Development of a cell-penetrating… (R43CA265503) – Project Grant to Sapience Therapeutics, Inc.

Abstract: Dysregulation of WNT/-catenin signaling is found in more than 20% of all cancers, including 50% of breast can- cers, and contributes to cancer initiation, angiogenesis, tumor migration and metastasis. However, attempts at developing a drug to inhibit -catenin have been thwarted by the inability of small molecule inhibitors to separate -catenin's oncogenic from homeostatic functions, producing a toxic safety profile. BCL9 is a transcriptional CO-activator that regulates oncogenic SS-catenin-mediated gene transactivation. Disrup- tion of BCL9 interaction with SS-catenin results in potent inhibition of -catenin-mediated oncogenic gene trans- activation without the GI toxicity associated with loss of signaling via APC or axin. As BCL9 is highly expressed in tumors, but generally not normal cells, the SS-catenin interaction with BCL9 represents an attractive, novel therapeutic target. Based on the above, we hypothesize that a peptide antagonist of SS-catenin interaction with BCL9 will prove a safe and effective strategy for WNT-driven cancers. Sapience has designed and synthesized a panel of SS-catenin antagonist peptides (bcaps) to disrupt the inter- action of SS-catenin with BCL9, in which we introduced amino acid substitutions to the native BCL9 HD2 domain to enhance target affinity, included a non-toxic cell penetrating domain (CPD) for intracellular entry and d-amino acids to protect from proteolysis and confer chemical stability. Through structure-activity relationship (SAR)- based design, we developed a lead candidate, bcap-58, with improved potency in vitro and in vivo. Through this sbir program, we propose to develop an innovative inhibitor of -catenin/BCL9 interaction as a therapeutic for WNT/-catenin-driven cancers, starting with breast cancer. We propose to characterize the in vitro (specific aim #1) and in vivo (specific aim #2) activity of bcap-58. Initial experiments will evaluate the binding affinity of bcap-58 with -catenin (aim 1.1). Subsequently, the impact of bcap-58 on WNT/SS-catenin activity will be determined by topflash reporter, SS-catenin phosphorylation and SS-catenin subcellular localization (aim 1.2). Finally, we will test the impact and target specificity of bcap-58 on SS-catenin-target gene expression by qpcr (aim 1.3), and on cell proliferation and viability (aim 1.4), against a panel of WNT-dependent or -independent cell lines of various breast cancer subtypes and patient-derived tumoroids. To establish proof of concept for bcap- 58 as a therapeutic for WNT-dependent breast cancer, we will assess its repeat-dose toxicity and in vivo efficacy. First, we will establish a no adverse effect level (noael) and PK profile in mice, to define the upper dosing limit (aim 2.1). Next, we will investigate the dose-dependent activity of bcap-58 in mouse models of the subtypes that demonstrate susceptibility to bcap-58 in aim 1 (aim 2.2). Finally, we will characterize the impact of bcap- 58 on SS-catenin-mediated gene transactivation in vivo (aim 2.3). Successful results will validate advancing bcap-58 to IND-enabling preclinical evaluation, identify a maximally effective regimen and support a subsequent phase II proposal, in support of an IND application.

Action	Federal	Non-federal	Date
Amendment	$0	$0	Jul 26, 2023
Amendment	$409,295	$0	Sep 2, 2021
Original award	$409,295	$409,295	Sep 2, 2021

Development of a cell-penetrating beta-catenin antagonist peptide as a therapeutic candidate for WNT-driven breast cancer

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