Amy Yee

A. HBP1, Breast Cancer and Tumor Suppresssion. We are investigating new molecular mechanisms of tumor suppression to design new diagnostic and therapeutic strategies in breast cancer. We combine investigations in signaling pathways and in transcriptional regulation with directed clinical studies. We focus on the Wnt pathway, which has emerged as a major pathway in breast and other cancers, and HBP1, as a transcriptional repressor that is also a suppressor of Wnt signaling. HBP1 mutations are clinically associated with invasive breast cancer. Thus, HBP1 is a new tumor suppressor gene with clinical and molecular impact on invasive breast cancer.

B. Tumor-Immune Interactions and Therapeutics. Our recent work addresses the tumor and local immune cell interactions and strategies to improve immune checkpoint inhibitor(ICI) actions. While ICIs are effective in some cancers, ~75% of patients have no-to-modest responses with limiting side effects—due to immunologically "cold" tumors. There are no approved therapeutics that trigger "cold-to-hot" transitions and resulting ICI susceptibility. We focus on triple negative breast cancers (TNBC) with brain metasases. Our lead compound CHA1 pre-clinically induces cold-to-hot reprogramming of the tumor and immune environment, while priming for maximal ICI efficacy. CHa1 additionally attenuates TNBC brain metasases because the constituents of CHA1 cross the blood brain barrier. We have elaborated a complex mechanism with features of epigenetics, Wnt and interferon signaling. Our Epigenetics-Plus platform features multi-factorial quantitative criteria for future discovery. We are using thoughtful design, rigorous science, and patient safety considerations to advance new therapeutics into human clinical trials and to improve outcomes for breast and other cancer patients.

C. Wnt Signaling and Genetic Epilepsies. Our recent work has delineated an intricate role for HBP1 and Wnt signaling in epileptogenesis in pre-clinical and experimental models. Elevated Wnt signaling and a novel Warburg effect is part of the early epileptogenic mechanisms in a pilocarpine-induced model. While the Warburg effect is usually associated with tumors, we delineated a composite Warburg effect that occurred in the glial and neuronal cells of the hippocampus. A primary role for Wnt signaling is the induction of a Warburg metabolism that is centered around pyruvate dehydrogenase, a gatekeeeper enzyme between a glycolytic and an oxidative metabolism. Pharmacological attenuation of Wnt signalling in early epileptogenesis delays or eliminates the onset of chronic seizures, underscoring the importance of Wnt signaling in the etiology of epilepsies.

HBP1 and Genetic Epilepsies. Genetic epilepsies are rare disease, but understanding the mechanism is central to defining susceptibility mechanisms for epilepsy onset. Two lines of inquiry led us to investigate a possible role of HBP1 and Wnt signaling as a mechanism for genetic epilepsies. By our observations, HBP1 lies in a region of ~10 genes that is associated with genetic epilepsies. Our mouse deleted in HBP1 undergoes spontaneous seizures with the hallmarks of recurrent seizures in their brains. We have recently identified eight HBP1 gene mutations in a cohort of pediatric epilepsy patients and are investigating their functions. By combining biochemistry and the new human genetics, we seek to understand the basis of the HBP1 gene, Wnt signaling and other key pathways in the etiology of epileptogenesis to gain insights into devastating pediatric epilepsies.