Novel SCD1 inhibitors for treatment of cancer

DESCRIPTION provided by applicant Metastatic clear cell renal cell carcinoma mccRCC is an incurable cancer with a year survival of less than for which novel therapeutic agents need to be developed urgently It is notoriously resistant to chemotherapy and radiation Although molecularly targeted therapies have led to an improvement in survival the benefit is rather limited due to eventual development of drug resistance We have discovered a gene stearoyl CoA desaturase SCD to be aberrantly and specifically overexpressed in all patient ccRCC tissues examined to date including metastatic disease andgt without any expression in normal renal epithelial cells We have published that SCD acts as an oncogene to mediate survival and proliferation Silencing SCD in ccRCC leads to endoplasmic reticulum ER mediated apoptosis An SCD inhibitor combined with FDA approved mTOR inhibitor temsirolimus provided antitumor synergy in cell culture and a ccRCC mouse model Importantly SCD expression has been shown to be elevated in numerous cancers and correlated with poor outcome Thus we have identified a novel signaling and targetable pathway in mccRCC that may improve patient outcomes Furthermore we have recently developed highly specific small molecule SCD inhibitors with the intent to develop these compounds as drugs to be tested in clinical trials in combination with mTOR inhibitors for metastatic ccRCC We now demonstrate excellent bioavailability of our lead SCD inhibitor In Aim Hazlehurst Modulation Therapeutics Incorporated in vivo Non GLP toxicology and toxicokinetic characterization of the two lead SCD inhibitors will be determined In Aim the Copland laboratory will demonstrate single dose efficacy and antitumor synergy of our lead SCD inhibitor in combination with an mTOR inhibitor using a ccRCC metastatic tumor model and a patient derived xenograft PDX tumor model derived from a patient with metastatic disease In summary we have progressed from discovery of elevated SCD expression in patient clinical samples to the development of novel SCD inhibitors with remarkable bioavailability Importantly our data indicate that SCD inhibitors cause synergistic inhibition of tumor growth when combined with FDA approved mTOR inhibitors We anticipate by the completion of this phase I application we will have obtained sufficient data to have a pre IND meeting The goal of the Phase II STTR application will be to complete the IND application and initiate the Phase I clinical trial PUBLIC HEALTH RELEVANCE There are currently few treatment options for patients presenting with metastatic clear cell renal cell carcinoma and developing novel strategies are required to improve patient outcomes We recently discovered that Stearoyl CoA desaturase SCD was overexpressed in this deadly tumor Moreover data generated in our laboratory has shown that SCD expression promotes tumor growth and metastasis To further test this novel strategy as a therapeutic approach we developed potent SCD inhibitors The goal of this proposal will be to i define the therapeutic window and ii utilize robust and well defined patien derived xenograft models to test the efficacy and potency of our lead SCD inhibitor