Novel SCD1 inhibitors for treatment of cancer

Project Summary Metabolic reprogramming plays a critical role in carcinogenesisin part due its ability to promote immune suppressive properties within tumorsHoweverit is unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicityHerewe show for the first time that inhibition of stearoyl CoA desaturaseSCDthe rate limiting enzyme involved in fatty acid synthesis converting saturated acidsSFAto monounsaturated fatty acidsMUFAsand a potential prognostic marker for human cancersincreases the immunogenicity of poorly immunogenic tumorsOur results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell based cancer immunotherapyIn so doingwe will evaluate our novel lead SCDinhibitorSSIsinglyand in combination with immune checkpoint inhibitors using immune competent mouse modelsas a prelude to an early phase clinical trialWe will also optimize efficacy and seek predictive biomarkers of response that could be clinically usefulSCDis universally upregulated in aggressive cancers and validated by SSIantitumor activity across a broad range of cancer cell lines and tumor mouse modelsMechanisticallyMUFA deprivation in addicted cancer cells leads to endoplasmic reticulumERstress mediating apoptotic cell deathWe discovered in immune competent mouse cancer models that SSIactivates the adaptive immune response via calreticulin PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and thereby promoting anti PDantibody therapyCombined with anti PDinhibitorSSIsensitizes tumors to immune checkpoint inhibitors leading toandcomplete regressionCRand long term survival interpreted as cures in two HERbreast cancer mouse modelsBased upon these dataour central hypothesis is that aberrant de novo lipogenesis is linked to attenuation of tumor immunogenicityTwo aims are proposed in this PhaseSTTR proposalAimwill validate antitumor synergy of SCDand immune checkpoint blockade using immune competent breast mouse models to generalize the observed data toAimis focused upon filing an application for investigation of new drugINDfor FDA approval in which the following tasks will be accomplishedidetermine SSIcompound stability iiperform non GLP toxicity studies in rats and dogs iiiconvene a pre IND meeting with the FDA to discuss regulatory strategy ivperform GLP toxicity studiesvdesign the phase I clinical trial and vicomplete the IND applicationIn summarywe envision SCDas a broad spectrum anti cancer target overexpressed in aggressive malignanciesTherapeutically usefulSSIincreases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockadeleading to dramatic adaptive immune mediated tumor cell killingThusthis combination therapy should enhance patient response rates and be well tolerated in patients Project Narrative A novel fatty acid synthesis inhibitorSSIsensitizes cancers to immune checkpoint inhibitorsThis new therapeutic strategy should increase the number of patients responding to treatment and may lead to cures through prolonged activation of immune T cells