Associate Director for Translational Science
Associate Professor of Medicine
Rutgers Robert Wood Johnson Medical School
Chief, Molecular Oncology
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey
Areas of Focus: Treatment, Tumor Biology
Co-Investigator: Darren Carpizo, MD, PhD, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey
To identify novel anti-cancer drugs for aggressive breast cancers, such as triple negative and BRCA-driven breast cancers.
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. Ganesan and Carpizo 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.
The team continues to conduct laboratory tests of ZMCs. This year they will test it in combination with other therapies including chemotherapy and radiation, which are standard treatment for patients with TNBC.
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 approved targeted therapies. Drs. Ganesan and Carpizo 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 laboratory studies.
Full Research Summary
FULL RESEARCH SUMMARY
Research area: Identifying new targeted therapies for very aggressive breast cancers.
Impact: New therapies are urgently needed for patients with triple negative breast cancer (TNBC), which tends to grow faster than other subtypes of the disease and has a poorer prognosis. While some patients with TNBC may benefit from the new PARP inhibitors or immunotherapies, most patients will receive standard chemotherapy and radiations. Drs. Ganesan and Carpizo are focused on the gene TP53, which is often mutated in TNBC as well as in BRCA1 cancers. They have identified a new class of anti-cancer drugs called zinc metallochaperones (ZMCs) that target tumors with mutations in TP53. 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 other therapies in models of TNBC and BRCA-driven breast cancer.
What they’ve learned so far: Drs. Ganesan and Carpizo found that ZMCs are particularly effective in tumors with BRCA1 mutations both alone and in combination with PARP inhibitors. 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 both the zinc-loaded compounds and synergistic ZMCs in laboratory models of breast cancer with BRCA1 mutations.
Dr. Shridar Ganesan is the Associate Director for Translational Science at the Rutgers Cancer Institute of New Jersey, Chief of the Section of Molecular Oncology, and Associate Professor of Medicine at the Rutgers Robert Wood Johnson Medical School. Dr. Ganesan received an A.B. from Princeton University, and completed his medical and graduate studies at Yale University, followed by post-graduate and post-doctoral training at the Brigham and Women’s Hospital and the Dana Farber Cancer Institute.
He is a medical oncologist with clinical interest in triple-negative breast cancer and rare cancers. His research interests include genomic classification of cancer and investigations of mechanisms of DNA repair with a focus on the biology of BRCA1 and BRCA2 and their role in genomic and epigenetic stability. The overall goal of this project is to better understand the genomic evolution of cancers and develop novel targeted therapeutic strategies.