term problems in the population that may be missed in smaller samples. But they can also be pressed into service to support basic research. And a group of researchers led by Sanford Barsky of Ohio State University College of Medicine in Columbus has done just that. As they reported on June 2nd to a meeting of the American Society of Clinical Oncology, in Chicago, they have used one such registry to support the increasingly popular idea that many if not all cancers are caused by stem cells gone bad.
Each organ and tissue in the body has its own collection of stem cells. When these cells divide, they produce two very different daughter cells. One resembles the parent stem cell and thus allows the whole process to continue. The progeny of the other differentiate into mature cells within the skin, kidney, lung or what have you. This is how organs renew themselves over the life of an individual. In a healthy organ, the stem cells divide only when needed—usually in response to injury or when other cells have died. Some cancer scientists, however, think that stem cells can lose this control function and thus divide endlessly, leading to tumours.
Dr Barsky reasoned that if the cancer stem-cell hypothesis is true, then stem cells from a donor organ may cause cancer somewhere else in a transplant recipient's body. Looking in a patient registry, he identified 280 people who had undergone an organ transplant and later developed a solid tumour. In nearly half of these cases donor and recipient were of different sexes, which means the cells from each would have different sex chromosomes (women have two X chromosomes, men an X and a Y). That makes a cancer derived from the transplant easy to identify.
To find out if the tumour cells were the same sex as the body they inhabited, Dr Barsky labelled slices of tumour with green fluorescent tags that bind to the X chromosome and red tags that bind to the Y. And he found transplant-derived cancers in abundance: in 12% of cases, the sex of the tumour matched the donor rather than the recipient. For example, a 48-year-old woman developed skin cancer nine months after receiving a bone-marrow transplant from a man. The tumour cells had a Y chromosome, indicating that the cancer arose from the donated bone marrow. In another case, a 62-year-old man developed colon cancer ten years after receiving a kidney transplant from a female donor. The colon-cancer cells lacked a Y chromosome.
Closer examination of the DNA in the tumour cells and surrounding tissue showed that the tumours definitely did originate from the donor organs, not the recipients. Dr Barsky also found that if a tumour formed in the transplanted organ, it could be derived from either recipient or donor cells.
In each of these cases, the tumour that formed resembled any other tumour that would form in that site. The 48-year-old woman's looked like skin cancer, not cancer of the bone marrow. The 62-year-old man's looked like colon cancer and not like a kidney tumour. Thus, once a cell migrated to a new site, it took on the behaviour and appearance appropriate to that location—losing the identity it had held in its organ of origin.
This observation does not absolutely prove that the migrating cells are stem cells, but it would be astonishing if fully differentiated cells from one tissue could up sticks to another organ and then take on the characteristics of that organ. Besides, biologists do know that stem cells in the bone marrow move into the blood stream. Thus the formation of donor-derived tumours in distant tissues after a bone-marrow transplant is not entirely unexpected. A few reports also exist in the medical literature of donor-derived tumours arising after a solid organ, such as a liver or a kidney, has been transplanted. Dr Barsky's data, though, show that this is not such a rare event after all. Stem cells in one organ thus seem malleable enough to adopt a whole new developmental programme in another organ, even late in a person's life.
More important, though, in Dr Barsky's opinion, is that the new data support the idea that tumours arise from stem cells that have gone wrong. It is not clear whether those stem cells are healthy when they migrate to a new site and mutate into cancer stem cells after they have taken up residence, or if they mutate first and then migrate. Either way, however, transplant registries may just have shed light on a fundamental question in cancer biology.
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Old 05-22-2009, 03:56 PM   #4
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OU Cancer Institute scientists’ discovery could help treat cancer

May 22, 2009
TULSA – A new discovery could provide a major step closer to a cure for cancer.
University of Oklahoma Cancer Institute scientists discovered how stem cell proteins work in the growth of cancer.
Cancer researchers have known for some time certain proteins in cells cause tumors to grow, but they never completely understood why, according to the OU Cancer Institute.
Research from two scientists at the University of Oklahoma Health Sciences Center found a new cancer protein and discovered how the protein works to turn off a natural tumor suppressor and turn on a cancer-causing gene.
Courtney Houchen, cancer biologist at the OU Cancer Institute, said it is the first evidence of a stem cell protein regulating a tumor suppressor.

“This is a great advancement for the field,” he said. “We have filed a patent for the work.”
This research is on the forefront of identifying and targeting cancer stem cells, said Robert Mannel, director of the OU Cancer Institute.
“Cancer stem cell research holds tremendous potential in the fight against cancer – it points to new avenues for cancer drug development,” he said.
When the protein, which is found in cancer, was increased, it caused the tumor suppressor to go down and the tumor grew in research models. When the protein was reduced, the level of tumor suppressor went up and the tumor stopped growing.
Scientists also found that when they stopped the protein, the expression of a cancer-causing gene also went down.
By targeting the new protein, researchers can develop new therapies that will specifically target cancer stem cells and stop cancer from growing and reoccurring.
“What we are saying is that if you target this it will work,” said Houchen. “I am confident that if you develop a drug through this protein or through two other markers we have found, you’re going to treat a lot of cancers.”
The work revolves around the scientists’ belief that the answer to cancer lies in cancer stem cells, which are not targeted by current therapies.

Five years ago, the OU researchers were among a handful of scientists in the nation studying cancer stem cells. But in the last two years cancer stem cells have become a rapidly emerging field, according to the institute.
The latest research from the OU Cancer Institute will appear in the upcoming issue of the journal Gastroenterology.
OU Cancer Institute members are conducting more than 100 cancer research projects supported by more than $20 million.
“From here we would like to understand more about how the protein works and we would like to develop the drugs to target the cells in the cancer,” said Houchen. “We hope we can generate more funding to accelerate the research.”



Stem cell research could 'weed' out cancer

A breakthrough by British scientists could help attack the root cause of cancer in the same way that weeding helps your garden.
By Richard Alleyne, Science Correspondent
Published: 7:30AM GMT 26 Jan 2010

The research could speed up attempts to wipe out cancer by targeting tumour stem cells that drive the disease.
A team from Oxford University has developed a new method of isolating cancer stem cells that can then be grown and studied in the laboratory.
The technique could pave the way to developing drugs that attack cancer at its root.
Dr Trevor Yeung, from the Weatherall Institute of Molecular Medicine at Oxford University, said: "Cancer stem cells drive the growth of a tumour. If we could target treatments against these cells specifically, we should be able to eradicate cancer completely."
Until now research on cancer stem cells has been slow, since the cells are difficult to identify and isolate from tumours.
In the past scientists have tried to find cancer stem cells in tissue samples taken from patients.
The new research involves better ways of using molecular markers to identify cancer stem cells, and maintaining the cells in simple laboratory cultures.
Instead of using biopsy samples, the scientists worked with established bowel cancer cell lines.
They found that the proportion of cancer stem cells within different bowel cancers varies widely, with aggressive tumours containing higher numbers.
The research is reported today in the journal Proceedings of the National Academy of Sciences.
Dr Yeung said: "Radiotherapy and chemotherapy work against all rapidly dividing cells. But there is increasing evidence that cancer stem cells are more resistant than other cells to this treatment. Cancer stem cells that have not been eradicated can lead to later recurrence of cancer.
"It's like trying to weed the garden. It's no good just chopping off the leaves, we need to target the roots to stop the weeds coming back.
"People have assumed that cancer stem cells made up a small proportion of the cells in a tumour, but it is becoming increasingly clear that this is not correct. The most aggressive tumours can have a majority of cells that are cancer stem cells."
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Old 05-22-2009, 05:41 PM   #5
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The Economist article mentions that Tykerb was shown to work on cancer stem cells - this is great news and shows the promise of this drub in breast cancer treatment. I'm currently taking in as part of my neoadjuvant chemo and hope that it's doing its job!

Thank you for posting all this research here.
__________________
ER+ (30%)/PR-/HER-2+, stage 3

Diagnosed on 02/18/09 at 38 with a huge 12x10 cm tumor, after a 6 month delay. Told I was too young and had no risk factors. Found swollen node during breastfeeding.
March-August 09: neo-adjuvant chemo, part of a trial at Stanford (4 DD A/C, 4 Taxotere with daily Tykerb), loading dose of Herceptin
08/12/09 - bye bye boobies (bilateral mastectomy)
08/24/09 - path report shows 100 % success in breast tissue (no cancer there, yay!), 98 % success in lymphatic invasion, and even though 11/13 nodes were still positive, > 95 % of the tumor in them was killed. Hoping for the best!
September-October 09: rads with daily Xeloda
02/25/10 - Cholecystectomy
05/27/10 - Bone scan clear
06/14/10 - CT scan clear, ovarian cyst found
07/27/10 - Done with Herceptin!
02/15/11 - MVA-BN HER-2 vaccine trial
03/15/11 - First CA 15-3: 12.7 and normal, yay!
10/01/11 - Bone scan and CT scan clear, fatty liver found
now on Tamoxifen and Aspirin


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Old 05-23-2009, 10:01 AM   #6
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The study by Chang, U of Michigan:
http://clinicaltrials.gov/ct2/show/NCT00645333

Phase I/II Study of MK-0752 Followed by Docetaxel in Advanced or Metastatic Breast Cancer
This study is currently recruiting participants.
Verified by University of Michigan Cancer Center, August 2008
First Received: March 24, 2008 Last Updated: August 8, 2008 History of Changes
Sponsored by: University of Michigan Cancer Center
Information provided by: University of Michigan Cancer Center
ClinicalTrials.gov Identifier: NCT00645333
Purpose New and better therapies for locally advanced and metastatic breast cancer are needed because, even if standard treatment is successful in shrinking the cancer, there is still a high chance that the cancer will recur. Recent research suggests that breast tumors have a small number of cells in them that are "breast cancer stem cells", which are very resistant to standard treatment. It is thought that the reason that many patients cannot be cured of their breast cancers is that the stem cells are unable to be killed and remain in the body after standard treatment. Laboratory research has shown that a new drug, MK-0752, can target stem cells and prevent tumor recurrences when the drug is combined with docetaxel, a chemotherapy drug commonly used to treat breast cancer.
We know that MK-0752 is safe when given by itself to people. We do not know if treatment with MK-0752 and docetaxel combined is safe or if it will kill "breast cancer stem cells" in people with breast cancer. This clinical trial is being done to determine the safety of several doses of MK-0752 in combination with docetaxel. Preliminary data about the effectiveness of MK-0752 in combination with docetaxel will be collected. Also, tumor biopsy samples will be taken from some patients who have tumors that can be easily biopsied. The samples will be used to perform research tests to help determine if the "breast cancer stem cells" are being killed by the drug combination.


Condition Intervention Phase
Metastatic Breast Cancer
Drug: MK-0752 and Docetaxel
Drug: MK-0752
Phase I
Phase II

Genetics Home Reference related topics: breast cancer
MedlinePlus related topics: Breast Cancer Cancer
Drug Information available for: Docetaxel
U.S. FDA Resources
Study Type: Interventional
Study Design: Treatment, Open Label, Single Group Assignment
Official Title: Phase I/II Trial of MK-0752 Followed by Docetaxel in Locally Advanced or Metastatic Breast Cancer: A Study by the Stem Cell Clinical Consortium

Further study details as provided by University of Michigan Cancer Center:

Primary Outcome Measures:
  • dose limiting toxicity (DLT) [ Time Frame: first 21 days ] [ Designated as safety issue: Yes ]


Secondary Outcome Measures:
  • measurability of lesions, objective status at each evaluation,best response, performance status, CTC response [ Time Frame: course of study ] [ Designated as safety issue: No ]


Estimated Enrollment: 30
Study Start Date: February 2008
Estimated Study Completion Date: March 2012
Estimated Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
1: Experimental Drug: MK-0752 and Docetaxel Dose Level MK-0752 Docetaxel Peg-filgrastim
1 300 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 2 450 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 3 600 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 4 800 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9

Drug: MK-0752 Dose Level MK-0752 Docetaxel Peg-filgrastim
1 300 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 2 450 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 3 600 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9 4 800 mg po daily, days 1-3 80 mg/m2 IV Day 8 6 mg SQ day 9





Eligibility

Ages Eligible for Study: 18 Years and older
Genders Eligible for Study: Both
Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
  • Men or women with metastatic (Stage IV) breast cancer, or with locally advanced breast cancer (Stages IIIA > 10 cm, or Stages IIIB and IIIC) that did not respond to first-line anthracycline-based chemotherapy, for whom docetaxel is a recommended therapy
  • Presence of measurable or evaluable disease
  • Adequate organ function
  • Ability to swallow intact study drug capsules
  • Zubrod Performance Status of 0-1 with at least a 3 month life expectancy
  • Appropriate time must have elapsed since prior anti-neoplastic therapy with resolution of acute toxicity.
Exclusion Criteria:
  • Concurrent treatment with hormonal therapy intended to treat cancer
  • Radiotherapy within 7 days prior to first dose
  • Symptomatic CNS, and/or epidural metastases or symptomatic carcinomatous meningitis or with radiation treatment completed within the past 8 weeks
  • Serious comorbid illness which will limit the ability of the patient to safely receive anticancer treatment
  • Patients who are pregnant or nursing
  • Confounding factors present to provide misinterpretation of data (i.e., concurrent malignancy)



Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00645333

Contacts
Contact: Cancer Answer Line 1 800 865-1125 canceranswerline@umich.edu
Contact: Judith Luckhardt, R.N. 734 647-5345 jluck@umich.edu

Locations
United States, Massachusetts
Dana Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02115
Contact: Ian Krop, M.D., Ph.D. 616-632-5958 ikrop@partners.org
Contact: Jason Russak 617 632-4915 jason_russak@dfci.harvard.edu
United States, Michigan
University of Michigan Cancer Center Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Cancer Answer Line 800-865-1125 canceranswetline@umich.edu
Contact: Judith Luckhardt, RN 734 647-5345 jluck@umich.edu
Principal Investigator: Anne F Schott, M.D.
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Jenny Chang, M.D. 713-798-1905 jcchang@bcm.tmc.edu
Contact: Anne Pavlick, CRC ll 713 798-1975 acpavlic@bcm.tmc.edu
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Old 05-23-2009, 10:19 AM   #7
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OSI Pharmaceuticals Provides Update on OSI-906 Data Being Presented on May 30th at the Upcoming Annual Meeting of the American Society of Clinical Oncology (ASCO)


Posted : Fri, 15 May 2009 11:30:39 GMT





MELVILLE, N.Y. - (Business Wire) OSI Pharmaceuticals, Inc. (NASDAQ: OSIP) announced today preliminary data from two Phase I dose escalation studies of oral OSI-906, a small molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors. The studies, along with a third on-going Phase I trial assessing OSI-906 in combination with Tarceva, comprise part of the Company’s principal oncology development program targeting the IGF-1R. The program also includes translational research and biomarker development activities around this highly attractive oncology target. In an intermittent oral dosing study, OSI-906 was well-tolerated up to doses of 450mg and has provided preliminary evidence of anti-tumor activity, with one confirmed partial response in an adrenocortical carcinoma (ACC) patient; one minor response in a patient with non-small cell lung cancer (NSCLC); 14 patients with stabilization of their disease for longer than 12 weeks including 7 patients with stabilization of their disease for longer than 24 weeks (out of 27 patients evaluable for tumor response to date). In a continuous dosing study, OSI-906 also had an acceptable safety profile and disease stabilization for longer than 12 weeks has been observed in 8 out of 29 patients evaluable for tumor response to date. Both Phase I studies continue to accrue patients at higher doses to determine the maximum tolerated dose (MTD) for both intermittent and continuous dosing of OSI-906, and to establish a recommended dose and dosing schedule for a Phase II clinical trial of OSI-906. “We believe these data, along with early data from an additional combination Phase I study with Tarceva, continue to position OSI-906 as a potential first-in-class small molecule inhibitor of the IGF-1R,” stated Colin Goddard, Ph.D., Chief Executive Officer of OSI Pharmaceuticals. “Our extensive research around this crucial oncology signaling target has led us to develop a comprehensive development effort that includes targeting tumors such as ACC and ovarian cancer, where IGF-2 over-expression could indicate a particular dependence on this signaling pathway, and also NSCLC, where our understanding of EMT and compensatory signaling mechanism suggest that a Tarceva/OSI-906 combination could be particularly effective. With continued progress in our program we believe we could begin two registration-oriented trials – a monotherapy study in ACC in 2009 and a Tarceva combination study in NSCLC in 2010.”
The OSI-906 Phase I single-agent data will be presented in two poster presentations at the Annual Meeting of the American Society of Clinical Oncology (ASCO) in Orlando, FL on May 30, 2009 between 8 a.m. and noon EDT (Abstracts #3544 and #2559).
Study Results
Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small molecule insulin like growth factor -1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors- C.P. Carden, et al. (Abstract #3544)
The primary objective of this study (OSI-906-102) is to determine the maximum tolerated dose (MTD) and recommended Phase II dose of oral OSI-906 for three intermittent dosing schedules: Schedule 1: days 1-3, every 14 days; Schedule 2: days 1-5, every 14 days; Schedule 3: days 1-7, every 14 days. Secondary objectives include safety profile, pharmacokinetics (PK) and pharmacodynamics (PD) profiles and preliminary anti-tumor activity.
Preliminary results from 33 patients evaluable to date showed that OSI-906 was well-tolerated up to doses of 450mg, with no dose limiting toxicities (DLTs) and no grade 3 or 4 toxicities reported to date. Most common adverse events were grade 1 rash, diarrhea, fatigue and peripheral edema. Frequency and severity of toxicities did not correlate with dose level. Two cases of hyperglycemia (one grade 1; one grade 2) were reported.
Encouraging anti-tumor activity was seen in the study, with one partial response in an ACC patient at the 450mg dose (in the Schedule 1 group), 14 patients with stable disease for ≥ 12 weeks including 7 patients with stable disease for ≥ 24 weeks. Of particular note, anti-tumor activity was seen in two ACC patients and one NSCLC patient:
  • One 2nd-line ACC patient, a 35-year old woman with metastatic disease, had a partial response (PR) confirmed at 16 weeks of treatment with OSI-906. No drug-related toxicities have been observed to date and this patient continues on therapy.
  • One 4th-line NSCLC patient, a 77-year old man with metastatic disease, had a minor response per the treating physician and a best response (per RECIST) of stable disease for 43 weeks.
  • One 3rd-line ACC patient had stable disease for 30 weeks.
The study authors also note that PK is dose-proportional up to 450mg. An exploratory analysis from glucose monitoring also indicates that significant hyperglycemia was not observed in patients in spite of hyperinsulinemia at higher doses.
The MTD in this study has not yet been reached and patient accrual is on-going.
Phase I dose escalation study of continuous oral dosing of OSI-906, an insulin like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor, in patients with advanced solid tumors- C.R. Lindsay, et al. (Abstract #2559)
The primary objective of this study (OSI-906-101) is to determine the MTD and recommended Phase II dose of oral OSI-906 administered either once daily or twice daily. Secondary objectives also included safety profile, PK and PD profiles and preliminary anti-tumor activity.
Preliminary results from 37 patients with advanced solid tumors (9 colorectal, 6 pancreatic, 3 renal, 3 esophageal and 16 other tumor types) also show that continuous oral dosing of OSI-906, given either once or twice a day, has an acceptable safety profile. One recent DLT of asymptomatic grade 3 hyperglycemia was reported at the 450mg once-a-day dose, however, this patient was asymptomatic and glucose returned to normal by Day 2, and no dose interruptions or reductions were necessary. OSI-906 plasma concentrations exceed concentration required for anti-tumor efficacy in preclinical models, with twice-a-day dosing providing improved coverage above threshold. Further, PD target modulation and disease stabilization were observed. While no objective tumor responses have been reported to date, 8 patients had stable disease ≥ 12 weeks including 4 patients who had stable disease ≥ 24 weeks.
The MTD in this study has not yet been reached and patient accrual is on-going.
Additional Background on OSI-906
IGF-1 and IGF-2 are growth factors, or hormones, known to stimulate growth and survival of cancerous cells. IGF-1R has been viewed as an important therapeutic target due to its involvement in the growth and proliferation of a variety of human cancers, including colorectal, prostate, non-small cell lung, breast and ovarian cancers.
In preclinical studies, OSI-906 blocked the ability of IGF-1R to signal in xenograft mouse models of human colorectal cancer. Preclinical research also showed that colon cancer tumor cells respond to OSI-906 because they produce and are dependent on the growth-promoting effects of IGF-2. In addition to colorectal cancer, OSI-906 has also been shown to inhibit growth of human pancreatic and thyroid cancers in animal models. The IGF/IGF-1R signaling pathway has also been implicated in protecting tumor cells from apoptosis induced by a number of cytotoxic agents as well as molecular targeted therapies including EGFR inhibitors. Preclinical data also suggest that OSI-906 may be synergistic with Tarceva in non-small cell lung and pancreatic human tumor xenografts.
About OSI Pharmaceuticals
OSI Pharmaceuticals is committed to "shaping medicine and changing lives" by discovering, developing and commercializing high-quality, novel and differentiated targeted medicines designed to extend life and improve the quality of life for patients with cancer and diabetes/obesity. For additional information about OSI, please visit http://www.osip.com.
This news release contains forward-looking statements. These statements are subject to known and unknown risks and uncertainties that may cause actual future experience and results to differ materially from the statements made. Factors that might cause such a difference include, among others, OSI's and its collaborators' abilities to effectively market and sell Tarceva and to expand the approved indications for Tarceva, OSI’s ability to protect its intellectual property rights, safety concerns regarding Tarceva, competition to Tarceva and OSI’s drug candidates from other biotechnology and pharmaceutical companies, the completion of clinical trials, the effects of FDA and other governmental regulation, including pricing controls, OSI's ability to successfully develop and commercialize drug candidates, and other factors described in OSI Pharmaceuticals' filings with the Securities and Exchange Commission.

OSI Pharmaceuticals, Inc.
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Kathy Galante, 631-962-2043
Senior Director
or
Media:
Kim Wittig, 631-962-2135
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Old 06-05-2009, 11:08 AM   #8
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Breast Cancer Stem Cells Seem to Survive Radiation Therapy

TUESDAY, Dec. 19 (HealthDay News) -- Breast cancer stem cells, a type of cell that scientists have recently discovered is difficult to kill, may be especially resistant to radiation therapy, a new study suggests.
In fact, the radiation can even increase the growth of these stubborn stem cells, report researchers from the University of California, Los Angeles, David Geffen School of Medicine.
"This population of stem cells is more radiation-resistant than are non-stem cells," said Dr. Frank Pajonk, an assistant adjunct professor of radiation oncology at UCLA and corresponding author on the study. "We are the first to report this."
Radiation treatment involves exposure to high-energy rays or particles that destroy cancerous cells. It is often recommended after surgery for breast cancer, according to the American Cancer Society.
Pajonk and his colleagues exposed breast cancer stem cells and "normal" breast cancer cells to either single or multiple doses of radiation. More of the stem cells, also called cancer-initiating cells, lived through the radiation than did the other breast cancer cells.
One good example, according to Pajonk: While 46 percent of the stem cells survived treatment with 2 Gray of radiation (a dose typically used for breast cancer treatment), only 20 percent of normal breast cancer cells did.
Then, the team simulated clinical treatment that is interrupted -- a challenge that Pajonk and other health-care providers face when patients don't make all their scheduled appointments due to fatigue, inconvenience or other factors. Pajonk and his colleagues suspect this reduces the effectiveness of radiation, and the study suggests they are correct.
When Pajonk's team exposed the cells to a higher dose of 3 Gray, every day for five days, then stopped the treatment before what would be considered a full round, the proportion of stem cells actually increased.
Pajonk's team speculated that this may happen because the radiation activates a signaling pathway that gives the stem cells the messages to self-renew.
How is it that these cells are resistant to radiation? "They may have something like a natural radiation protectant inside of them that prevents the radiation-induced DNA damage that normally kills the breast cancer cells," Pajonk said.
The findings are published in the Dec. 20 edition of the Journal of the National Cancer Institute.
The new study sends a clear message to cancer researchers, said Dr. Maximilian Diehn, a resident in radiation oncology and postdoctoral fellow at the Stanford University School of Medicine. He co-authored an editorial accompanying the study results. "The main take-home point is that this gives more evidence that we should be studying cancer stem cells more," he said. "Those cells have properties different than the rest of the tumor."
Eventually, he said, scientists may be able to develop new drugs that would overcome this resistance to radiation, he said.
The concept of cancer stem cells is fairly new, said Diehn and Pajonk. For five years or so, it has been increasingly the topic of discussion in breast cancer research, as well as prostate cancer, melanoma and other types of tumors.
A better understanding of cancer stem cells could go a long way toward treatment success, Diehn said. "Often, less than one percent of cancer cells in a tumor are actually cells critical for keeping the tumor alive and potentially spreading the cancer. This is the cancer stem cell," he said.
The new research should not discourage women from getting radiation therapy if it is recommended, Diehn and Pajonk agreed. "Radiation treatment is still one of the best treatments available for women with breast cancer," Diehn said. It's also important, he said, to follow the treatment schedule as recommended and not to have gaps in treatment because that could make the stem cells proliferate.
In another new study, Dutch researchers found that comparing current mammograms to previous ones is valuable and can reduce referrals for lesions that turn out not to be cancerous. The researchers asked 12 experienced radiologists to read 160 mammograms twice; in one case, they had previous mammograms to refer to and, in the other, they did not.
When they had access to the previous mammograms, their detection performance improved. Having the prior mammogram to look at reduced referrals by 44 percent for suspicious areas that turned out not to be cancerous.
The findings are published in the January issue of the journal Radiology.

SOURCES: Maximilian Diehn, M.D., Ph.D., resident in radiation oncology and postdoctoral fellow, Stanford University School of Medicine, Stanford, Calif.; Frank Pajonk, M.D., Ph.D., assistant adjunct professor of radiation oncology, University of California, Los Angeles, David Geffen School of Medicine; Dec. 20, 2006, Journal of the National Cancer Institute; January 2007, Radiology



1: J Natl Cancer Inst. 2006 Dec 20;98(24):1777-85. Links

Comment in:
J Natl Cancer Inst. 2006 Dec 20;98(24):1755-7.
The response of CD24(-/low)/CD44+ breast cancer-initiating cells to radiation.

Phillips TM, McBride WH, Pajonk F.
Department of Radiation Oncology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave., Los Angeles, CA 90095-1714, USA.
BACKGROUND: If cancer arises and is maintained by a small population of cancer-initiating cells within every tumor, understanding how these cells react to cancer treatment will facilitate improvement of cancer treatment in the future. Cancer-initiating cells can now be prospectively isolated from breast cancer cell lines and tumor samples and propagated as mammospheres in vitro under serum-free conditions. METHODS: CD24(-/low)/CD44+ cancer-initiating cells were isolated from MCF-7 and MDA-MB-231 breast cancer monolayer cultures and propagated as mammospheres. Their response to radiation was investigated by assaying clonogenic survival and by measuring reactive oxygen species (ROS) levels, phosphorylation of the replacement histone H2AX, CD44 levels, CD24 levels, and Notch-1 activation using flow cytometry. All statistical tests were two-sided. RESULTS: Cancer-initiating cells were more resistant to radiation than cells grown as monolayer cultures (MCF-7: monolayer cultures, mean surviving fraction at 2 Gy [SF(2Gy)] = 0.2, versus mammospheres, mean SF(2Gy) = 0.46, difference = 0.26, 95% confidence interval [CI] = 0.05 to 0.47; P = .026; MDA-MB-231: monolayer cultures, mean SF(2Gy) = 0.5, versus mammospheres, mean SF(2Gy) = 0.69, difference = 0.19, 95% CI = -0.07 to 0.45; P = .09). Levels of ROS increased in both mammospheres and monolayer cultures after irradiation with a single dose of 10 Gy but were lower in mammospheres than in monolayer cultures (MCF-7 monolayer cultures: 0 Gy, mean = 1.0, versus 10 Gy, mean = 3.32, difference = 2.32, 95% CI = 0.67 to 3.98; P = .026; mammospheres: 0 Gy, mean = 0.58, versus 10 Gy, mean = 1.46, difference = 0.88, 95% CI = 0.20 to 1.56; P = .031); phosphorylation of H2AX increased in irradiated monolayer cultures, but no change was observed in mammospheres. Fractionated doses of irradiation increased activation of Notch-1 (untreated, mean = 10.7, versus treated, mean = 15.1, difference = 4.4, 95% CI = 2.7 to 6.1, P = .002) and the percentage of the cancer stem/initiating cells in the nonadherent cell population of MCF-7 monolayer cultures (untreated, mean = 3.52%, versus treated, mean = 7.5%, difference = 3.98%, 95% CI = 1.67% to 6.25%, P = .009). CONCLUSIONS: Breast cancer-initiating cells are a relatively radioresistant subpopulation of breast cancer cells and increase in numbers after short courses of fractionated irradiation. These findings offer a possible mechanism for the accelerated repopulation of tumor cells observed during gaps in radiotherapy.
PMID: 17179479 [PubMed - indexed for MEDLINE]
1: J Cell Biochem. 2009 Jul 21. [Epub ahead of print]

Radiation responses of cancer stem cells.

Vlashi E, McBride WH, Pajonk F.
Division of Molecular and Cellular Oncology, Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, California.
Recent experimental evidence indicates that many solid cancers have a hierarchical organization structure with a subpopulation of cancer stem cells (CSCs). The ability to identify CSCs prospectively now allows for testing the responses of CSCs to treatment modalities like radiation therapy. Initial studies have found CSCs in glioma and breast cancer relatively resistant to ionizing radiation and possible mechanisms behind this resistance have been explored. This review summarizes the landmark publications in this young field with an emphasis on the radiation responses of CSCs. The existence of CSCs in solid cancers place restrictions on the interpretation of many radiobiological observations, while explaining others. The fact that these cells may be a relatively quiescent subpopulation that are metabolically distinct from the other cells in the tumor has implications for both imaging and therapy of cancer. This is particularly true for biological targeting of cancer for enhanced radiotherapeutic benefit, which must consider whether the unique properties of this subpopulation allow it to avoid such therapies. J. Cell. Biochem. (c) 2009 Wiley-Liss, Inc.
PMID: 19623582 [PubMed - as supplied by publisher]
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Old 06-05-2009, 09:21 PM   #9
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Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits? Ciara S. O’Brien1, Sacha J. Howell1, Gillian Farnie1 and Robert B. Clarke1
(1) Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK

Robert B. Clarke
Email: robert.clarke@manchester.ac.uk
Received: 16 December 2008 Accepted: 10 February 2009 Published online: 28 February 2009
Abstract From a developmental point of view, tumors can be seen as aberrant versions of their tissue of origin. For example, tumors often partially retain differentiation markers of their tissue of origin and there is evidence that they contain cancer stem cells (CSCs) that drive tumorigenesis. In this review, we summarise current evidence that breast CSCs may partly explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ERα−. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ERα and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ERα+ tumor cells. Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in endocrine-resistant breast cancers reflects an increased proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ERα− and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ERα expression, further indicating the mutual exclusion between ERα+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ERα in these cells in diverse breast tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.

Full article:
http://www.springerlink.com/content/.../fulltext.html
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Old 06-05-2009, 11:12 PM   #10
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1: Cell Adh Migr. 2009 Jul 7;3(3). [Epub ahead of print] Links
L1 cell adhesion molecules as regulators of tumor cell invasiveness.

Siesser PF, Maness PF.
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA.
Fast growing malignant cancers represent a major therapeutic challenge. Basic cancer research has concentrated efforts to determine the mechanisms underlying cancer initiation and progression and reveal candidate targets for future therapeutic treatment of cancer patients. With known roles in fundamental processes required for proper development and function of the nervous system, L1-CAMs have been recently identified as key players in cancer biology. In particular L1 has been implicated in cancer invasiveness and metastasis, and has been pursued as a powerful prognostic factor, indicating poor outcome for patients. Interestingly, L1 has been shown to be important for the survival of cancer stem cells, which are thought to be the source of cancer recurrence. The newly recognized roles for L1CAMs in cancer prompt a search for alternative therapeutic approaches. Despite the promising advances in cancer basic research, a better understanding of the molecular mechanisms dictating L1-mediated signaling is needed for the development of effective therapeutic treatment for cancer patients.
PMID: 19483471

1: Breast Cancer Res Treat. 2009 Jul 11. [Epub ahead of print]
Antimitotic chemotherapeutics promote adhesive responses in detached and circulating tumor cells.

Balzer EM, Whipple RA, Cho EH, Matrone MA, Martin SS.
Program in Molecular Medicine, University of Maryland School of Medicine, Marlene and Stewart Greenebaum Cancer Center, Baltimore, MD, 21201, USA.
In the clinical treatment of breast cancer, antimitotic cytotoxic agents are one of the most commonly employed chemotherapies, owing largely to their antiproliferative effects on the growth and survival of adherent cells in studies that model primary tumor growth. Importantly, the manner in which these chemotherapeutics impact the metastatic process remains unclear. Furthermore, since dissemination of tumor cells through the systemic circulation and lymphatics necessitates periods of detached survival, it is equally important to consider how circulating tumor cells respond to such compounds. To address this question, we exposed both nontumorigenic and tumor-derived epithelial cell lines to two antitumor compounds, jasplakinolide and paclitaxel (Taxol), in a series of attached and detached states. We report here that jasplakinolide promoted the extension of microtubule-based projections and microtentacle protrusions in adherent and suspended cells, respectively. These protrusions were specifically enriched by upregulation of a stable post-translationally modified form of alpha-tubulin, and this occurred prior to, and independently of any reductions in cellular viability. Microtubule stabilization with Taxol significantly enhanced these effects. Additionally, Taxol promoted the attachment and spreading of suspended tumor cell populations on extracellular matrix. While the antiproliferative effects of these compounds are well recognized and clinically valuable, our findings that microfilament and microtubule binding chemotherapeutics rapidly increase the mechanisms that promote endothelial adhesion of circulating tumor cells warrant caution to avoid inadvertently enhancing metastatic potential, while targeting cell division.
PMID: 19593636 [PubMed - as supplied by publisher]
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Old 06-09-2009, 02:50 PM   #11
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Resistance to Endocrine Therapy: Are Breast Cancer Stem Cells the Culprits? Ciara S. O’Brien1, Sacha J. Howell1, Gillian Farnie1 and Robert B. Clarke1
(1) Breast Biology Group, School of Cancer and Imaging Sciences, Paterson Institute for Cancer Research, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK
Robert B. Clarke
Email: robert.clarke@manchester.ac.uk Received: 16 December 2008 Accepted: 10 February 2009 Published online: 28 February 2009
Abstract From a developmental point of view, tumors can be seen as aberrant versions of their tissue of origin. For example, tumors often partially retain differentiation markers of their tissue of origin and there is evidence that they contain cancer stem cells (CSCs) that drive tumorigenesis. In this review, we summarise current evidence that breast CSCs may partly explain endocrine resistance in breast cancer. In normal breast, the stem cells are known to possess a basal phenotype and to be mainly ERα−. If the hierarchy in breast cancer reflects this, the breast CSC may be endocrine resistant because it expresses very little ERα and can only respond to treatment by virtue of paracrine influences of neighboring, differentiated ERα+ tumor cells. Normal breast epithelial stem cells are highly dependent on the EGFR and other growth factor receptors and it may be that the observed increased growth factor receptor expression in endocrine-resistant breast cancers reflects an increased proportion of CSCs selected by endocrine therapies. There is evidence from a number of studies that breast CSCs are ERα− and EGFR+/HER2+, which would support this view. CSCs also express mesenchymal genes which are suppressed by ERα expression, further indicating the mutual exclusion between ERα+ cells and the CSCs. As we learn more about CSCs, differentiation and the expression and functional activity of the ERα in these cells in diverse breast tumor sub-types, it is hoped that our understanding will lead to new modalities to overcome the problem of endocrine resistance in the clinic.

Full article:
http://www.springerlink.com/content/.../fulltext.html
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Old 06-10-2009, 01:26 AM   #12
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Mk-0752

is a gamma secretase inhibitor which interferes with the notch pathway, which is felt to be essential for cancer stem cells.

Dr. Max Wicha has been talking about using gamma secretase inhibitors as cancer stem cell specific drugs for years--this particular one has been studied quite a while as it has been under development against Alzheimer's

Rich sounds like you have now discovered the cancer stem cell literature. I urge you to read Dr. Wicha's publications and listen/look at his talks at AACR, ASCO, etc (many are online). He GETS it. I was present for that Barsky talk at the AACR in 2008--it was a precedent-setting talk, but got no coverage and most oncologists and cancer researchers never heard its results.

I recently spoke with a friend whose husband had two stem cell transplants for lymphoma (lasting 12+ years) who suddenly died of lung cancer (donor was same sex, but they were looking into other genetic tell-tale signs of
the lung cancer being "donated" along with the stem cells.

Dr. Wicha thinks radiation therapy may make things worse rather than better.

I encourage you to seek out his contributions.
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Old 06-10-2009, 10:14 AM   #13
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Patents (1426 Stem Cell Patents)



Isolation and use of solid tumor stem cells

Patent Number: 7,115,360

Date of First Priority Issue: Thursday August 3rd, 2000
Date Issued: Tuesday October 3rd, 2006
Assignee: Regents of the University of Michigan (Ann Arbor, MI)
Inventors: Clarke; Michael F. (Ann Arbor, MI), Morrison; Sean J. (Ann Arbor, MI), Wicha; Max S. (Ann Arbor, MI), al-Hajj; Muhammad (La Jolla, CA)

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The cancer stem cell is very important since there is numerous investigators in the field that believe the majority of cancer cells making up a tumor mass are only the products of a specific cell subpopulation with high repopulating potential. What this means is that usually the drugs developed for cancer are developed to kill not the stem cell of the tumor, but actually the progeny of the tumor stem cell. This means (if the theory is correct) that the majority of cancer treatments are bound to fail since they do not address the cell subpopulation that maintains to other tumor cells.

This patent covers methods of detecting compounds that are capable of killing the cancer stem cell.

The patent is focus on cancer stem cells from epithelial tumors that have the phenotype of CD44+ and lineage negative. Specific lineage markers that are not found on cancer stem cells include CD2, CD3, CD10, CD14, CD16, CD31, CD45, CD64, and CD140b: according to this patent.

View this patent on the USPTO website.
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Old 06-10-2009, 10:18 AM   #14
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Oncology Times:Volume 29(9)10 May 2007p 26-28
Cancer Stem Cell Theory Heads to the Clinic


[Article]
Tuma, Rabiya S. PhD



The idea that cancer stem cells drive tumor growth and recurrence has been gaining momentum in recent years, as researchers expand the list of malignancies that appear to harbor such cell populations.
Yet clear evidence that cancer stem cells are important in human disease is lacking. Now, several researchers have recently launched clinical trials, or plan to do so in the next few months, that will test the importance of these cells in human cancer.
I fully believe that there are stem cells in almost every cancer but one of the interesting things is that there has never been any clinically derived benefit from any of those findings, said William Matsui, MD, Assistant Professor of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, who identified a putative stem cell population in multiple myeloma.
Hypothesis


According to the stem cell hypothesis, cancers have a small group of cells that are uniquely responsible for repopulating the tumor. The bulk of the tumor, in contrast, is made up of differentiated or partially differentiated cells that cause symptoms and physiological problems for the patient but that cannot reestablish a tumor when transplanted to an immune-compromised mouse.
Figure. William Matsui, MD: I fully believe that there are stem cells in almost every cancer but one of the interesting things is that there has never been any clinically derived benefit from any of those findings.

For example, when Michael Clarke, MD, Associate Director of the Stanford Institute for Stem Cell and Regenerative Medicine, was still at the University of Michigan, his team showed that as few as 100 breast tumor cells that carried particular cell surface markers (CD44 positive and CD24 negative or low), could give rise to a new tumor when injected into a mouse, while injection of more than 20,000 of the tumor cells that lack these cell surface markers did not.
Moreover, when the newly formed tumors were examined, they looked much like the original human tumor, containing few of the CD44+CD24-/low stem cells and the majority of the cells looking more differentiated.
The hypothesis for now suggests that a specific cell population from a given tumor type are the crux of the problem from the beginning of a disease to a patient's death. That is probably overly simplified, Dr. Matsui said.
For example, the stem cells are likely to change over the course of the disease even while they remain critical for disease progression. Like any new theory we tend to oversimplify it, but it does give us a kind of framework to sit down with and imagine how and when relapse would occur, he said. Our job now is to show that they are somehow clinically relevant.
Finding the Right Targets


There is growing evidence that the stem cell populations in various malignancies are resistant to standard therapies that reduce the bulk of the tumor. For example, Dr. Matsui and colleagues found that bortezomib and lenalidomide kill myeloma plasma cells but not the stem cells that produce the plasma cells. Thus, if the stem cell hypothesis is correct, new therapies that kill these cells need to be identified.
Figure. Craig Jordan, PhD: There is a convergence of two fields. Over the last several decades cancer biologists have identified key pathways in cancer cell growth, and now researchers are testing whether those same pathways are relevant to the stem cells.…By bringing the two fields together we are going to leapfrog some of the drug-development process.

For example, Duke University researchers reported earlier this year that glioblastoma stem cells, which carry the CD133 cell surface marker, are less susceptible to radiation damage than are the other cells in the tumor.
Upon closer examination the researchers discovered that all of the cancer cells sustained a similar amount of DNA damage from the radiation, but that the stem cells had better repair mechanisms. When activation of cell cycle checkpoints was blocked, the irradiated stem cells died.

Convergence of Two Fields


There is a convergence of two fields here, explained Craig Jordan, PhD, Associate Professor of Medicine at the University of Rochester School of Medicine. Over the last several decades cancer biologists have identified key pathways in cancer cell growth; and now researchers in the cancer stem cell field are testing whether those same pathways are relevant to the stem cells.
Fortuitously a lot of those key cancer pathways are probably also important in stem cells. So by bringing the two fields together we are going to leapfrog some of the drug-development process, rather than having to start at the beginning again, he said.
One approach to targeting the stem cells is to hit some of the cell surface markers that appear on multiple malignancies. For example, CD44 appears on stem cells from breast, head and neck, and pancreatic tumor cells, while CD20 characterizes multiple myeloma and melanoma stem cells. Thus some therapies may be effective in multiple malignancies.
It remains to be proven, but my prediction is that that is exactly what will happen, said Max Wicha, MD, Professor of Internal Medicine and Director of the University of Michigan Comprehensive Cancer Center.
Significantly, some of the cell surface markers that characterize cancer stem cells have already been targeted with successful drugs. For example, rituximab, ibritumomab tiuxetan (Zevalin), and iodine-131 tositumomab (Bexxar), which are approved for the treatment of non-Hodgkin's lymphoma, target the CD20 antigen.
It may be that drugs like Bexxar will have some efficacy in treating the stem cells in melanoma, for which we don't have very good therapies, so this is really very exciting, Dr. Wicha said.
The catch to targeting markers shared by several different cancer stem cells is that they might also be present on normal stem cells, either in the tissue where the malignancy forms or elsewhere in the body. I think part of the challenge of stem cell based therapies is trying to figure out what we can do without completely kiboshing every stem cell in the body, Dr. Matsui said.
CD44 is a case in point. As reported earlier this year, CD44 is involved in engraftment of leukemic stem cells and may aid metastasis in other diseases. Therefore blocking the cell surface marker could be a valuable weapon in disease control, if it is not too toxic for a variety of healthy stem cells that also carry the marker.
CD44 is expressed on normal stem cells, so I would be worried about a magic bullet-sort of strategy. It may be unnecessarily toxic, said Richard Van Etten, MD, PhD, Professor of Medicine at Tufts-New England Medical Center.
That doesn't completely rule out the use of such antibodies, though. For example, the CD44 cell surface marker is expressed on the putative stem cells in chronic myelogenous leukemia (CML). Imatinib induces rapid responses, but patients relapse if they go off the drug, suggesting that the stem cells escape the drug's effects, an observation supported by in vitro data.
Dr. Van Etten said that if the field goes back to using autologous transplantation to treat these patients, their harvested cells could be treated with a CD44 antibody in vitro, prior to reintroduction. Because CML stem cells rely on the CD44 cell surface protein for engraftment in a way that healthy stem cells do not, the pretreatment could prevent relapses down the line.
Clinical Trials Moving Forward


Despite the challenges, several trials are in the works-either already enrolling patients or in the final design stages-including three trials testing anti-CD20 antibody therapies in multiple myeloma.
The drugs do not affect the mature plasma cells that comprise most of the neoplastic cells, which lack the CD20 antigen, so all of the trials require that the patients undergo some debulking therapy as well.
* In a Phase II trial at the University of Michigan Comprehensive Cancer Center, Andrzej Jakubowiak, MD, PhD, Director of the Multiple Myeloma Center, is testing iodine-131 tositumomab as a consolidation therapy in patients with Stage II or III disease who have had at least a partial response to standard therapies. The research team will follow patients' progress with serial bone marrow biopsies.
* At the Sidney Kimmel Cancer Center at Johns Hopkins, Carol Ann Huff, MD, a multiple myeloma specialist, and Dr. Matsui are combining the use of cyclophosphamide and rituximab in a Phase II trial.
Figure. Max S. Wicha, MD, is planning the first trial to test the stem cell hypothesis in a solid cancer. The trial will be run at three centers-the University of Michigan, Dana-Farber, and Baylor-and will test an inhibitor of the Notch signaling pathway, which is active in most stem cells.

Patients with relapsed or refractory disease receive two doses of the antibody followed by the standard high-dose cyclophosphamide regimen. Following the chemotherapy, patients receive four weekly doses of the antibody, and three subsequent doses at three-month intervals. As with the Michigan protocol, patient progress is being followed via repeated bone marrow biopsies.
So far, about half of the approximately 40 patients planned for the trial have been treated. It is too early to say whether the anti-CD20 antibody is having an effect, but the team expects some good correlative data within the next year, Dr. Matsui said. What we are after is proof of principle-in other words, can the team show that cancer stem cells exist in human disease and have a clinical role in progression?
* In an ongoing trial at Tufts-New England Medical Center, Andreas Klein, MD, Clinical Director of Lymphoma and Myeloma Services, is testing the ability of yttrium-90 ibritumomab tiuxetan to improve the clinical outcomes of myeloma patients undergoing autologous stem cell transplants.
Patients who have an incomplete response to chemotherapy prior to transplantation receive the Zevalin according to the standard dosing protocol, and progress is assessed after four and 10 weeks, after which the patients proceed to standard autologous transplant.
* Several other teams are working on trials in leukemia, though they are using different molecular targets to hit the stem cells. Dr. Jordan's group in Rochester found that parthenolide, which is the main compound in the herbal remedy feverfew, is toxic to both the stem cells and the differentiated leukemic cells. The researchers have developed a derivative of the agent that has better pharmacologic properties and expect to start a Phase I trial sometime this summer.
Preclinical data indicate that the drug has broad activity in hematologic malignancies, so the enrollment criteria will not be limited to one type of leukemia. Our drug seems to have limited toxicity in preclinical studies, Dr. Jordan. It seems to target a step in leukemia molecular biology that is relatively unique to those cells and not particularly relevant to healthy cells or normal stem cells.
* Stemline Therapeutics, Inc. in New York City has an ongoing trial testing the drug SL-401, which targets the interleukin-3 receptor (IL-3R, also called CD123) on leukemia stem cells. Thirty patients are enrolled thus far, and the maximally tolerated dose of the drug has not been reached, said Ivan Bergstein, MD, the company's Chairman and CEO.
We are seeing activity at these doses, with very few side effects, he added. We've basically gotten our green light in terms of gearing up for Phase II trials, but we may end up having a higher dose than we currently have used. The IL-3R is expressed at a higher level on leukemic stem cells than on healthy ones, so the group expects there to be a nice therapeutic window, he said.
When asked why the company chose to venture into the realm of stem cell-targeted therapy before the clinical importance of cancer stem cells has been proven, Dr. Bergstein pointed to the expanding body of preclinical and laboratory data to support the notion. He also notes, however, that the IL-3R protein exists on all of the leukemic cells, not just the stem cells-so the drug's success is not entirely based on the accuracy of the stem cell hypothesis.
* Meanwhile, Dianna Howard, MD, of the University of Kentucky Markey Cancer Center, is testing the combination of two established drugs in acute myeloid leukemia (AML) patients. In vitro work shows that combined bortezomib and idarubicin kills differentiated AML cells as well as the less-differentiated cancer stem cells.
The trial is already recruiting patients over age 60 with newly diagnosed disease or patients over the age of 18 with relapsed or refractory disease. The primary endpoint is to establish the safety and maximally tolerated doses for the regimen. The secondary endpoints include clinical response and bortezomib-induced inhibition of the NF-kappa B signaling pathway, which is active in leukemic stem cells.
* Similarly, Doug Smith, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins, and colleagues at other centers are testing imatinib in combination with both new and old therapies. Unlike patient responses to imatinib, which are frequent and rapid, only a fraction of patients respond to interferon, and the full response can take years.
However, when patients are taken off the drug, they appear, based on long-term follow-up data, to be free of disease, suggesting that the drug kills the stem cells. Dr. Smith is therefore combining imatinib, interferon, and granulocyte macrophage colony-stimulating factor (GM-CSF), which appears to speed interferon response, in one arm of a randomized Phase II trial. The second arm combines imatinib with the whole cell vaccine K562 and GM-CSF.
We don't know which is better yet, the vaccine or interferon, says Dr. Matsui, who is involved with the trial. The multicenter trial aims to recruit about 56 patients with chronic-phase CML, and to examine the rate of molecular remission and toxicity of the regimens.
* Finally, Dr. Wicha is putting together the first trial to test the stem cell hypothesis in a solid cancer. The trial will be run at three centers including the University of Michigan, Dana-Farber Cancer Center, and Baylor College of Medicine, and will test an inhibitor of the Notch signaling pathway, which is active in most stem cells.
Dr. Wicha said he is not ready to disclose which Notch inhibitor the group will be using, other than to say that it is from a big pharmaceutical company and that the company will be involved with the trial.
'A Healthy Degree of Skepticism'


One key issue facing the clinical researchers is how to define success when evaluating a potential stem cell therapy.
Standard tumor regression assessments, such as Response Evaluation Criteria in Solid Tumors (RECIST), are not appropriate for these therapies. The ideal response criteria would be an improvement overall in survival, but that will take too long to be of practical use. Correlative laboratory data will help bolster the case, but is not typically adequate for regulatory approval.
To tackle this question, the NCI plans to hold a meeting in January, but for now, cancer stem cell pioneer Max S. Wicha, MD, Director of the University of Michigan Comprehensive Cancer Center, said he remains optimistic that the proper trial designs can be found and that the problem is a passing one.
It will only be a problem until some group proves that patients live longer on these therapies. As soon as that happens, I think everybody will jump into this. Until that happens I think one should have a healthy degree of skepticism because it remains a theory. We think it is a promising theory, but until you can actually prove that it makes a difference for patients, you have to say it remains a theory.
These Cancers Appear to Have Stem Cells

Brain
Breast
Colon
Head and Neck
Ovary
Liver
Prostate
Pancreas
Leukemias
Myeloma
Melanoma
Sarcomas


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Old 06-10-2009, 10:45 AM   #15
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Journal of Clinical Oncology, Vol 26, No 17 (June 10), 2008: pp. 2795-2799
© 2008 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2008.17.7436

Cancer Stem Cells: A Step Toward the Cure

Bruce M. Boman Helen F. Graham Cancer Center, Newark, DE; Thomas Jefferson University, Philadelphia, PA
Max S. Wicha
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
This special issue of Journal of Clinical Oncology is devoted to the emerging field of cancer stem cells (CSCs). The goal of this article is to introduce general concepts of CSC biology to clinicians, and to provide a framework for their understanding the CSC-based approach to the development of novel diagnostics, therapeutics, and prevention strategies in oncology.

5 page article with PDF:

http://jco.ascopubs.org/cgi/content/full/26/17/2795
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Old 06-11-2009, 02:24 PM   #16
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1: Clin Cancer Res. 2009 Jun 9. [Epub ahead of print]
Association of Breast Cancer Stem Cells Identified by Aldehyde Dehydrogenase 1 Expression with Resistance to Sequential Paclitaxel and Epirubicin-Based Chemotherapy for Breast Cancers.

Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, Tamaki Y, Noguchi S.
Authors' Affiliation: Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.
PURPOSE: Breast cancer stem cells have been shown to be associated with resistance to chemotherapy in vitro, but their clinical significance remains to be clarified. The aim of this study was to investigate whether cancer stem cells were clinically significant for resistance to chemotherapy in human breast cancers.EXPERIMENTAL DESIGN: Primary breast cancer patients (n = 108) treated with neoadjuvant chemotherapy consisting of sequential paclitaxel and epirubicin-based chemotherapy were included in the study. Breast cancer stem cells were identified by immunohistochemical staining of CD44/CD24 and aldehyde dehydrogenase 1 (ALDH1) in tumor tissues obtained before and after neoadjuvant chemotherapy. CD44(+)/CD24(-) tumor cells or ALDH1-positive tumor cells were considered stem cells.RESULTS: Thirty (27.8%) patients achieved pathologic complete response (pCR). ALDH1-positive tumors were significantly associated with a low pCR rate (9.5% versus 32.2%; P = 0.037), but there was no significant association between CD44(+)/CD24(-) tumor cell proportions and pCR rates. Changes in the proportion of CD44(+)/CD24(-) or ALDH1-positive tumor cells before and after neoadjuvant chemotherapy were studied in 78 patients who did not achieve pCR. The proportion of ALDH1-positive tumor cells increased significantly (P < 0.001) after neoadjuvant chemotherapy, but that of CD44(+)/CD24(-) tumor cells did not.CONCLUSIONS: Our findings suggest that breast cancer stem cells identified as ALDH1-positive, but not CD44(+)/CD24(-), play a significant role in resistance to chemotherapy. ALDH1-positive thus seems to be a more significantly predictive marker than CD44(+)/CD24(-) for the identification of breast cancer stem cells in terms of resistance to chemotherapy.
PMID: 19509181 [PubMed - as supplied by publisher]
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Old 06-13-2009, 12:53 PM   #17
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A blog that tracks this issue;
http://cancerstemcellnews.blogspot.com/
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Old 06-13-2009, 01:51 PM   #18
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Company working on prostate cancer treatment has explanation of CSCs with strong parallels to BC:

http://www.pro-curetherapeutics.com/...stem_cells.asp
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Old 06-13-2009, 05:10 PM   #19
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Interview with Max Wicha which includes reference to Repertaxin as well as discussion of Her2 connection to cancer stem cells.

Breast Cancer Stem Cells as Novel Therapeutic Targets: An Expert Interview With Dr. Max S. Wicha CME

Published: 01/20/2009



Editor's Note:
Increasing evidence suggests that breast cancers might be targets of transformation during carcinogenesis and that deregulation of self-renewal carried out by stem cells might be one of the key events involved in breast carcinogenesis. The understanding of the molecular pathways underlying these changes is increasing; these alterations are now known to involve pathways such as Hedgehog and Notch, which may represent novel targets of breast cancer development and recurrence. Studies are also identifying markers of stem cells, which may help further characterize the basal, luminal, and other subtypes of breast cancer. At the 31st Annual San Antonio Breast Cancer Symposium (SABCS), several presentations focused on breast cancer stem cells. Research in this area is just beginning and ultimately may help inform clinical practice and enable the development of novel treatment approaches. Medscape Oncology recently spoke about these advances with Max S. Wicha, MD, Distinguished Professor of Oncology at the University of Michigan, Ann Arbor. Dr. Wicha is principal investigator for some of the seminal studies in this area.
Medscape: What is the current thinking on the role of stem cells in the pathology and treatment of breast cancer?
Dr. Wicha: We have been interested in the concept that cancers are driven by a small component of cells that have stem cell properties and that targeting these cells may result in improved outcomes for patients with cancer. Our laboratory was the first to identify a small population of cells with stem cell properties in human breast cancers, and we found that these cells could be prospectively identified with use of cell surface markers.[1] Properties of these stem cells include the ability to be serially transplanted into immunosuppressed mice, as well as the ability to reproduce the heterogeneity of cells found in the initial tumor.
Research involving cell cultures and animal models has demonstrated that cancer stem cells are relatively resistant to chemotherapy and radiation therapy.[2,3] Recent clinical studies have supported this concept, including one study of neoadjuvant chemotherapy that demonstrated that the proportion of cells with stem cell markers increases after neoadjuvant chemotherapy.[4] In this neoadjuvant therapy study, women whose tumors overexpressed HER-2 had a higher number of stem cells than those with tumors that did not overexpress this gene. Furthermore, in contrast with chemotherapy, addition of the HER-2 inhibitor lapatinib recently has been found to reduce the proportion of breast cancer stem cells present following neoadjuvant therapy.[5] These results may be explained by our laboratory's recent findings that HER-2 is an important regulator of breast cancer stem cells and that HER-2 inhibitors such as trastuzumab or lapatinib are able to selectively target cancer stem cells.[6]
One of the biggest challenges we now face in breast cancer treatment is to develop more effective therapies that are able to target the breast cancer stem cell population. At the 2008 SABCS, I presented data showing that breast cancer stem cells are regulated by the tumor microenvironment.[7] Specifically, our group demonstrated that mesenchymal stem cells, which we believe originate in the bone marrow and "traffic" into tumors, are able to regulate breast cancer stem cells. The feedback loops between mesenchymal stem cells and breast cancer stem cells provide new targets for therapies aimed at eliminating the cancer stem cell population. We also found that when breast cancers are treated with chemotherapy, the dying cancer cells secrete the chemokine interleukin (IL)-8. This occurs as part of a normal damage response. However, IL-8 is able to stimulate cancer stem cells through the CXCR1 chemokine receptor. The interaction between dying cancer cells producing IL-8 and CXCR1 stimulation of cancer stem cells contributes to the increase in cancer stem cells following chemotherapy. In mouse models we have shown that we can block these pathways with use of an antibody or a small molecule inhibitor to the CXCR1 receptor and can thus directly target and reduce the cancer stem cell population.
Medscape: Would blocking the CXCR1 receptor be expected to reduce recurrence?
Dr. Wicha: Yes, that is our hypothesis -- that targeting cancer stem cells through the CXCR1 receptor would reduce recurrence, which may be driven by chemotherapy-resistant cancer stem cells. This is consistent with our findings in mouse models.
Medscape: What agents did you use against IL-8 or CXCR1 in your studies?
Dr. Wicha: We used antibodies against IL-8 or a small molecule inhibitor of CXCR1 called repertaxin. Repertaxin was developed as an anti-inflammatory agent to be used to prevent heart damage after myocardial infarction. Repertaxin has been tested in phase 1 clinical trials. Our studies indicate that this approach may provide a strategy to selectively target breast cancer stem cells.
Medscape: What other pathways might be involved in mediating stem cell signaling?
Dr. Wicha: It is becoming clear that a number of other signaling pathways regulate cancer stem cells. One important pathway is the Notch pathway. Small molecules, such as gamma secretase inhibitors, are able to inhibit Notch signaling; in mouse models, this Notch inhibitor has been shown to reduce the population of cancer stem cells. On the basis of this concept, phase 1 clinical trials that utilize gamma secretase inhibitors are now in progress at our cancer center as well as others. We are also trying to combine Notch inhibitors with cytotoxic chemotherapy such as docetaxel, inasmuch as our preclinical findings suggest that these signaling agents may sensitize cancer stem cells to chemotherapy.
The Hedgehog pathway may also regulate stem cells. The ligands for Hedgehog may act on cells in the tumor stroma, and the interaction between the stroma and breast cancer stem cells may regulate their growth. Small molecule Hedgehog inhibitors have now been tested in phase 1 clinical trials and are about to enter phase 2 trials for breast cancer. In light of recent studies[8,9] that have confirmed an important role for cytokine signaling in the regulation of breast cancer stem cells, future approaches may combine agents that can inhibit stromal cell signaling with stem cell inhibitors such as Notch and Hedgehog.
Recent studies suggest that characteristics of molecular subcategories of breast cancer may be driven by stem cells that can be identified with different markers.[10,11] These differences may result from the origin of breast cancers -- whether stem or progenitor cells -- or different mutations that drive the various molecular subtypes. Ultimately, molecular analysis of breast cancer self-renewal pathways may allow for the individualization of therapy designed to target these different stem cell populations.
Medscape: What were some other important findings related to breast cancer stem cells presented at SABCS this year?
Dr. Wicha: A study by Atkas and colleagues demonstrated that cancer cells that express stem cell markers could be isolated from circulating blood in 28 patients with metastatic breast cancer.[12] Furthermore, they showed that these cells expressed not only the stem cell marker aldehyde dehydrogenase (ALDH)-1 but also markers of epithelial-mesenchymal transition (EMT), a phenotypic change that may allow cells to travel to the site of metastasis formation while avoiding elimination by standard treatment. Markers of EMT that have been investigated include Twist, Akt2, and PI3K. Samples were also investigated separately for the stem cell marker ALDH-1. Circulating tumor cells (CTCs) were detected in 12 of 28 (43%) breast cancer samples. In the samples that were positive for CTCs, 50% were positive for at least one EMT marker and 42% were positive for ALDH-1. In the group that was negative for CTCs, only 19% and 12% expressed EMT markers or ALDH-1, respectively. These studies suggest that cancer stem cells can display an EMT phenotype and that these cells are relatively resistant to chemotherapy and can be detected in the circulation.
Medscape: What are some of the important stem cell markers currently under investigation?
Dr. Wicha: Our laboratory was the first to show that expression of the enzyme ALDH is a useful marker for normal and malignant breast stem cells.[13] ALDH also can be used to isolate breast cancer stem cells from human tissue. Jolicoeur and colleagues found that ALDH tends to be expressed on basal-type rather than luminal-type breast cancers.[14] These researchers studied formalin-fixed, paraffin-embedded specimens from 57 patients with breast cancer. The samples were assessed with immunohistochemistry for ALDH-1 as well as the estrogen and progesterone receptors (ER and PR, respectively) and HER-2. Basal cell markers investigated included epidermal growth factor receptor (EGFR)-1, CK5, CK14, CK17, and smooth muscle alpha-actin (SMA); luminal cell markers included CK19 and epithelial membrane antigen (EMA).
These investigators found that breast cancer specimens that were triple negative (ie, negative for ER, PR, and HER-2) and also expressed at least one basal cell marker were more likely to be positive for ALDH-1 staining. These findings suggest that basal cancers may arise from primitive mammary stem cells. At least some of the luminal cancers (which have a more favorable prognosis) are not as likely to express ALDH. These findings support the concept that different molecular subcategories of breast cancer may be derived from different cells and may express distinct markers.
Other markers that have been used to identify breast cancer stem cells include CD44 positivity and CD24 negativity.[1] It has been relatively difficult to identify these markers using immunohistochemistry. According to study findings presented at SABCS, however, Rimm and colleagues used the fluorescent AQUA [automated quantitative analysis] technique[15] to combine ALDH staining with CD44 expression and demonstrated that ALDH-positive CD44 cells correlated with a poor prognosis. On the basis of their findings, they suggest that combining ALDH and CD44 may be superior to use of either marker alone for the detection of breast cancer stem cells.
Medscape: What are some other important issues with respect to stem cells in breast cancer?
Dr. Wicha: A study by Latimer and colleagues suggests that racial differences in breast carcinogenesis may relate in part to the differences in the ability of breast stem cells to differentiate in white vs African-American women.[16] African-American women are more likely to die from breast cancer, and the incidence of breast cancer is higher in African-American women under 40 years of age compared with white women of the same age. With use of a mammary tissue module, these researchers found that race was a modifying factor in the ability of cells to form ductal structures in vitro, which significantly increased the rate of differentiation. They suggest that if breast tissue from African-American women has a more robust differentiation potential than that of white women, it may also contain more stem cells, associated with an aggressive tumor type. In addition, our group has found different frequencies of ALDH positivity in African-American women compared with white populations. Together, these studies may provide a partial explanation for the increased incidence of breast cancer in African-American women.
Medscape: Do you think that the key stem cell markers have been identified, or do several stem cell markers remain to be found?
Dr. Wicha: The field of cancer stem cell research is in its early stages. It is going to be very important to search for more stem cell markers, particularly for luminal breast cancers. We currently have effective markers for identifying stem cells in basal breast cancers, but it is becoming clear that luminal breast cancers may be driven by different stem cells.
Another important question exists regarding the relationship of HER-2 expression and cancer stem cells. Our laboratory has recently shown that HER-2 overexpression increases cancer stem cell frequency. This finding is also consistent with our clinical data that show an increase in ALDH-positive cells in HER-2-positive breast cancers. The remarkable efficacy of agents such as trastuzumab and lapatinib in treating metastatic and early-stage breast cancer may relate to the fact that these agents are able to target breast cancer stem cells. Mechanisms of trastuzumab resistance as well as the question of whether trastuzumab can benefit women without HER-2-amplified tumors are open questions that need further investigation.
Medscape: How far away is the application of these findings in clinical practice?
Dr. Wicha: Cancer stem cell research is still in its infancy. However, use of stem cell inhibitors such as gamma secretase inhibitors to inhibit Notch signaling or Hedgehog inhibitors is currently being investigated in early-phase clinical trials. Neoadjuvant trial designs such as those reported by Dr. Jenny Chang at Baylor College of Medicine in Houston, Texas, will provide important new information on the ability of these agents to specifically target breast cancer stem cells.[5] In these studies, it will also be important to measure the effect of treatment on stem cell markers as well as on the pathways that drive cancer stem cells.
This activity is supported by an independent educational grant from Susan G. Komen for the Cure.

References
[ CLOSE WINDOW ]
References

  1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100:3983-3988. Abstract
  2. Chen MF, Lin CT, Chen WC, et al. The sensitivity of human mesenchymal stem cells to ionizing radiation. Int J Radiat Oncol Biol Phys. 2006;66:244-253. Abstract
  3. Wicha MS. Identification of murine mammary stem cells: implications for studies of mammary development and carcinogenesis. Breast Cancer Res. 2006;8:109.
  4. Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672-679. Abstract
  5. Chang JC, Li X, Creighton C, et al. Decrease in tumorigenic breast cancer stem cells -- final results of a neoadjuvant trial in primary breast cancer patients. Program and abstracts of the 6th European Breast Cancer Conference (EBBC); April 15-19, 2008; Berlin, Germany. Abstract 204
  6. Korkaya H, Paulson A, Iovino F, Wicha MS. HER-2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene. 2008;27:6120-6130. Abstract
  7. Wicha M. Molecular targets in breast cancer stem cells. Program and abstracts of the 31st Annual San Antonio Breast Cancer Symposium (SABCS); December 10-14, 2008; San Antonio, Texas. Basic Science Panel Discussion.
  8. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557-563. Abstract
  9. Beider K, Abraham M, Peled A. Chemokines and chemokine receptors in stem cell circulation. Front Biosci. 2008;13:6820-6833. Abstract
  10. Dontu G. Breast cancer stem cell markers -- the rocky road to clinical applications. Breast Cancer Res. 2008;10:110.
  11. Honeth G, Bendahl PO, Ringnér M, et al. The CD44+/CD24- phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 2008;10:R53.
  12. Aktas B, Tewes M, Hauch S, Fehm T, Kimmig R, Kasimir-Bauer S. Stem cell and epithelial-mesenchymal transition markers on circulating tumor cells in patients with metastatic breast cancer. Cancer Res. 2009;69(suppl 2):84s. Abstract 107.
  13. Ginestier C, Hur MH, Charafe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555-567.
  14. Jolicoeur F, Garcia de la Fuente I, Gaboury L, Balicki D. ALDH1 is a useful marker of basalness in human breast cancer and its stem/progenitor cells. Cancer Res. 2009;69(suppl 2):83s. Abstract 104.
  15. Rimm DL, Barlow WE, Harigopal M, et al. Multiplexed AQUA-based assessment of SWOG 9313 shows prognostic value of continuous ER, PR and HER-2 assessment. Cancer Res. 2009;69(suppl 2):97s.
  16. Latimer JJ, Lalanne NA, Myers NT, Courtney AB, Mock L, Grant SG. A new paradigm for African American breast cancer involving stem cell differentiation. Cancer Res. 2009;69(suppl 2):324s. Abstract 5051.

Contents of Highlights of SABCS 2008 All sections of this activity are required for credit.
  1. Highlights in HER-2-Positive Breast Cancer
  2. Highlights in Adjuvant Endocrine Therapy for Breast Cancer
  3. Breast Cancer Stem Cells as Novel Therapeutic Targets: An Expert Interview With Dr. Max S. Wicha
Earn CME Credit »
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Old 06-13-2009, 05:57 PM   #20
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1: Cancer Sci. 2009 Jun;100(6):1062-8. Epub 2009 Mar 9. Links
Stem cell marker aldehyde dehydrogenase 1-positive breast cancers are characterized by negative estrogen receptor, positive human epidermal growth factor receptor type 2, and high Ki67 expression.

Morimoto K, Kim SJ, Tanei T, Shimazu K, Tanji Y, Taguchi T, Tamaki Y, Terada N, Noguchi S.
Department of Breast and Endocrine Surgery, Osaka University Graduate School of Medicine, Suita City, Osaka, Japan.
Recently, aldehyde dehydrogenase (ALDH) 1 has been identified as a reliable marker for breast cancer stem cells. The aim of our study was to investigate the clinicopathological characteristics of breast cancers with ALDH1+ cancer stem cells. In addition, the distribution of ALDH1+ tumor cells was compared on a cell-by-cell basis with that of estrogen receptor (ER)+, Ki67+, or human epidermal growth factor receptor type 2 (HER2)+ tumor cells by means of double immunohistochemical staining. Immunohistochemical staining of ALDH1 was applied to 203 primary breast cancers, and the results were compared with various clinicopathological characteristics of breast cancers including tumor size, histological grade, lymph node metastases, lymphovascular invasion, ER, progesterone receptor, HER2, Ki67, and topoisomerase 2A as well as prognosis. Immunohistochemical double staining of ALDH1 and ER, Ki67, or HER2 was also carried out to investigate their distribution. Of the 203 breast cancers, 21 (10%) were found to be ALDH1+, and these cancers were significantly more likely to be ER- (P = 0.004), progesterone receptor- (P = 0.025), HER2+ (P = 0.001), Ki67+ (P < 0.001), and topoisomerase 2A+ tumors (P = 0.012). Immunohistochemical double staining studies showed that ALDH1+ tumor cells were more likely to be ER-, Ki67-, and HER2+ tumor cells. Patients with ALDH1 (score 3+) tumors showed a tendency (P = 0.056) toward a worse prognosis than did those with ALDH1- tumors. Breast cancers with ALDH1+ cancer stem cells posses biologically aggressive phenotypes that tend to have a poor prognosis, and ALDH1+ cancer stem cells are characterized by ER-, Ki67-, and HER2+.
PMID: 19385968 [PubMed - in process
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