Targeting estrogen receptor alpha (ER?) is a major anticancer strategy in the treatment of ER?-positive breast cancer. However, current targeted therapies for ER? have only cytostatic activity and do not induce rapid quantitative killing of cancer cells, ultimately leading to resistance. A major resistance mechanism is ER? mutation leading to constitutively activation that drives tumor growth and metastasis, with Y537S and D538G accounting for the majority of driver mutations. These resistant tumors maintain overexpression of ER?, suggesting an opportunity to develop novel small molecules that can leverage aberrant ER?WT/Mut expression. We have discovered one such compound, ErSO, that has profound cytotoxic activity against ER?WT/Mut positive cancer cells, via rapid activation of the ER?WT/Mut-dependent anticipatory unfolded protein response (aUPR). The power of this cytotoxic activity has been observed with multiple examples of complete eradications of ER?WT/Mut-positive breast tumors in orthotopic and metastatic murine models. While there is a high translational potential for ErSO with a Phase 1 clinical trial planned for 2020, herein we discuss features of ErSO that demonstrate ErSO may only be an ideal candidate treating brain metastases. There is ample need for a second- generation ErSO with better pharmacokinetic properties and safer toxicity profile for the treatment of ER?- positive cancer. Planned work (F99 phase) consists of synthesizing more polar derivatives of ErSO, which will be assessed in mechanistic studies, in vivo tolerability, blood-brain barrier penetration, and efficacy models. These second generation compounds will likely have increased bioavailability, minimal neurotoxicity, and a safer toxicity profile, enabling their translational potential for addressing the treatment of ER?-positive cancer. While targeted anticancer therapy has altered the clinical landscape for challenging cancers, hepatocellular carcinoma (HCC) remains highly lethal with a rising mortality and incidence rate. HCC is vastly heterogenous disease with the only conserved driver mutations found in TERT and CTNNB1, which currently lie in the ?undruggable? target space. Herein, I describe efforts study CTNNB1 mutant allele imbalance (MAI) as a measure of CTNNB1 oncogenic addiction and propose in-depth cellular studies to annotate the impact of CTNNB1 MAI on oncogenic metabolism (K00 Phase). This exploration will provide insights into potential therapeutic targets for the treatment of HCC. These F99/K00 proposals seek produce a well-rounded, in-depth skill set to prepare me for success as an independent PI. Specifically, the F99 proposed work will refine my work in drug discovery and small molecule development. Planned K00 work will expand my expertise with new experiences in managing complex data sets to elucidate conclusions about fundamental cancer biology. Completion of this training will produce a powerful basis for my career in developing novel translational solutions for clinical oncology.
ER?-positive cancers remain a major clinical need and proposed herein (F99) we seek to explore novel derivatives of ErSO, our newly discovered cytotoxic drug for the treatment of ER?-positive breast cancers. Further, hepatocellular carcinoma is a highly lethal cancer type with a major breakthrough for disease management yet to be elucidated. This proposal (K00) seeks to address this clinical need via study of the mutant allele imbalance (MAI) of CTNNB1 oncogenic mutations, studying this imbalance on tumor metabolism, and ultimately provide insights into CTNNB1 MAI with implications for targeted therapies for hepatocellular carcinoma.