PROJECT SUMMARY / ABSTRACT
Clinical significance: Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and
represents 15-20% of new cases (1). Given that TNBC lacks molecular expression of hormonal receptors and
HER2 amplification, chemotherapy remains the go-to treatment option (2). The prognosis for TNBC patients is
grim, and after initial surgery/chemotherapy, patients often relapse with metastases to lung, brain, liver, and
bone (3). Understanding the mechanisms that govern TNBC progression and metastasis can reveal new targets
for therapeutic intervention which is an urgent and unmet clinical need for this patient population (4,5).
Rationale: Autophagy is a metabolic program that is highly utilized by TNBC cells to survive, particularly upon
exposure to chemotherapy (6). While reagents such as chloroquine can block autophagy, their clinical impact is
yet to be realized due to unknown mechanisms of action and toxicity (7,8). However, focusing on specific key
nodes that regulate the program with highly selective inhibitors is possible. Investigating upstream initiators of
the autophagy program, emerging evidence from our group demonstrates that Unc-51 like kinase 3 (ULK3)
expression, as opposed to the more commonly studied ULK1, correlates with TNBC aggressiveness. Further,
genetic analyses confirm a key role for ULK3 in controlling TNBC autophagy and survival. No ULK3 inhibitors
currently exist but excitingly, we have generated novel ULK3 selective inhibitors that are effective in preliminary
in vitro experiments. Here, we plan to focus on our lead ULK3 inhibitor, RF1024, to test our hypothesis that ULK3
is a tractable and therapeutic target for the effective treatment of triple negative breast cancer.
Proposed studies: In Aim 1 we will assess the efficacy of RF1024 in limiting TNBC growth in vitro using
immortalized cell lines and in vivo using two preclinical metastatic TNBC models (4T1, SUM159). In Aim 2, we
will determine ULK3 expression in TNBC patients. We will also investigate autophagy status and ULK3 levels as
a response/prognosis biomarker in a robust data set of TNBC patient biopsies. We propose to determine a
retrospective study (patient samples from 2010 - to date) on TNBC patient specimens collected at Moffitt with
the purpose to validate for the first time ULK3 protein as a possible biomarker. At the conclusion of our studies,
we expect to have fully interrogated the efficacy of a novel ULK3 inhibitor that can be rapidly translated to the
clinical setting for the treatment of TNBC patients