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Darren Carpizo, MD, PhD
Professor, Department of Surgery
University of Rochester Medical Center
Rochester, New York
Goal: To identify novel anti-cancer drugs for aggressive breast cancers, such as triple-negative and BRCA-driven breast cancers.
Impact: Many cancers develop mutations in a tumor suppressor gene called TP53. In its normal form, TP53 prevents cancer formation by forcing cells with unrepairable DNA damage to self-destruct, thereby preventing the cell from dividing and passing the damaged DNA to new cells. When TP53 becomes mutated, this protection goes away allowing these cells to divide and form tumors. Drs. Carpizo and Ganesan have developed a class of drugs called zinc metallochaperones (ZMCs) that can restore the normal activity of mutated TP53. Their work may lead to new, targeted approaches for very aggressive breast cancers.
What’s next: The team continues to test of ZMCs in combination with other therapies, including PARP inhibitors, as well as with chemotherapy and radiation, which are standard treatment for patients with TNBC.
Mutation of the tumor suppressor gene TP53 is common in many cancers. Drs. Carpizo and Ganesan have identified a new class of anti-cancer drugs called zinc metallochaperones (ZMCs) that target tumors with mutations in TP53, a potent suppressor of tumor growth, and are currently testing its efficacy in combination with other therapies.
Full Research Summary
Research area: Identifying new targeted therapies for very aggressive breast cancers.
Impact: People who have inherited mutations in the BRCA gene have a high risk of developing breast cancer. Most BRCA breast cancers tend to be of the triple-negative (TNBC) subtype, which is particularly aggressive and lacks targeted therapy options. Drs. Carpizo and Ganesan have identified a new class of anti-cancer drugs called zinc metallochaperones (ZMCs) that target tumors with mutations in TP53, a potent suppressor of tumor growth. If proven effective, this could provide another option for patients with aggressive breast cancers.
Current investigation: The team has been conducting laboratory studies to test ZMC inhibitors in combination with PARP inhibitors and chemotherapies in models of TNBC and BRCA-driven breast cancer.
What they’ve learned so far: Drs. Carpizo and Ganesan found that ZMCs in combination with PARP inhibitors are more effective than either agent alone against tumors with BRCA1 mutations. They also discovered that these drugs can be made more effective by adding zinc to the formulation, and they now have novel zinc-loaded compounds that can potentially be brought to the clinic. In addition, they recently found a new class of ZMCs that are synergistic with chemotherapy and radiation.
What’s next: The team will test combination ZMC-PARP inhibitor and ZMC-chemotherapy and radiation therapies in laboratory models of breast cancer with BRCA1 mutations.
Darren Carpizo, MD, PhD, is a surgical oncologist specializing in the management of hepato-biliary and pancreatic cancers. Seventy-five percent of his time is devoted to laboratory research in the area of Developmental Therapeutics in both the basic and translational science arenas. Dr. Carpizo’s laboratory recently made a significant contribution to the field of p53 targeted drug development by identifying a lead compound that reactivates mutant p53. He is currently leading a multi-disciplinary group of investigators studying the mechanism of the mutant p53 reactivating drug which including biochemists, structural biologists and medicinal chemists. He is also leading a translational clinical trial to understand the mechanism of action of Hedgehog inhibitors in patients with surgically resectable pancreatic cancer.