Project Summary & Abstract
Targeting estrogen receptor alpha (ERa) is a major anticancer strategy in the treatment of ERa-positive
breast cancer. However, current targeted therapies for ERa have only cytostatic activity and do not induce rapid
quantitative killing of cancer cells, ultimately leading to resistance. A major resistance mechanism is ERa
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 ERa,
suggesting an opportunity to develop novel small molecules that can leverage aberrant ERaWT/Mut expression.
We have discovered one such compound, ErSO, that has profound cytotoxic activity against ERaWT/Mut
positive cancer cells, via rapid activation of the ERaWT/Mut-dependent anticipatory unfolded protein response
(aUPR). The power of this cytotoxic activity has been observed with multiple examples of complete eradications
of ERaWT/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 ERa-
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 ERa-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.