By Liz Szabo, USA TODAY
Margo Adler-Libstag isn't cancer-free.
But the Vermont mother of two says an experimental drug is keeping her rare form of ovarian cancer in check, leaving her feeling fairly well most of the time.
"You always want cancer out of your body," says Adler-Libstag, 51, whose cancer has spread throughout her abdomen. "But people live with chronic disease. I could live with a little bit of cancer, as long as it's stable and I have a good quality of life." FORUM: Living with Cancer
Adler-Libstag says the 16 pills she takes each day as part of a clinical trial fight cancer in a new way — by robbing her tumors of the tools they use to repair themselves. FIND MORE STORIES IN: Georgetown University | American Society of Clinical Oncology
Researchers this weekend will discuss the results of several studies of these new drugs, called PARP inhibitors. Although the drugs haven't yet been studied in the kind of large, rigorous studies required for Food and Drug Administration approval, early studies appear promising, says Joyce O'Shaughnessy, who will present her findings Sunday at the American Society of Clinical Oncology meeting in Orlando. Researchers are studying PARP inhibitors — available only in clinical trials — in a number of cancers, including breast, ovarian, uterine, brain and pancreatic tumors. But O'Shaughnessy says PARP inhibitors may work especially well in the 15% of breast cancer patients whose tumors don't respond to hormones or Herceptin.
Doctors are also studying the drugs in women such as Adler-Libstag who inherit a defect in a critical repair protein called BRCA1 or BRCA2, says O'Shaughnessy, of the Texas Oncology-Baylor Charles A. Sammons Cancer Center in Dallas.
Normally, these proteins fix damaged DNA. When these proteins don't work properly, people can accumulate mistakes in their DNA, leading to cancers of the breast and ovaries, O'Shaughnessy says.
One might expect that tumors like these would be easy to kill with chemotherapy. After all, tumors with malfunctioning BRCA protein can't perform their usual repairs.
Yet these cancers have a backup plan.
They turn to PARP, a repair enzyme that's abundant in cancer cells, says researcher Claudine Isaacs of Georgetown University's Lombardi Comprehensive Cancer Center. Because PARP is so good at cleaning up mistakes, it can help cancer cells survive — even after being poisoned by chemotherapy, Isaacs says.
Blocking PARP, however, is like taking away a race car's pit crew.
Isaacs says it's too soon to know how PARP inhibitors will affect healthy cells.
In her study, O'Shaughnessy will present early results in 86 of 120 patients. She plans to release more complete details in coming months.
Barbara Brenner of Breast Cancer Action, an advocacy group, cautions patients not to put too much faith in the results of early studies.
"It may turn out to be great, but let's finish the (larger) Phase 3 studies and find out," she says.
And Adler-Libstag, whose cancer has relapsed four times since she was diagnosed in 2004, knows she may not be cured. But a PARP inhibitor helped shrink her tumors, which now appear stable. And she says there are even rare times, when she's doing yoga, that she can forget that she has cancer.
"I'm either the luckiest unlucky person, or the unluckiest lucky person ever," Adler-Libstag says. "I can't figure that one out."
PARP inhibitors 'can treat many cancers'
A twice-a-day pill designed to treat breast cancer may be able to tackle other forms of the disease, scientists have discovered. PARP inhibitors have previously shown promise for treating cancers associated with a BRCA gene mutation, but research from Breakthrough Breast Cancer has found that they may useful for fighting other forms of the disease linked to a faulty PTEN gene. Faults in this gene are thought to be linked to 30-80% of all breast, prostate, skin, womb and colon cancer cases.
The research found that tumours with a faulty PTEN gene were 25-times more sensitive to the drug than those with a normal copy of the gene.
Professor Alan Ashworth, director of the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research, called the results "exciting".
"PARP inhibitors are potentially a powerful targeted treatment with few side effects which may help a broad range of cancer patients," he added.
There are more than 200 different types of cancer, but four of them – breast, lung, bowel and prostate – account for over half of all new cases.
Wednesday 16th September 2009A new type of drug could be used to treat thousands of cancer patients after experts found it can be used on different types of the disease.
The research, published in the EMBO Molecular Medicine journal, concludes that the drug - known as a PARP inhibitor - is showing "positive signs" in the treatment of breast and ovarian cancer, caused by the faulty BRCA gene.
Scientists now believe the drug could also kill cancers caused by the faulty PTEN gene, including prostate, skin (melanoma), womb and colon cancers. Research shows that the cancer cells are 25 times more sensitive to PARP inhibitors than cells with a normal PTEN gene.
Professor Alan Ashworth, director of the Breakthrough Breast Cancer Research Centre at the Institute of Cancer Research, hailed the results of the study as "exciting".
He said: "These results are exciting because they show that PARP inhibitors are potentially a powerful targeted treatment with few side-effects which may help a broad range of cancer patients."
Prof Ashworth added that tests need to be carried out on a "much larger group of patients with PTEN-related tumours".
Re: (PARP inhibitors) Experimental cancer drugs cut tumors off from repair tools
Research article
A selective eradication of human non-hereditary breast cancer cells by phenanthridine derived polyADP-ribose polymerase inhibitors
Dana Inbar-Rozensal, Asher Castiel, Leonid Visochek, David Castel, Francoise Dantzer, Shai Izraeli and Malka Cohen-Armon Breast Cancer Research 2009, 11:R78doi:10.1186/bcr2445
Published:
5 November 2009
Abstract (provisional)
Introduction
PARP-1 (polyADP-ribose polymerase-1) is known to be activated in response to DNA damage, and activated PARP-1 promotes DNA repair. However, a recently disclosed alternative mechanism of PARP-1 activation by phosphorylated externally regulated kinase (ERK) implicates PARP-1 in a vast number of signal transduction networks in the cell. Here, PARP-1 activation was examined for its possible effects on cell proliferation in both normal and malignant cells. Methods
In-vitro (cell cultures) and in vivo (xenotransplants) experiments were performed. Results
PARP inhibition by phenanthridine derived PARP inhibitors interfered with cell proliferation by causing G2/M arrest in both normal (human epithelial cells MCF10A and mouse embryonic fibroblasts) and human non-hereditary breast cancer cells MCF-7 and MDA231. However, while the normal cells were only transiently arrested, G2/M arrest in the malignant breast cancer cells was permanent and was accompanied by a massive cell death. In accordance, treatment with phenanthridine derived PARP inhibitor prevented the development of MCF-7 and MDA231 xenotransplants in female nude mice. Quiescent cells (neurons and cardiomyocytes) are not impaired by these PARP inhibitors. Conclusions
These results outline a new therapeutic approach for a selective eradication of abundant non-hereditary human breast cancers.
Selective Eradication Of Malignant Cells
05 Nov 2009
The ultimate goal in cancer research, a treatment that kills cancer cells whilst leaving healthy cells untouched, is brought nearer by the success of a new therapeutic approach. The potential therapy, published in BioMed Central's open access journal Breast Cancer Research, targets proliferation of cancer, but not normal, cells.
An international research team led by Professor Cohen-Armon of Tel-Aviv University found that potent phenanthridine derived polyADP-ribose polymerase (PARP) inhibitors that were originally designed to protect cells from cell-death under stress conditions (e.g. stroke or inflammation), efficiently eradicate MCF-7 and MDA231 breast cancer cells without impairing normal proliferating cells, such as human epithelial cells (MCF-10A), nor normal non-proliferating cells, such as neurons and cardiomyocytes.
Human cancers depending on a constitutive activity of externally regulated kinase (ERK) were examined. The rationale for testing PARP inhibitors in these cancers was the recently disclosed up-regulation of ERK signals in the nucleus by activated PARP-1. However, other mechanisms are apparently involved. The phenanthridine PJ-34 caused a permanent G2/M cell-cycle arrest and cell death within 48-72 hours in breast cancer MCF-7 and MDA231 cells. In contrast, normal proliferating cells overcame the imposed G2/M cell-cycle arrest within 12 hours, survived and continued to proliferate.
In vivo, PJ-34 prevented the development of MCF-7 and MDA231 xenotransplants in nude mice without affecting their growth, development or behaviour.
Other PARP inhibitors were recently proved efficient only for treating relatively rare hereditary human cancers developed in individuals with an impaired DNA repair (BRCA gene mutation). However, in the current research, breast cancer cells lacking the BRCA mutation were efficiently eradicated.
According to Professor Cohen-Armon, "This research provides a new therapeutic approach for a selective eradication of abundant human cancers."
Notes:
A selective eradication of human non-hereditary breast cancer cells by phenanthridine derived polyADP-ribose polymerase inhibitors
Dana Inbar-Rozensal, Asher Castiel, Leonid Visochek, David Castel, Francoise Dantzer, Shai Izraeli and Malka Cohen-Armon Breast Cancer Research (in press) http://breast-cancer-research.com/
Article on expanding PARP uses including short video clip discussing efficacy against "hypoxic" tumors. CSCs are thought to be hypoxic
Small molecule enzyme (PARP) inhibitors may serve as a potent approach for prevention of BRCA related breast cancer. However, the use of this strategy for therapeutic treatment for hereditary breast cancers is dependent on the continued susceptibility of BRCA mutant cells to PARP inhibitors, which may be achieved by using a combination with other agents (Int J Med Sci. 2006: 3(4): 117-123).
Although the theory behind enzyme inhibitor targeted therapy is appealing, the reality is more complex. For example, cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.
In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell. Another challenge is to identify for which patients the targeted treatment will be effective (enzyme inhibitors, proteasome inhibitors, angiogenesis inhibitors, and monoclonal antibodies).
Recent studies on targeted therapy have shown that tumors can become resistant to a targeted treatment. This means that the drug no longer works, even if it has previously been effective in shrinking a tumor. To solve this problem, new drugs are being designed or combined with existing ones to target the tumor more effectively.
The cancer state is typically characterized by a signaling process that is unregulated and in a continuous state of activation. These drugs promise to become an essential part of the physician's armament against cancer, particlarly those cancers that have developed resistance to other forms of treatment.
However, setbacks with drugs that specifically target specific pathways, reflect a lack of validated biomarkers. What is needed is to test the concept of targeted cancer drugs with biomarkers as pharmacodynamic endpoints, and with the ability to measure multiple parameters in cellular screens now in hand using flow cytometry.
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