In devising ways to outwit cancer, scientists find themselves confronting a master of improvisation.
For a prime example of just how changeable cancer can be, consider research in a breakthrough class of drugs known as PARP inhibitors, which have been approved for women with some types of breast or ovarian cancer. In many patients, the drugs hold the
disease in check for a year or two, sometimes more. As so often happens with cancer, however, the disease eventually sidesteps the drugs and begins to grow again. Although the drugs can improve a patient's quality of life, they generally don't lengthen
At Dana-Farber's Susan F. Smith Center for Women's Cancers, scientists are plotting ways to block cancer's escape routes from PARP inhibitors. They're
doing so with a new modeling system that enables them to obtain answers much faster than in the past.
"PARP inhibitors are one of the best examples of how our knowledge of the basic workings of cancer cells can inspire new ways of attacking the disease," says Alan D'Andrea, MD, director
of the Susan F. Smith Center. "But cancer is clever. If we shut down one of the pathways tumor cells need to survive, they often find others. To have a lasting impact, we may need to disable two or more pathways."
That is the strategy behind Dr. D'Andrea and his colleagues' current research. In it, they're taking aim at one of cancer cells' most important survival mechanisms – their ability to repair damage to their DNA.
DNA damage can occur in any number of ways – from environmental hazards such as pollutants, chemicals, or radiation,
or simply from bad luck, such as an error in the process of DNA duplication prior to cell division. A nick or bruise here or there in the genome often doesn't have much of an effect. But if enough damage accrues over time, it can erode cells' ability
to function and survive.
Human cells are far from helpless in the face of these mishaps. They can mobilize up to half a dozen crews of proteins to repair their DNA.
Unfortunately, cancer cells share the very qualities that make healthy cells so resilient. Chemotherapy, radiation therapy, and newer targeted therapies work largely by damaging tumor cells' DNA, wreaking such genetic havoc that the cells may opt to die
rather than carry on in a weakened state. Often, however, the cells manage to patch up the damage well enough that they can continue proliferating.
"In some tumors, one or more of these repair mechanisms, or pathways, may be out of commission because of a mutation or other abnormality in certain genes," Dr. D'Andrea explains. "The best-known of these genes are BRCA1 and BRCA2, which help fix breaks
that occur in both strands of DNA." About 1 in 400 people carry an inherited mutation in BRCA1 or 2. In women, such mutations can substantially increase the risk of developing breast and/or ovarian cancer (as well as certain other cancers for which
men are also at risk).
Menacing as they can be, mutations in BRCA1 and 2 also present doctors with a therapeutic opportunity. Cancer cells in which BRCA1 or 2 isn't functioning properly often fall back on other DNA-repair pathways. One of these goes by the clunky name poly(ADP-ribose)
polymerase, or PARP, which specializes in fixing single-strand DNA breaks. In concert with other DNA-repair pathways, PARP can often compensate for the loss of BRCA.
To scientists, this evidence of cancer's tenacity suggested a potential vulnerability. In cancer cells where the BRCA pathway is idle because of a mutation, a drug that inhibits the PARP protein could be the blow that finishes the cells off, researchers
reasoned. Unable to summon the BRCA or PARP repair teams, the cells would acquire so much genetic damage that they would have no alternative but to die. The strategy is the equivalent of delivering an upper cut to a boxer already wobbling from a right
Since they first entered clinical trials in 2010, PARP-inhibiting drugs have gained an important niche in cancer treatment, particularly in arresting the advance of breast and ovarian cancers with BRCA mutations. But after a year or two, the cancer often
becomes resistant to PARP inhibitors and starts growing again. Resistance arises because cancer cells deprived of BRCA and PARP pathways have still other alternatives for making DNA repairs. To Dr. D'Andrea and his colleagues, the implications are
clear: augment PARP inhibitors with drugs that shut down other repair pathways.
"In the lab, we've shown that tumors resistant to PARP inhibitors become hyper-dependent for their survival on another pathway," he remarks. Two such pathways, named for the key proteins within them, are the ATR and CHK1 pathways. By good fortune, drugs
targeting these pathways already exist and are entering clinical trials.
Dr. D'Andrea's lab is currently studying combinations of ATR and CHK1 inhibitors with PARP inhibitors in laboratory samples of tumor cells. In doing so, they have the benefit of a new system for modeling how well these combinations might work in human
patients. Called a three-dimensional organoid culture, it allows tumor cells to grow in an environment that closely mimics that within the body. It also returns results more quickly than other techniques: researchers can grow enough cells in about
a week to experiment on.
"We're using 3D organoid cultures to assess the best sequence for these combinations – is it best to administer the drugs at the same time, or should PARP inhibitors be used first? – as well as the proper dosing and schedule," Dr. D'Andrea remarks. Once
researchers have answers to these questions, they hope to test the combinations in clinical trials.
Panos Konstantinopoulos, MD, PhD (left), and Ursula Matulonis, MD, are working to combine PARP inhibitors with other therapies.
Even as they work to overcome the problem of drug resistance, Susan F. Smith Center clinician-scientists are studying ways to make PARP inhibitors more effective. As with Dr. D'Andrea's laboratory research, these clinical efforts involve combining PARP
inhibitors with other drugs.
Chief of Gynecologic Oncology Ursula Matulonis, MD, has been instrumental in bringing PARP inhibitors into mainstream use. She led the research behind the recent Food and Drug
Administration approval of the PARP inhibitor niraprib. In addition, she and her colleagues are leading trials of PARP inhibitors in tandem with a variety of other therapies, including angiogenesis inhibitors (which constrict tumors' access to the
blood supply), immunotherapy agents, and targeted drugs. The number of possible combinations is nearly limitless, so investigators have established guidelines for which
possibilities to pursue. "We focus on combinations for which laboratory research provides evidence of their effectiveness," Dr. Matulonis states. "We also prioritize types of cancer where there is an unmet need for better treatments, such as ovarian
cancer that resists platinum-based chemotherapy and doesn't have a BRCA mutation."
Studies have suggested that PARP inhibitors may be more versatile than originally expected – that they may be effective in some cancers with malfunctions in DNA-repair pathways other than PARP. To see if that's the case, Judy Garber, MD, MPH, director of the Center for Cancer Genetics and Prevention at Dana-Farber, is launching a clinical trial for patients whose breast cancer carries abnormalities in these other pathways. As part
of the study, Geoffrey Shapiro, MD, PhD, director of Dana-Farber's Early Drug Development Center, will analyze tumor tissue with technology capable of determining whether
certain repair pathways are functioning in the tumor cells.