SBIR-STTR Award

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.

Public Health Relevance Statement:


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 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.

Project Terms:
Address; advanced disease; Adverse effects; Affinity; Apoptosis; Attenuated; Biological Assay; Biological Availability; Biological Markers; cancer cell; cancer therapy; Cell Culture Techniques; Cell Line; Cell Proliferation; Cell Survival; Cells; chemotherapy; Chronic Disease; Clear Cell; Clinical; Clinical Trials; combinatorial; Data; Dependence; desaturase; design; Development; Disease; Dose; Drug Kinetics; Drug resistance; effective therapy; efficacy testing; Endoplasmic Reticulum; endoplasmic reticulum stress; Epithelial Cell Proliferation; Epithelial Cells; experience; FDA approved; Fibrous capsule of kidney; Gene Expression Profile; Genes; Goals; Growth; Human; Immune; Implant; improved; In Vitro; in vivo; inhibitor/antagonist; innovation; Kidney; Laboratories; Lead; Legal patent; Link; lipid biosynthesis; Luciferases; Lung; Malignant Neoplasms; Maximum Tolerated Dose; Measurement; Mediating; meetings; Messenger RNA; Metabolic Pathway; Metastatic to; Modeling; molecular marker; Mono-S; Monounsaturated Fatty Acids; mouse model; mTOR Inhibitor; Mus; Neoplasm Metastasis; novel; novel strategies; novel therapeutics; Oncogenes; Outcome; outcome forecast; overexpression; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; pre-clinical; Principal Investigator; Proteins; public health relevance; Publications; Publishing; Quality of life; Radiation; Renal Cell Carcinoma; Renal Tissue; Resected; Resistance; response; Sampling; Saturated Fatty Acids; Signal Pathway; Signal Transduction; Small Business Technology Transfer Research; small hairpin RNA; small molecule; Specimen; Staging; Stearoyl-CoA Desaturase; targeted treatment; Testing; Therapeutic; Therapeutic Agents; therapeutic evaluation; therapy design; Tissues; tool; Toxic effect; Toxicokinetics; Toxicology; tumor; Tumor Biology; tumor growth; tumor microenvironment; Tumor Tissue; tumor xenograft; tumorigenic; Xenograft Model; Xenograft procedure

Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. However, it is unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. Here, we show for the first time that inhibition of stearoyl CoA desaturase 1 (SCD1), the rate limiting enzyme involved in fatty-acid synthesis converting saturated acids (SFA) to monounsaturated fatty acids (MUFAs) and a potential prognostic marker for human cancers, increases the immunogenicity of poorly immunogenic tumors. Our results indicate that inhibition of tumorigenic de novo lipogenesis represents a novel approach to enhance T cell based cancer immunotherapy. In so doing, we will evaluate our novel lead SCD1 inhibitor (SSI-4) singly, and in combination with immune checkpoint inhibitors using immune competent mouse models, as a prelude to an early phase clinical trial. We will also optimize efficacy and seek predictive biomarkers of response that could be clinically useful. SCD1 is universally upregulated in aggressive cancers and validated by SSI-4 antitumor activity across a broad range of cancer cell lines and tumor mouse models. Mechanistically, MUFA deprivation in addicted cancer cells leads to endoplasmic reticulum (ER) stress mediating apoptotic cell death. We discovered in immune competent mouse cancer models that SSI-4 activates the adaptive immune response via calreticulin/PERK arm of the ER stress pathway enhancing activated T cell tumor infiltration and thereby promoting anti-PD1 antibody therapy. Combined with anti-PD1 inhibitor, SSI-4 sensitizes tumors to immune checkpoint inhibitors leading to 80% and 30% complete regression (CR) and long-term survival interpreted as cures in two HER2 breast cancer mouse models. Based upon these data, our central hypothesis is that aberrant de novo lipogenesis is linked to attenuation of tumor immunogenicity. Two aims are proposed in this Phase 2 STTR proposal. Aim 1 will validate antitumor synergy of SCD1 and immune checkpoint blockade using immune competent breast mouse models to generalize the observed data to. Aim 2 is focused upon filing an application for investigation of new drug (IND) for FDA approval in which the following tasks will be accomplished; i) determine SSI-4 compound stability ii) perform non-GLP toxicity studies in rats and dogs iii) convene a pre-IND meeting with the FDA to discuss regulatory strategy iv) perform GLP toxicity studies, v) design the phase I clinical trial and vi) complete the IND application. In summary, we envision SCD1 as a broad spectrum anti-cancer target overexpressed in aggressive malignancies. Therapeutically useful, SSI-4 increases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade, leading to dramatic adaptive immune mediated tumor cell killing. Thus, this combination therapy should enhance patient response rates and be well tolerated in patients.