A 2017 AAPS Foundation fellowship recipient focuses on HER3 cancer therapy.
John Schardt is a fifth year doctoral candidate at the University of Maryland, working with advisor Steven M. Jay, Ph.D. With the support of the AAPS Foundation, he can continue his research on Engineered Multivalency for Improved HER3 Downregulation and Cancer Therapy.
Cancer has affected me on a personal level: My grandfather had just 30 days to live after being diagnosed with leukemia, and my childhood friend and classmate beloved by our hometown community died young at age 23 after battling leiomyosarcoma for five years. My personal connection to cancer and awareness of the effects this disease exerts on patients, families, and friends provide significant motivation for our research. I hope that our research will inform and lead to the development of improved, clinically available cancer therapeutics that ultimately save lives. It is an honor and privilege to know that my efforts on a daily basis contribute in some small part to the fight against cancer, a leading killer that affects millions of individuals each year.
The receptor tyrosine kinase HER3 has emerged as a therapeutic target in multiple cancers due to its potent activation of the PI3K/Akt pathway and mediation of drug resistance. Numerous monoclonal antibody and small molecule inhibitor approaches directed at HER3 have begun to emerge but have displayed limited potency as single agents. Thus, innovative strategies to enhance the efficacy of HER3-targeted therapies are needed and would benefit a wide range of patients.
Our research seeks to evaluate the potential of multivalent presentation, through protein engineering, as a strategy to enhance the therapeutic effectiveness of HER3-targeted ligands. We have developed a novel multivalent approach designed specifically to promote HER3 sequestration, defined as the locking of HER3 into nonsignaling homotypic interactions.
Our current research demonstrates that engineered multivalent HER3 affibodies inhibit HER3 mitogenic signaling and reduce cancer cell survival more effectively than the monovalent version of the same affibody. These multivalent ligands, in contrast to monovalent versions, induce rapid and prolonged HER3 downregulation in numerous cancer cell lines. Further, combination strategies with bivalent HER3 affibodies significantly reduce the mean inhibitory concentration of several Food and Drug Administration-approved chemotherapeutics compared to monovalent affibody combination and single agent chemo treatment.
Overall, our research highlights the promise of engineered multivalency for enhanced efficacy of HER3-targeted affibodies against a variety of cancers and establishes the potential of this strategy for broad utility in myriad anticancer applications. Our ongoing research aims to position HER3 multivalent ligands for clinical translation through improved half-life and more effective combination therapy.
My ultimate career goal is to run an independent therapeutic research and development laboratory combining experimental and computational approaches toward the discovery and translation of novel protein-based pharmaceuticals aimed at treating cancer and various other pathologies. The AAPS graduate student fellowship will provide a valuable stepping-stone toward my future career in pharmaceutical research. I am thoroughly excited by the professional and research development opportunities provided through the fellowship, and I especially look forward to interacting with and learning from renowned leaders in the field of pharmaceutical science and disseminating our research at the AAPS annual meeting.
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