Natalia Jura, Assistant Professor at UCSF, in collaboration with Nevan Krogan, Jennifer Grandis and Silvio Gutkind. The receptor tyrosine kinase HER3 is a multi-site scaffold for the phosphoinositide-3 kinase (PI3K), whose downstream signaling to Akt constitutes one of the most frequently deregulated pathway in human cancer, including head and neck cancer. Recent studies in the Krogan and Grandis laboratories found that a subset of PI3KCA mutations present in head and neck cancer cells preferentially associate with HER3. Moreover, the Gutkind lab showed that these PI3KCA mutants are dependent on HER3 binding to elicit its oncogenic signaling. These exciting findings point to a unique mechanism by which HER3 activates PI3KCA, whose understanding will help develop personalized therapies for the affected patients. At present, the nature of this selectivity is unknown due to the lack of direct insights into the mechanism of PI3KCA/HER3 binding. This project seeks to address this gap through the biophysical and structural characterization of the PI3KCA/HER3 interaction and its modulation by the cancer mutations. The proposed work will provide a platform for the development of specific inhibitors that disrupt the signaling junction between HER3 and PI3K in disease.

Olivier Harismendy, Associate Professor at UC San Diego, in collaboration with Laura Esserman. The widespread adoption of breast cancer screening has increased the detection of premalignant lesions. Although most of these lesions will not become invasive, almost all patients are treated with surgery and radiation. A major challenge now is to better identify patients with lesions that are less likely to progress so to prevent their overtreatment.

Polygenic risk scores have recently been shown to accurately represent risk using common SNPs. This approach is applicable to all women regardless of their family history and is intended to capture a woman’s genetic risk outside of the rare, highly penetrant genes such as BRCA1/2. In this work, we will compare the breast cancer polygenic risk scores of patients with premalignant lesions who have developed invasive carcinomas with patients who have not. The study will use samples from the ATHENA DCIS registry established between UCSF and UC San Diego which contains data for 4,944 patients diagnosed with premalignant lesions between 1986 and 2016. Retrospective registries with well annotated follow-up such as this are extremely rare. We hope that our analysis of these samples will result in a accurate model of premalignant lesion progression in breast cancer.