Modulation of cancer induced immune suppression via inhibition of SCD1

通过抑制 SCD1 调节癌症诱导的免疫抑制

• 批准号: 10546697
• 负责人: John A. Copland
• 金额: $ 40万
• 依托单位: MODULATION THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546697
• 关键词: Acids; Adjuvant Therapy; Affect; Anabolism; Analytical Chemistry; Apoptotic; Biological Availability; Biological Markers; Bladder; Breast; Cancer Model; Cancer cell line; Canis familiaris; Cell Death; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Chemoresistance; Clinical Trials; Clinical Trials Design; Colon; Combined Modality Therapy; Data; Disease; Dose; Drug Formulations; Drug Kinetics; Drug resistance; ERBB2 gene; Enzymes; Essential Fatty Acids; Fatty Acids; Food and Drug Administration Drug Approval; Formulation; Generations; Grant; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunocompetent; Immunology; Immunosuppression; Immunotherapy; Infiltration; Inflammatory; Investigational Drugs; Investigational New Drug Application; Kidney; Lead; Link; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Mediating; Mediator of activation protein; Melanoma Cell; Membrane; Metabolic; Monounsaturated Fatty Acids; Mus; No-Observed-Adverse-Effect Level; Nutrient; Oncogenic; Oral; Ovarian; PD-1 inhibitors; Pathway interactions; Patients; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Phase III Clinical Trials; Phenotype; Play; Principal Investigator; Property; Proteins; Reporting; Role; Saturated Fatty Acids; Signal Transduction; Site; Small Business Innovation Research Grant; Small Interfering RNA; Solid Neoplasm; Stearoyl-CoA Desaturase; Synthesis Chemistry; T-Lymphocyte; Therapeutic; Thyroid Gland; Toxic effect; Toxicology; Translations; Tumor-infiltrating immune cells; adaptive immune response; adaptive immunity; antagonist; anti-PD1 antibodies; anti-PD1 therapy; anti-cancer; antitumor effect; arm; attenuation; base; calreticulin; cancer cell; cancer immunotherapy; cancer type; capsule; carcinogenesis; cell killing; clinical practice; combat; computational chemistry; deprivation; design; early phase clinical trial; endoplasmic reticulum stress; fatty acid biosynthesis; fatty acid metabolism; first-in-human; immune activation; immune checkpoint blockade; immunogenic; immunogenicity; in vivo; inhibitor; insight; lipid biosynthesis; lipid metabolism; malignant breast neoplasm; mouse model; neoplastic cell; novel; novel strategies; novel therapeutic intervention; overexpression; patient response; patient stratification; phase I trial; predictive marker; refractory cancer; response; response biomarker; small molecule; synergism; targeted treatment; therapeutic target; therapeutically effective; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor microenvironment; tumorigenic

PROJECT SUMMARY Metabolic reprogramming plays a critical role in carcinogenesis, in part due its ability to promote immune suppressive properties within tumors. It remains unclear whether inhibition of fatty acid metabolism in tumors affects their immunogenicity. We show 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), 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, our novel lead SCD1 inhibitor (MTI-301; aka SSI-4) singly, and in combination with immune checkpoint inhibitors (ICIs) using immune competent mouse models demonstrates anti-tumor synergy sensitizing tumors to ICIs, as a prelude to an early phase clinical trial. We will also optimize efficacy and seek predictive biomarkers of response that could be useful for the design and stratification of patients in the critical Phase III clinical trial. SCD1 is universally upregulated in aggressive cancers and validated by MTI-301 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 using immune competent mouse cancer models that MTI-301 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, MTI-301 sensitizes tumors to immune checkpoint inhibitors in mouse triple negative breast cancer (TNBC) and 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. Three aims are proposed in this fast-track Phase 1/2 SBIR proposal. In Aim 1 (Milestone 1, Phase I SBIR), GLP dog toxicology study will be completed to identify the No-observed- adverse-effect level (NOAEL) enabling calculation of the first in human dose for the phase I clinical trial. In Aim 2 (Milestone 2, Phase II SBIR), GMP MTI-301 will be synthesized and capsulated along with submission of the investigation of new drug (IND) application for FDA Phase I trial approval. In Aim 3 (Milestone 3, Phase II SBIR), a Phase I clinical trial will be performed and exploratory biomarkers including identification of immune infiltrates into the tumor site will be assessed. In summary, we envision SCD1 as a broad-spectrum anti-cancer target overexpressed in aggressive malignancies. Therapeutically useful, MTI-301 increases the immunogenicity of poorly immunogenic tumors thereby sensitizing to immune checkpoint blockade, leading to dramatic adaptive immune mediated tumor cell killing. This combination therapy should enhance patient response rates and be well tolerated in patients.

项目总结