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.

项目摘要 代谢重编程在癌变中起关键作用，部分原因是它促进免疫 肿瘤内的抑制特性。目前尚不清楚肿瘤中脂肪酸代谢的抑制是否 影响其免疫原性。我们表明抑制stearoyl coa去饱和酶1（SCD1），速率限制 参与脂肪酸合成的酶将饱和酸（SFA）转化为单不饱和脂肪酸 （MUFA），增加免疫原性肿瘤的免疫原性。我们的结果表明抑制 肿瘤性脂肪生成是一种增强基于T细胞癌的新方法 免疫疗法。这样，我们的小说铅SCD1抑制剂（MTI-301;又名SSI-4）单独使用，并与 免疫检查点抑制剂（ICI）使用免疫胜任的小鼠模型证明了抗肿瘤协同作用 将肿瘤对ICIS的敏感性，作为早期临床试验的前奏。我们还将优化效力并寻求 预测性生物标志物的反应生物标志物可能对关键的患者的设计和分层有用 第三阶段临床试验。 SCD1在侵略性癌症中普遍上调，并通过MTI-301抗肿瘤验证 在各种癌细胞系和肿瘤小鼠模型中的活性。从机械上讲，MUFA剥夺 在上瘾的癌细胞中，导致介导凋亡细胞死亡的内质网（ER）应力。我们 使用免疫胜任的小鼠癌模型发现MTI-301激活适应性免疫 通过ER应力途径的钙网蛋白/PERK组的反应，增强了活化的T细胞肿瘤浸润和 从而促进抗PD1抗体疗法。 MTI-301与抗PD1抑制剂结合使用，使肿瘤敏感 小鼠三重阴性乳腺癌（TNBC）和HER2乳腺癌小鼠中的免疫检查点抑制剂 型号。基于这些数据，我们的中心假设是，从头脂肪形成与众不同。 肿瘤免疫原性的衰减。在此快速轨道1/2 SBIR提案中提出了三个目标。在 AIM 1（Milestone 1，I期SBIR），GLP DOG毒理学研究将完成，以识别未观察到的 - 不良效应水平（NOAEL）可以在I期临床试验中对人剂量的第一个计算计算。目标 2（里程碑2，第二阶段SBIR），GMP MTI-301将合成并批准以及提交 FDA I期试验批准的新药（IND）申请的调查。在AIM 3（Milestone 3，II期SBIR）中， 将进行I期临床试验并进行探索性生物标志物，包括鉴定免疫浸润。 将评估进入肿瘤部位。总而言之，我们将SCD1设想为广谱的抗癌目标 过表达侵略性恶性肿瘤。治疗上有用，MTI-301增加了免疫原性 免疫原性肿瘤不良，因此对免疫检查点封锁敏感，导致戏剧性适应性 免疫介导的肿瘤细胞杀死。这种组合疗法应提高患者的反应率，并 患者的耐受性良好。