beta-Catenin inhibitors: A novel immuno-therapy for Colorectal Cancer

ABSTRACT Although cancer immunotherapy is considered a great breakthrough in cancer therapya significant proportion of patients do not respond to these treatmentsRecent studies have shown that clinical benefits of the most potent immunotherapy lay in the presence of a T cell inflamed tumor microenvironment at baselinehot tumorDysregulated Wntcatenin signaling has been implicated in the lack of immune cell infiltration in tumors and underlies the pathogenesis of a broad range of human cancersSpecificallyupon association with cofactor and onco gene Bclcatenin promotes transcription of genes associated with stemnessproliferationsurvival and metastasisOver expression or mutations in Bclorcatenin have been associated with tumor progressiondecreased survivaland poor clinical outcome in a broad range of human cancers including colorectal cancerIn additionrecent studies in mouse melanoma tumor models have shown that cell intrinsiccatenin signaling plays a critical role in evasion of immuno surveillanceBoth Bclandcatenin expression have been shown to correlate with poor immune cell infiltration and survival in metastatic melanoma andof patients with non T cell inflamed melanoma lesion show evidence of activation of the Wntcatenin pathwayThusthis pathway is hypothesized to be an important target to restore immune infiltration in tumorsMoreoverBclcatenin modulation is hypothesized to be synergistic with treatment modalities that boost the anti tumor immune responseWe have developed a series of nuclearcatenin inhibitors that selectively interfere with Bclcatenin interactions and hold the promise of mediating the Wntcatenin pathway towards restoring anti tumor T cell activitywhile avoiding toxic effects associated withcatenin inhibition or disruption of other routine non immunological activities ofcateninOur three preliminary lead compounds VTXab and cshowed a significant capacity to specifically inhibit nuclear BCLcatenin interactions and the subsequent induction of cancer associated gene transcription in two human colon carcinoma cell linesFurthermorethese compounds have demonstrated promising ADME and pharmacokineticPKprofiles in mice in vivo upon oral administrationWe propose to expand on our lead series of selective nuclearcatenin inhibitorsas well as evaluate and determine the mechanistic and efficacy properties of our compounds on Wntcatenin signaling and immune exclusion in colorectal cancerCRCmodelstowards advancing acatenin inhibitor capable of turning these tumors hot and increasing the viability of cancer immunotherapyWe first propose to utilize a scalable and modular synthetic route for rapid generation of analogswhich we have developedto readily access a vast number of analogs and rapidly assess not only their activity in our initialcatenin assays but also evaluate their ADME and PK characteristicsSpecific AimThenwe will characterize our leads in vitroSpecific AimFinallywe will test for the efficacy of VTXc and yielded analogs that emerge from Specific Aimin murine syngeneic colon carcinoma transplant modelsSpecific AimNARRATIVE Although immunotherapy is considered a major breakthrough for cancer patientsa significant proportion of patients do not respond to immunotherapy treatments and that percentage is estimated betweenThis is a major unmet medical need of our timeRecent studies have shown that clinical benefits of the most potent immunotherapy lay in the ability of immune cells to infiltrate deep into the tumorBased on evidence implicating a signaling process unique to tumorswe have developed a series of potential target drugs that has the potential to enhance tumor infiltration by immune cellsWe propose to develop this series further for treatment of colorectal cancerand potentially for other cancers in the futureThis will represent a breakthrough for the treatment paradigm for current refractory un responsive tumors with immunotherapies and expand the survival benefit for millions