Metastatic clear cell renal cell carcinoma (mccRCC) is an incurable cancer with a 5 year survival of less than 10%, 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 1 (SCD1) to be aberrantly and specifically overexpressed in all patient ccRCC tissues examined to date including metastatic disease (>125) without any expression in normal renal epithelial cells. We have published that SCD1 acts as an oncogene to mediate survival and proliferation. Silencing SCD1 in ccRCC leads to endoplasmic reticulum (ER) mediated apoptosis. An SCD1 inhibitor combined with FDA approved mTOR inhibitor, temsirolimus, provided antitumor synergy in cell culture and a ccRCC mouse model. Importantly SCD1 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 SCD1 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 SCD1 inhibitor.
In Aim 1 (Hazlehurst, Modulation Therapeutics Incorporated), in vivo Non-GLP toxicology and toxicokinetic characterization of the two lead SCD1 inhibitors will be determined.
In Aim 2, the Copland laboratory will demonstrate single dose efficacy and antitumor synergy of our lead SCD1 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 SCD1 expression in patient clinical samples to the development of novel SCD1 inhibitors with remarkable bioavailability. Importantly, our data indicate that SCD1 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.
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 1 (SCD1) was overexpressed in this deadly tumor. Moreover, data generated in our laboratory has shown that SCD1 expression promotes tumor growth and metastasis. To further test this novel strategy as a therapeutic approach, we developed potent SCD1 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 SCD1 inhibitor.
