There is new hope on the horizon for many women with breast cancer. New drugs have been discovered that could treat 10 to 20 percent of women with breast cancer, especially those who have an inherited predisposition to the disease due to defective BRCA1 and BRCA2 genes.
For some time we knew that either inherited or spontaneously mutated genes caused cancer. But we’ve also learned that two genes in particular, BRCA1 and BRCA2, play a role in both. Women with a BRCA1 mutation have an estimated 55 to 65 percent chance of developing breast cancer before the age of 70. For women with a BRCA2 mutation, that number is 45 percent. Most of these mutations occur spontaneously, though a smaller fraction—about five to 10 percent—are inherited.
Why these genes? BRCA1 and BRCA2 are involved in the repair of double-stranded breaks in DNA, which occur regularly in all cells as they grow and multiply. Ongoing repair is especially important for cancer cells, which grow at a faster rate than healthy ones, and even more so for BRCA deficient cancer cells, which require additional support to survive.
Two enzymes, it turns out, can step in to assist with DNA repair if BRCA1 and BRCA2 cannot. One is poly-ADP ribose polymerase, which acts by binding to the site of a double-stranded break and producing a long ADP ribose chain that attracts other DNA repair enzymes. The other is DNA polymerase theta—one of the enzymes that poly-ADP ribose polymerase attracts.
In the past 10 to 15 years, researchers have developed drugs that selectively kill cancer cells by inhibiting poly-ADP ribose polymerase. These poly-ADP ribose polymerase inhibitors have been successful in causing remission of both spontaneous and inherited BRCA deficient tumors. The main drawback is that within a year to 18 months, cancer cells can develop resistance to these drugs, meaning the patients who take them cease to benefit. But according to two recently published research papers, new drugs that target polymerase theta instead might be able to help.
First, a bit of backstory. For many years Alan D’Andrea, a cancer researcher and former student of mine, has worked on DNA damage and repair, first as an undergraduate and now as director of both the Susan F. Smith Center for Women’s Cancers and Center for DNA Damage and Repair at Dana-Farber Cancer Institute.
Some years ago, D’Andrea was studying a rare genetic blood disorder called Fanconi anemia. While conducting research interviews at a summer camp that had pediatric Fanconi anemia patients, he fortuitously encountered a mother and child—an 11-year-old girl with Fanconi—who held the key to his next scientific breakthrough. The mother, D’Andrea noticed, had her arm in a sling; she had breast cancer and was recovering from a recent mastectomy, despite being younger than 40. Her husband, on the other hand, was in good health, but his own mother had ovarian cancer. D’Andrea later discovered that both parents were carriers of defective BRCA genes, which led him to speculate that might be linked to their daughter’s disease. This speculation proved correct. Two copies of a damaged BRCA gene causes Fanconi anemia.
“I studied this disease with the idea that if we could clone BRCA genes and figure out their pathway,” D’Andrea told me in an interview, “we would learn something fundamental about cancer and the general population.” He was right. In the years that followed D’Andrea began examining other requirements for DNA repair, finding that in addition to poly-ADP ribose polymerase, BRCA detective cancer cells also depended on polymerase theta to retain viability. His work stimulated his colleagues and others to commence an intensive search for potential polymerase theta inhibitors. Two promising candidates have been identified since, one by D’Andrea’s laboratory and another by a research team based mostly in London. Both drugs, used alone or in addition to poly-ADP ribose polymerase inhibitors, have great potential to treat BRCA defective tumors.
Of the thousands of molecules D’Andrea and his team tested that might inhibit polymerase theta, the antibiotic Novobiocin was most effective. The results of their experiments, published in Nature Cancer in June, show that by latching onto the polymerization site directly, Novobiocin could selectively eliminate cells that were either BRCA deficient or resistant to poly-ADP ribose polymerase inhibitors in both cell lines and animal models. The latter mechanism in particular is incredibly significant. In D’Andrea’s words, “Overcoming PARP [poly-ADP ribose polymerase] inhibitor resistance is what this story is really about.”
The other study, which appeared almost simultaneously in Nature Communications, investigates a small molecule drug that does this allosterically instead: ART558. Like Novobiocin, ART558 can be used to selectively damage and kill BRCA1/2 defective cancer cells and combat resistance to poly-ADP ribose polymerase by inhibiting DNA polymerase theta. The study’s authors also suggest that ART558 will augment the benefits of poly-ADP ribose polymerase inhibitors while mitigating their adverse effects.
The need for polymerase theta inhibitors is dire, as the correlation between defective BRCA1 and BRCA2 genes and an increased risk of breast cancer is significant. As I mentioned previously, these defects can either appear spontaneously or through inheritance. Of the latter, women of Ashkenazi Jewish descent are at higher risk, in large part due to the loss of genetic diversity that occurs when a population shares only a small number of ancestors—otherwise known as the founder effect. According to the CDC, one in 40 Ashkenazi Jewish women inherit at least one BRCA founder mutation, increasing the chance they will develop breast cancer at an early age. In recent years studies have also linked BRCA1 and BRCA2 mutations to ovarian, prostate, and pancreatic cancers.
Given the high stakes, these recent discoveries are worth celebrating. If both drug candidates prove safe and effective in clinical trials, the implications for cancer patients and their loved ones will be vast. According to D’Andrea, using Novobiocin as a polymerase theta inhibitor could reduce up to 50 percent of high-grade ovarian cancers; 10 to 20 percent of breast cancers; 10 to 20 percent of pancreatic cancers; and 10 percent of prostate cancers. Dana-Farber is already launching a Novobiocin trial that will test its effects in cancer patients who are BRCA1/2 deficient and PARP inhibitor resistant. The pharmaceutical company Artios is doing the same for ART558. Watch this space—it could be where history is made.