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.
Hanna Yoko Irie, M.D., Ph.D.
Assistant Professor of Medicine, Mount Sinai School of Medicine (Tisch Cancer Institute), New York, NY
Novel Strategies to Overcome Her2 Targeted Therapy Resistance
"Despite advances in screening and detection, nearly 40,000 women die yearly of breast cancer, mostly from treatment-resistant, metastatic disease. This mandates an improved understanding of the processes that regulate metastatic potential, as well as identification of novel therapeutic strategies tailored for individual patients. For patients with Her2+ breast cancers, targeted therapies including antibodies (Herceptin) and small molecule inhibitors (Lapatinib) have been incorporated into standard of care with improvement in patient outcomes. However, responses are not uniform and often incomplete, as evidenced by recurrent or progressive disease; strategies to enhance sensitivity to or overcome resistance to these therapies are needed. My laboratory utilizes an integrated approach to developing therapeutic strategies for treatment-refractory Her2+ breast cancers; we combine tumor genetic data with functional genomic and proteomic screens to understand the diverse mechanisms by which Her2+ breast cancer cells evade therapies, identify promising novel candidate therapeutic targets and develop biomarkers to identify individual Her2+ tumors that will respond to specific target inhibition.
"The AACR-Genentech BioOncology Career Development Award will enable in-depth evaluation of novel regulators of Her2+ breast cancer cell survival as candidate therapeutic targets. We identified these candidates in a genomic screen and include genes that regulate survival of Her2+ breast cancer cells that are resistant to Lapatinib, either intrinsically or acquired through continuous drug exposure. These candidates will be evaluated for their role in in vivo tumor growth and metastasis formation. Several of these validated candidates are amplified in Her2+ breast tumors and will also be evaluated as prognostic biomarkers. In addition, this screen has provided insight into novel mechanisms by which sensitivity to Lapatinib treatment is regulated, and these mechanisms will be further elucidated.
"This award will allow me as a physician-scientist and medical oncologist to continue to pursue an active, independent laboratory-based research program while caring for patients at the Dubin Breast Center of the Icahn School of Medicine at Mount Sinai. My patients have always helped me focus my research questions on unmet clinical challenges that many of them face during the course of their care. The award will help support the pre-clinical studies needed to evaluate novel therapeutic strategies for refractory Her2+ breast cancer and to position them for rapid clinical translation."
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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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