One in every eight women in the United States will develop breast cancer throughout her lifetime, sadly making breast cancer the most common malignancy in women worldwide. Between 15-20% of all breast cancers are classified as human epidermal growth factor 2 (HER2)-positive. HER2-positive breast cancers are caused by the amplification of the erythroblastic oncogene B (ERBB2) oncogene.  When the ERBB2 oncogene is amplified, it disrupts normal cell control and growth mechanisms and instead gives rise to aggressive ERBB2-positive breast cancer cells.

(Image credit to Ana Escalante)

(Image credit to Ana Escalante)

Current Food and Drug Administration (FDA)-approved anti-ERBB2 therapies include anti-ERBB2 monoclonal antibodies and small molecule ERBB2 kinase-inhibiting drugs. However, even when combined with taxane-based chemotherapy, these therapies often lead to treatment resistance because they all target the ERBB2 receptor on the cell membrane. This clinical resistance demonstrates the need for alternative therapies: one option currently being undertaken is to inhibit the ERBB2 protein expression pathway much earlier on. This can be done by epigenetically inhibiting the ERBB2 mRNA within the nucleus, a process called "nuclear ERBB2 mRNA decay."

Under the mentorship of Dr. Chris Benz and Dr. Gary Scott in the Benz Lab at the Buck Institute for Research on Aging, I am researching the efficacy of two novel P300/CBP domain inhibitors. The proteins P300 and CBP are both transcriptional regulators of nuclear ERBB2 mRNA, so we can achieve nuclear ERBB2 mRNA decay by inhibiting specific domains of these proteins. The first drug candidate, NEO-2734, is a bromodomain (Brd) inhibitor of P300/CBP while the second drug candidate, A-485, is a histone acetyltransferase (HAT) domain inhibitor of P300/CBP. To investigate the anti-ERBB2 therapeutic potential of both NEO-2734 and A-485 in vivo, we are using a BT-474 breast cancer mouse xenograft model developed by MuriGenics.