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In the tiny and turbulent world of the cell, the double-stranded DNA that runs the cell's control program is constantly breaking. Cells have about half a dozen ways to combat their DNA damage — and if these self-repair jobs fail badly enough, cells die.
For decades, chemotherapies have bludgeoned away at this potential weakness in tumor cells, trying to destroy the cancer as it attempts to grow unchecked. But a new class of agents called PARP inhibitors offers a much more targeted attack on tumors whose self-repair is already under fire.
To date, the leading indications for these new drugs are tumors that develop in patients with mutations in the BRCA1 or BRCA2 genes, which dramatically heighten a woman's risk of breast or ovarian cancer.
"DNA repair pathways are very promising targets for therapy, particularly so for BRCA-related and triple-negative breast cancer and BRCA-related ovarian cancer," says J. Dirk Iglehart, MD, director of the Susan F. Smith Center for Women's Cancers. "We are hopeful that PARP inhibitors will become an important addition to the treatment of those cancers."
PARP, which stands for "poly (ADP-ribose) polymerase," is a family of enzymes found throughout the body. PARP is needed for a form of DNA repair known as break excision repair, which fixes glitches in one strand of DNA.
In 2003, work at Sheffield University in England showed that cells lacking PARP activity switch over to another repair mechanism that can fix breaks in both strands of DNA and is known as homologous recombination.
It so happens that the BRCA1 and BRCA2 genes are linchpins for this repair activity. If both copies of one BRCA gene are mutated in a tumor cell, the cell loses the ability to fix itself by homologous recombination. BRCA-related tumors thus must fall back on other ways to repair their DNA. But, in theory, if both BRCA and PARP mechanisms are broken, the cell dies.
Dr. Iglehart likens the situation to a pair of suspenders. "If your pants are held up by two suspenders, but one suspender is missing as it is in the tumor cell, all I have to do is cut one suspender and the pants fall down," he says. "But all the other cells still have another suspender."
"This could be a very elegant way to utilize a defect in DNA repair without inflicting the same amount of damage to normal cells, because normal cells aren't defective in this compensating repair pathway," adds Daniel Silver, MD, PhD, a physician-scientist in Dana-Farber's Breast Oncology Center.
Dr. Silver points out that this approach taps a concept in molecular biology called synthetic lethality, "a relationship between two genes, in which cells are perfectly happy if they're missing either one of the genes, but the cell dies if you have mutations in both genes," he says. "One of the reasons that PARP inhibitors have garnered a lot of attention is that they are really the first fruits of this idea of synthetic lethality to enter the clinic."
Pharmaceutical companies already had agents that inhibit PARP, developed with other applications in mind, on their shelves. In tests in human cells and in mice by Dana-Farber and other institutions, the drugs proved effective in killing BRCA-related tumors. Next came clinical studies.
Judy Garber, MD, MPH, director of the Center for Cancer Genetics and Prevention at Dana-Farber, led the Institute's effort in an early trial of AstraZeneca's PARP inhibitor olaparib for women with BRCA-related metastatic breast cancer. Rather than examining a tumor biopsy, "we had to do a blood test and find out if they had a mutation," she notes.
The trial results were quite positive. "In the trial, more than 40 percent of women had a measurable response to the PARP inhibitor alone, even though most of the women had needed a number of previous treatments, which can make their tumors resistant to new treatments," says Dr. Garber. "We did learn that the drug is not as selective as we had hoped. There are some side effects on normal cells, though most were manageable."
Results from this investigation, and other early studies of BRCA-related breast and ovarian cancers at Dana-Farber and elsewhere, then raised a clear question: If PARP inhibitors worked well by themselves, would they work better in combination with other cancer drugs?
Cisplatin, a conventional "platinum-based" chemotherapy agent that causes double-stranded breaks in DNA, was a likely candidate to make PARP inhibitors more effective. One study looked at the effect of combining cisplatin with olaparib in treating women with inherited BRCA-related breast cancer. It has been challenging to find the right combination of doses to maximize efficacy and simultaneously minimize side effects.
Another study will examine a preventive role for PARP inhibitors. The study, called the PIONEER Trial, will enroll healthy women with a BRCA mutation who are planning to have prophylactic mastectomies. Patients will receive veliparib, a PARP inhibitor from Abbott Laboratories, for a month before surgery. Researchers will then examine the breast tissue that was removed, to look for early changes that are consistent with a preventive effect.
"I don't envision women taking a PARP inhibitor every day all their lives to prevent breast (and ovarian) cancers, because it doesn't seem wise to turn off DNA repair altogether," Dr. Garber adds. "But it might be safe and effective to take a PARP inhibitor for short times – say, a month each year – to eliminate early cancer cells before a tumor can get started."
She points out, however, that one limitation for PARP inhibitors is the relatively small population of women with BRCA mutations, making pharmaceutical firms reluctant to invest heavily in drug development.
Most BRCA-related breast cancers are triple-negative. This difficult-to-treat group makes up about 10-15 percent of all breast cancers. (The disease is called triple-negative because the tumors do not have estrogen or progesterone receptors or the HER2/neu gene, and therefore are not sensitive to hormonal treatments like tamoxifen or aromatase inhibitors, or to the drug herceptin.)
Triple-negative cancers show very high levels of DNA damage, Dr. Iglehart's lab and many others have found. Those triple-negative tumors that lack an inherited BRCA mutation also look much like those that do show such a mutation. "These tumors tend to be high-grade, have similar growth patterns under the microscope, and have similar patterns of gene activation," notes Dr. Silver. "So a number of us were wondering whether they had similar defects in DNA repair."
Even before PARP inhibitors appeared, researchers led trials that treated women with triple-negative cancer with cisplatin or other conventional DNA-repair-damaging drugs. Many researchers hoped that PARP inhibitors would heighten the effect on the cancer.
In some early trials, the hopes appeared to be realistic. One small study that drew much attention in 2009 examined the effects of a PARP inhibitor called iniparib, made by Sanofi-aventis subsidiary BiPar Sciences. When added to a treatment with carboplatin and gemcitabine (another conventional chemotherapy agent) for women with metastatic triple-negative breast cancer, iniparib significantly improved survival compared to treatment with carboplatin and gemcitabine alone.
But in January 2011, Sanofi-aventis released preliminary information from a Phase 3 trial of the same combination. While full data won't be available until June, "the results from the Sanofi trial are disappointing," says Eric Winer, MD, director of the Breast Oncology Center, in Dana-Farber's Susan F. Smith Center for Women's Cancers. "The treatment improved clinical outcomes to a limited extent, but not enough to lead to a drug approval. In the end, it probably makes chemotherapy work better in a small group of patients, but we don't yet know how to identify them."
"We'll have to work harder to find out who are the right patients for these agents," comments Erica Mayer, MD, MPH, a medical oncologist in the Breast Oncology Center who leads clinical studies in triple negative breast cancer. "This will involve even closer collaboration with our laboratory-based colleagues.
"Figuring out how to treat triple negative breast cancer is just not that simple," she adds. "Even something that looks like a home run may turn out to be a ground-rule double."
How the trial results apply to other PARP inhibitors also is not yet clear, especially since iniparib is very different from all the other PARP inhibitors that are currently in testing.
More generally, "DNA repair is kind of an Achilles heel to attack BRCA1- and BRCA2-related tumors," Dr. Silver adds. "But the bad news is that the Achilles heel has its own Achilles heel." Studies in BRCA-mutated breast cancer cells and in platinum-based drugs in BRCA-related tumors suggest that additional mutations may restore DNA repair, he explains.
"It is clear that women who have advanced disease and take these drugs are not cured by them," says Dr. Garber. "But there are reasons to be very hopeful that we will make them an important part of therapy, at least for certain groups."
In addition to their potential roles in breast cancer, "these agents are quite promising for treating BRCA-associated inherited ovarian cancer," notes Dr. Winer. "They also appear to work in sporadic ovarian cancer, which may share many of the features of inherited ovarian cancer.
"While some of the clinical studies have been disappointing, and the preliminary results are not what we had hoped for, PARP inhibitors are a promising class of drugs for some of the most difficult-to-treat cancers," he sums up. "They certainly merit intensive research."
Turning Point 2011