The AACR-Genentech BioOncology Career Development Award for Cancer Research on the HER Family Pathway represents a joint effort to encourage and support junior faculty who are in the first four years of a faculty appointment (at the start of the grant term) to conduct cancer research on the HER family pathway and establish successful career paths in this field. Proposed research projects are restricted to basic, translational, clinical or epidemiological projects that substantially advance the field of cancer research on the HER family pathway.
Eddy Shih-Hsin Yang, M.D., Ph.D.
Assistant Professor, Comprehensive Cancer Center of the University of Alabama, Birmingham, AL
HER2 Overexpression Confers Susceptibility to PARP Inhibition
"The human epidermal growth factor receptor (EGFR, HER) superfamily modulates tumor proliferation, differentiation and survival, and has been a heavily targeted pathway in cancer therapeutics. Specifically, in approximately 20-30 percent of breast cancers, amplification and/or overexpression of HER2/ErbB2 portends a more aggressive phenotype and worse prognosis, and with targeted agents against HER2 such as trastuzumab and lapatinib, improved outcomes are being achieved. Unfortunately, many patients will ultimately relapse and fail therapy, thus necessitating novel therapeutic strategies.
"Recent attention has been given to the poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) due to their selective targeting of DNA repair deficient tumors, such as the BRCA-associated cancers. Importantly, these agents are very well tolerated with minimal side effects. Additionally, combinations of PARP inhibitors and DNA damaging agents such as chemotherapy or radiation have shown initial promise.
"My laboratory recently reported that a contextual synthetic lethality could be achieved with combination HER and PARP inhibition in multiple tumor types. Interestingly, in assessing this strategy in human HER2+ breast tumors, we made the unexpected observation that HER2+ breast cancers are exquisitely susceptible to PARPi as a single agent both in vitro and in vivo despite being DNA repair proficient. These results suggest the intriguing and novel possibility that susceptibility to PARPi may NOT be solely dependent on DNA repair mechanisms.
"Thus, the goals of this project are to investigate the mechanisms by which HER2+ breast cancer cells are susceptible to PARPi alone and to further validate this susceptibility in vivo. We will also assess whether the addition of PARPi to HER2 targeted agents can further delay the growth of tumors or suppress the onset of resistance to HER2 targeted therapy.
"Together, this research may potentially establish a novel therapeutic strategy against HER2 positive breast cancer. Importantly, because these are two very well tolerated agents, translation of this treatment strategy, if validated, can be tested to improve response and cure rates while reducing toxicities for HER2+ breast cancer patients. The generous support from the AACR-Genentech BioOncology Career Development Award for Cancer Research on the HER Family Pathway will be invaluable to achieve these goals and foster my career development as a physician-scientist in cancer research."
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