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.
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.
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.
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
© 2007 Lippincott Williams & Wilkins, Inc.