PHILADELPHIA – Cancer researchers from the Perelman School of Medicine at the University of Pennsylvania and the Basser Center for BRCA in the Abramson Cancer Center of the University of Pennsylvania, have received two major grants from the V Foundation for Cancer Research. Funded projects will work to better understand and treat cancers in patients with inherited mutations of the BRCA1 and BRCA2 genes, which produce tumor-suppressor proteins. These mutations significantly increase the risk for breast and ovarian cancer as well as other types of cancer in women and men.
The first grant, a three-year, $2.1 M Team Science Convergence Award, will be led by Roger A. Greenberg, MD, PHD, a professor of Cancer Biology, and Katherine L. Nathanson, MD, a professor of Medicine and Genetics. Comprising scientists and physicians from a number of schools, departments, and divisions at Penn, the team will seek to ultimately enhance the effectiveness of drugs called PARP inhibitors. PARP (poly-ADP ribose polymerase) is a protein that helps damaged cells repair themselves. In patients with cancer, PARP inhibitors stop PARP from repairing cancer cells, effectively killing them. These oral medications are effective and generally have fewer side effects than chemotherapy; however, they don’t work in all patients and resistance often develops.
Using sophisticated sequencing techniques, the Penn team will analyze primary tumors in patients with BRCA1/2 mutations, to identify small groups of cancer cells called “subclones” that resist PARP inhibitors and medications such as platinum-based chemotherapeutics. They aim to pinpoint the mechanisms behind this resistance.
Subclones are genetically distinct cancer cells that have varying genetic makeups that allow a subset of them to become resistant to targeted therapies, driving tumor formation and growth. The result is the major limitation to the clinical effectiveness of PARP inhibitors and platinum therapies in treating BRCA-related cancers.
Depending on the specific genetic characteristics of a particular subclone group of cells, many possibilities exist for targeted resistance at the single-cell level in complex tumors. Under the grant, the investigators will test their hypothesis that DNA repair-deficiency in PARP-sensitive cells can direct immune cells against resistant subclones in tumors. The hypothesis is based on proof of concept studies from Greenberg’s lab, published recently in the journal Nature, which described mechanisms of communication between DNA damage and immune responses that can promote anti-tumor immunity.
The second study, a three-year, $600,000 award, will be conducted by Fiona Simpkins, MD, an assistant professor of Obstetrics and Gynecology at the Hospital of the University of Pennsylvania, Eric J. Brown, PhD, an associate professor of Cancer Biology, and Payal Shah, MD, an assistant professor of Hematology Oncology. Like the Team Science Award, this project centers on resistance to PARP inhibitors, but focuses specifically on designing and optimizing a combination treatment strategy to improve patient outcomes.
Laboratory data from Simpkins and Brown show that a protein called ATR kinase is a promising key to overcoming PARP inhibitor resistance. The group found that combining PARP and ATR inhibition causes complete tumor regression in BRCA-associated ovarian cancer animal models, an effect that is superior to that observed with PARP alone.
To translate these novel findings into better treatment outcomes, Simpkins and Shah are leading a clinical trial that studies the PARP inhibitor olaparib combined with an ATR inhibitor in patients with advanced ovarian cancer, in whom other treatments have failed. Since the genetic makeup of ovarian cancer differs from one patient’s cancer to the next potentially impacting treatment responses, the team will use sophisticated genomic and protein-based techniques to analyze tumors for markers that best predict benefit from treatment.
Tumor samples from patients enrolled on the clinical trial will be used to create the most molecularly-defined ovarian cancer animal models to date, allowing researchers to observe the effects of multiple variations of the treatment on a single patient’s tumor. Notably, the team’s use of novel protein-based techniques to better understand exactly how the ATR and PARP inhibitors work together will pave the way for further improvements of this therapeutic strategy. Ultimately, the clinical trial and accompanying studies aim to overcome PARP inhibitor resistance and to optimize the PARP and ATR inhibitor combination strategies for individual patients.
The team’s goal is to develop the most effective and well-tolerated treatment for BRCA1/2-mutant ovarian cancers. The clinical trial is underway and actively recruiting new patients.
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