BRCA Experts Gather to Research DNA Repair for Better Treatments for Breast, Ovarian and Other Cancers
When it comes to unlocking the secrets of DNA repair, Ranjit BindraMD, PhD, don’t just think in terms of resources. Professor Harvey and Kate Cushing of Therapeutic Radiology and Professor of Pathology favors a much more powerful word: armamentarium. Based on the Latin word for “arsenal”, it describes the collection of drugs, equipment, and techniques used by a physician for a field of study.
The Yale Cancer Center has a particularly impressive arsenal in the study of BRCA1 and BRCA2, proteins involved in DNA repair which, when mutated, can cause cancers of the breast, ovaries, prostate and pancreas. So when a $1 million grant became available for BRCA gene research from the Gray Foundation in 2018, a diverse team of Yale experts whose perspectives on BRCA gene-induced malignancies offer a 360 degree view from bench to bedside combined their collective skills to secure the consequential gift.
Over the next three years, the Yale team made significant progress in targeting the BRCA-dependent DNA repair axis for cancer therapy.
“Both BRCA1 and BRCA2 proteins are involved in DNA repair,” said Megan King.doctorate, Associate Professor of Cell Biology and Molecular, Cellular, and Developmental Biology, and Co-Lead of the Radiobiology and Genome Integrity Research Program at Yale Cancer Center. “However, the work we’ve done has shown us that they have fundamentally different mechanisms. This is important because typically in clinical trials we group patients with BRCA1 and BRCA2 mutations. We need to think differently about these patient populations.
These mechanisms affect the type of therapies that might work once cancer patients relapse on PARP inhibitors, a treatment that prevents PARP proteins from repairing DNA damage in cancer cells and leads to cell death. For example, King identified that if BRCA1 tumors stop expressing the 53BP1 or REV7 protein, both of which play a role in DNA double-strand break repair, they become resistant to PARP inhibitors. This is because the absence of these proteins allows a third enzyme, called the Bloom Syndrome Protein (BLM), to not only resume resecting DNA double-strand breaks, but also to go into excessive repair, called “hyper-resection”.
King’s research has identified BLM as a novel therapeutic target. She already has a candidate in mind for the job: a new class of drugs called ATR kinase inhibitors. ATR kinase communicates DNA damage to the cell and activates DNA damage checkpoints, which halt the cell cycle to allow time for repairs.
“BLM’s hyper-resection is a vulnerability that makes it susceptible to ATR inhibitors,” King explained. She is working on the design of a clinical trial of ATR inhibitors in BRCA1 patients with Patricia LoRusso, DO, Gray Foundation team member, professor of medicine and associate director of the Experimental Cancer Center.
The team’s expert – and a global expert – on BRCA2 is Ryan Jensendoctorate, lecturer in therapeutic radiology and pathology. He was the first scientist to purify and study the properties of the full-length BRCA2 protein. In collaboration with AstraZeneca, Jensen focused on three BRCA2 reversion alleles, containing deletions in the BRCA2 gene that reactivate DNA repair functions, in the DNA of tumor cells from patients with prostate cancer. the ovary who relapsed with a PARP inhibitor.
He is currently investigating whether these alleles alone cause resistance to PARP inhibitors and other cancer treatments. Therefore, these studies could have an impact on the clinical management of patients with BRCA2 mutations. Additionally, by taking advantage of BRCA2 genetic changes directly in patients, Jensen’s team hopes this “reverse translation” approach will accelerate our understanding of why BRCA2 plays such a crucial role in the response to PARP inhibitors. .
Enter Bindra, whose expertise in drug development leads to the translation of these laboratory targets into therapies for patients. Its high-throughput testing capabilities allow it to perform 96- and 384-well plate screening assays in PARP-naive and resistant cell lines. Where it previously took a day to analyze one well of a microplate, Bindra can now examine 384 tiny wells overnight and analyze the images and automatically discover patterns.
Even more exciting is Bindra’s comprehensive library of DNA repair inhibitors and harmful agents. He mixes and combines them in new therapeutic combinations to create new compounds that can synergize or replace current PARP inhibitors.
“When we perform these tests in an academic rather than a pharmaceutical setting, we are able to profile all drug candidates and focus unbiasedly on the best combinations moving forward,” Bindra said. “This is not some fancy scientific investigation. Because they are clinically focused, these new combinations can be clinically tested within one to two years.
Bindra’s cell lines have proven invaluable in Yale’s DNA repair research beyond the limits of the Gray Foundation grant.
faye rogersPhD, Associate Professor of Therapeutic Radiology, brings her knowledge of DNA damage repair to the Gray Foundation team, but also pursues many other research projects. She exploited the library for a cell line in her research on the use of endophytes to develop new anti-cancer compounds. Endophytes are fungi or bacteria that live in symbiosis with plants and can produce the same natural products as their host plant. They are known as an untapped source for finding new bioactive natural products.
An undergraduate in Rogers’ lab collected endophytes to study in Ecuador with Yale’s Rainforest Expedition and Laboratory Course. Rogers has identified one that produces a compound that inhibits DNA double-strand break repair in cancers with repair deficiencies, such as PTEN-deficient glioblastomas. “We are now moving forward to provide a synthetic version of this compound and perform medicinal chemistry to improve its efficacy,” she said.
Rogers returned the favor to Bindra’s library. She advised Binda students on how to synthesize new classes of DNA repair inhibitors and noxious agents that will further expand Bindra’s capabilities for testing new compounds. Their teamwork is an example of the interdisciplinary collaboration exemplified by the Gray Foundation team.
“When you bring people together with different skills and perspectives,” Bindra said, “it adds so much more value to the conversation.” And adds even more invaluable tools to Yale’s DNA repair arsenal.
Originally published Feb 25, 2021; updated May 16, 2022.