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: 10896572
• 负责人: John A. Copland
• 金额: $ 130.18万
• 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 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10896572
• 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 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; Inflammatory; Inhibition of Cell Proliferation; Investigation; Kidney; Lead; Life; Link; Liver; Malignant Neoplasms; Malignant neoplasm of pancreas; Maximum Tolerated Dose; Measures; Mediating; Mediator; Melanoma Cell; Membrane; Metabolic; Monounsaturated Fatty Acids; Mus; New Drug Approvals; No-Observed-Adverse-Effect Level; Nutrient; Nutrient availability; 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; Signaling Molecule; Site; Small Business Innovation Research Grant; Small Interfering RNA; Solid Neoplasm; Stearoyl-CoA Desaturase; Synthesis Chemistry; T-Cell Activation; T-Lymphocyte; Therapeutic; Thyroid Gland; Toxic effect; Toxicology; Translations; WNT Signaling Pathway; adaptive immune response; adaptive immunity; antagonist; anti-PD1 antibodies; anti-PD1 therapy; anti-cancer; antitumor effect; arm; attenuation; calreticulin; cancer cell; cancer immunotherapy; cancer infiltrating T cells; cancer survival; 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 cell infiltrate; 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; novel therapeutics; 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-observedadverse-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.

项目概要 代谢重编程在致癌过程中发挥着关键作用，部分原因在于它能够促进免疫 肿瘤内的抑制特性。目前尚不清楚是否抑制肿瘤中的脂肪酸代谢 影响其免疫原性。我们发现，抑制硬脂酰辅酶 A 去饱和酶 1 (SCD1)（限速酶） 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），增加免疫原性差的肿瘤的免疫原性。我们的结果表明，抑制 致瘤性从头脂肪生成代表了一种增强 T 细胞癌症的新方法 免疫疗法。为此，我们的新型先导 SCD1 抑制剂（MTI-301；又名 SSI-4）可单独使用，也可与 使用具有免疫能力的小鼠模型证明免疫检查点抑制剂（ICIs）具有抗肿瘤协同作用 使肿瘤对 ICI 敏感，作为早期临床试验的前奏。我们还将优化效能并寻求 反应的预测生物标志物可用于危重患者的设计和分层 III期临床试验。 SCD1 在侵袭性癌症中普遍上调，并经 MTI-301 抗肿瘤药物验证 在广泛的癌细胞系和肿瘤小鼠模型中具有活性。从机制上讲，MUFA 剥夺 成瘾的癌细胞会导致内质网（ER）应激，介导细胞凋亡。我们 使用具有免疫活性的小鼠癌症模型发现 MTI-301 可以激活适应性免疫 通过 ER 应激途径的钙网蛋白/PERK 臂进行反应，增强激活的 T 细胞肿瘤浸润和 从而促进抗PD1抗体治疗。 MTI-301 与抗 PD1 抑制剂相结合，使肿瘤对 小鼠三阴性乳腺癌 (TNBC) 和 HER2 乳腺癌小鼠的免疫检查点抑制剂 模型。根据这些数据，我们的中心假设是异常的从头脂肪生成与 肿瘤免疫原性减弱。此快速通道第 1/2 阶段 SBIR 提案提出了三个目标。在 目标 1（里程碑 1，I 期 SBIR），GLP 狗毒理学研究将完成，以确定未观察到的不良反应水平 (NOAEL)，从而能够计算 I 期临床试验的第一个人体剂量。瞄准 2（里程碑 2，II 期 SBIR），将合成 GMP MTI-301 并封装，并提交 FDA I 期试验批准的新药 (IND) 申请调查。在目标 3（里程碑 3，第二阶段 SBIR）中， 将进行一期临床试验和探索性生物标志物，包括免疫浸润的识别 将评估进入肿瘤部位的情况。总之，我们设想 SCD1 作为一个广谱抗癌靶点 在侵袭性恶性肿瘤中过度表达。在治疗上有用，MTI-301 增加了免疫原性 免疫原性差的肿瘤因此对免疫检查点阻断敏感，导致显着的适应性 免疫介导的肿瘤细胞杀伤。这种联合疗法应能提高患者的反应率并 患者耐受性良好。