Combating Recalcitrant Cancer Types Through Rational Engineering of Antibody-Drug Conjugates
Abstract
I aim to become a leading investigator in the fields of antibody therapeutics, drug discovery, and the tumor microenvironment. I am particularly interested in applying my knowledge in this area to develop improved strategies for treatment of recalcitrant tumors, especially high-risk pediatric neuroblastoma and adult pancreatic cancer. My research strategy has two key goals: (1) delineate key molecular drivers or “hallmarks” of tumor and tumor microenvironment in order to discover optimal targets for cancer therapy and (2) develop antibody-based therapeutics to leverage these discoveries towards the clinic. My postdoctoral research has been focused on exploiting a subset of cancer-associated cell surface markers that allows for precise targeting of multiple different cancer types. Working in Dr. St. Croix’s laboratory at the National Cancer Institute (NCI) has provided me with access to world-class experts in neuroblastoma and pancreatic cancer. The Horizon Award will allow me to interact with these experts and become a leader in the research and treatment of these underserved cancers. Neuroblastoma is the most common cancer in infancy and the most prevalent solid tumor outside the cranium. The 5-year survival rate for this disease is between 40% and 50%. Pancreatic cancer is the fourth most frequent cause of cancer-related deaths and has a 5-year survival rate under 10%. Curative therapy for pancreatic cancer requires complete removal of the primary tumor but, unfortunately, in most patients the disease has already invaded or spread to other tissues at the time of diagnosis. Conventional chemotherapy is largely ineffective for both high-risk neuroblastoma and pancreatic cancer, which highlights the urgent need for improved therapies for both cancer types. This work encompasses three of the aims of the FY19 Peer Reviewed Cancer Research Program Horizon Award topic areas: “Neuroblastoma,” “Pancreatic Cancer,” and “Immunotherapy.” I am fortunate to work in the Tumor Angiogenesis Unit at the NCI. Angiogenesis, or new blood vessel formation, is a hallmark of cancer and provides expanding tumors with the vital oxygen and nutrients they need to grow. Previously, the Tumor Angiogenesis Unit discovered several markers that are overexpressed on the surface of the endothelial cells that line the tumor vasculature. One of these markers, called CD276, has become an attractive therapeutic target because it is overexpressed on the vessels of most solid tumors. In many cancer types, including neuroblastoma and pancreatic cancer, the tumor cells themselves also often overexpress CD276. Therefore, agents that can selectively bind to CD276, such as antibodies, can potentially be used to deliver drugs to both the tumor cells, and the tumor-associated vasculature. The frequent upregulation of CD276 in tumors, coupled with its low to undetectable expression in normal tissues, suggested it may represent an Achilles heel for targeted cancer therapy. Previous work from our group generated an antibody-drug conjugate (ADC) targeting CD276 which, in preclinical studies, was able to eradicate small tumors of multiple cancer types. This ADC used pyrrolobenzodiazepine (PBD), a potent DNA damaging agent, as the drug payload. However, this ADC displayed some off-target toxicity, was unable to cure mice of large tumors, and was ineffective against pancreatic cancer. I propose three aims to further leverage CD276 as a target for cancer therapy: (1) use high throughput gene expression tools to uncover molecular mechanisms that induce CD276 expression in tumors, (2) produce next-generation ADCs via chemical and genetic engineering to improve potency, reduce off-target toxicity, and increase drug stability and, (3) generate a new CD276 ADC utilizing the deathcap mushroom toxin amanitin to specifically target pancreatic cancer. While neuroblastoma cells are rapidly killed by our initial PBD payload, pancreatic tumors are intrinsically resistant. Aman
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010872
Entities
People
- James Dunleavey
Organizations
- National Cancer Institute
- United States Army