David J. Shapiro
Estrogens, acting via estrogen receptor a (ERa), play a key role in most breast cancers. The Shapiro laboratory has leveraged its expertise in ERa action in cancer to identify new pathways of hormone action that drive proliferation, metastases and therapy resistance and new types of selective anticancer therapeutics. They have identified a pathway conserved from insects to humans, and between steroid hormones and peptide hormones in which mitogenic hormones, such as estrogen, and epidermal growth factor (EGF), elicit extremely rapid anticipatory activation of the stress sensor, the unfolded protein response (UPR). UPR activation is protective and is a powerful new prognostic marker in ERa positive breast cancer. We target this pathway with our medically promising ERa biomodulator, BHPI, which uses the same UPR pathway as estrogen, but induces toxic UPR hyperactivation. BHPI’s action is distinct from endocrine therapies; it kills therapy resistant ERa positive cancer cells, including cells expressing recently described ERa mutations. In xenografts, BHPI induces rapid and dramatic regression of breast cancer and eradicates multidrug resistant ovarian tumors. With our collaborators we are moving toward clinical trials and working to understand how the anticipatory UPR pathways controls proliferation and therapy resistance in ERa positive breast, ovarian and endometrial cancer cells.