"When therapy of any kind doesn't eradicate a patient's cancer, the surviving tumor cells can set the stage for a return of the disease."
"When therapy of any kind doesn't eradicate a patient's cancer, the surviving tumor cells can set the stage for a return of the disease," says Ursula Matulonis, MD, chief of the Division of Gynecologic Oncology at Dana-Farber. "Understanding how cells become resistant to treatment, and how we can overcome resistance, is critical to improving outcomes for our patients. At the Susan F. Smith Center for Women's Cancers,
we're working to shed light on these resistance mechanisms."
Shifting Gears When Tumors Return
Tumors can foil cancer drugs in a variety of ways. If a drug targets a particular protein in a cell-growth pathway, a genetic mutation may alter that protein so it eludes the drug's grasp. If one part of a growth pathway is shut down by a drug, a mutation
may provide a detour around it, much as a stream, if dammed, may form new branches to reach its destination. Mutations can produce changes in proteins on the cell surface that prevent cancer drugs from binding there. Some tumor cells even develop
the ability to pump out drugs that have breached their membranes.
Metastasis is another part of cancer's evasive repertoire. "However cancer cells spread – via the bloodstream, the lymph system, or even through direct spread in the abdomen to areas such as the omentum [a fatty structure that drapes the intestines and
is a common site for metastatic ovarian cancer] – they may grow differently depending on their environment or 'neighborhood' they're in, and they also may respond differently to treatment depending on the organ or tissue they're in," Dr. Matulonis
observes. "Even within a single patient, different sets of tumor cells may exhibit different mechanisms of resistance."
To deal with these ploys, scientists are working on a range of countermeasures. They're developing techniques to destroy, rather than merely block, proteins involved in drug resistance. They're testing whether different drug doses or treatment schedules
can prevent resistance or reduce its likelihood. Most promisingly, they're working to decipher the genetic mechanisms behind resistance, looking for ways to block or circumvent them.
Today, when a patient's tumor stops responding to a drug or combination of drugs, physicians may recommend another regimen or a clinical trial of a novel treatment. But because tumors can become resistant to multiple therapies, new approaches are urgently
needed.
What to Do When PARP Inhibitors Fail
A recent study by Dana-Farber researchers exemplifies science's ability to get the upper hand over cancer drug resistance. Drugs known as PARP inhibitors have become a major part of the arsenal against cancers with mutations in the genes BRCA1 and BRCA2. The drugs employ the same strategy as a trade embargo against an outlaw nation. If some of that country's supply lines have already been disrupted, it's likely to be desperately dependent on its remaining suppliers. Shutting down
those sources would be devastating. BRCA1 and 2 help cells repair double-stranded breaks in their DNA. When those genes are knocked out of commission by a mutation, tumor cells rely more heavily on PARP proteins, which make single-stranded
DNA repairs. Blocking the PARP proteins with an inhibitor drug can create such a build-up of genetic damage that the tumor cells die.
"BRCA mutations are found in many breast, ovarian, prostate, and some pancreatic cancers," says
Alan D'Andrea, MD, director of Dana-Farber's Susan F. Smith Center for Women's Cancers and the Center for DNA Damage and Repair,
who led the new study with Raphael Ceccaldi, PhD, PharmD, of the Curie Institute in Paris. "For many patients with these cancers, or cancers with other DNA-repair deficiencies, PARP inhibitors can be extremely effective."
In nearly every case, though, tumors that were once susceptible to PARP inhibitors become resistant to them and mount a comeback, leaving patients in need of new options. Dr. D'Andrea and his team set out to find one. At a Harvard Medical School facility,
they screened thousands of molecules – approved drugs as well as experimental compounds – in BRCA-deficient tumors to see if they had any effect on tumor growth. The screenings were conducted in laboratory cell lines, in organoids – three-dimensional
cultures of tumor tissue – and in animal models.
Of all the drugs tested, one stood out for its ability to kill the tumor cells while leaving normal cells unharmed – the antibiotic novobiocin.
When they learned the identity of the protein that novobiocin targets within cells, they had a shock of recognition.
Back in 2015, Dr. D'Andrea's team had found that tumors with poorly functioning BRCA1 and 2 genes are overdependent for their growth and survival on an enzyme called POLθ, or POLQ. Like the BRCA proteins, POLQ specializes in
mending double-strand DNA breaks. In tumors with mutated BRCA genes, the POLQ pathway becomes all the more vital, and any drug that targets it could deliver a death blow to cells. Now, in the new study, Dr. D'Andrea's team had discovered
that novobiocin's protein target was none other than POLQ.