Development of first-in-class antagonists of the retinoid pathway as novel oral immunotherapies for solid cancers

开发类视黄醇途径的一流拮抗剂作为实体癌的新型口服免疫疗法

• 批准号: 10604218
• 负责人: Mark Esposito
• 金额: $ 39.8万
• 依托单位: KAYOTHERA INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-03 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604218
• 关键词: Achievement; Advanced Malignant Neoplasm; Antibodies; Antigen Presentation; Biological; Biological Assay; Biological Availability; CD8-Positive T-Lymphocytes; CTLA4 gene; Cancer Model; Cancer Patient; Cancer Remission; Canis familiaris; Cause of Death; Cells; Clinical Trials; Critical Pathways; Data; Dendritic Cells; Development; Diagnosis; Disease; Disease remission; Disseminated Malignant Neoplasm; Dose; Down-Regulation; Drug Kinetics; Enzymes; Exhibits; Family member; Freedom; Generations; Genetic; Grant; Growth; Half-Life; Hepatic; Human; ITGAM gene; ITGAX gene; Immune; Immune system; Immunocompetent; Immunologic Surveillance; Immunosuppression; Immunotherapy; In complete remission; Infiltration; Intellectual Property; Laboratories; Lead; Legal patent; Ligands; Localized Malignant Neoplasm; Macrophage; Malignant Neoplasms; Messenger RNA; Metabolic; Methods; Modeling; Monkeys; Mus; Neoplasm Metastasis; New Drug Approvals; Nuclear Receptors; Oral; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phase I Clinical Trials; Primary Neoplasm; Program Development; Property; Protein Isoforms; Publishing; Rattus; Regulatory T-Lymphocyte; Research; Research Proposals; Resistance; Resolution; Retinoids; Schedule; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Solid; Solid Neoplasm; Specificity; Structure; Survival Rate; Testing; Therapeutic; Therapeutic Agents; Toxicology; Tretinoin; Tumor Tissue; Tumor-infiltrating immune cells; United States; Work; antagonist; anti-PD-1; anti-PD1 therapy; biomarker identification; cancer immunotherapy; cancer survival; cancer type; clinical application; combinatorial; cross reactivity; drug development; drug discovery; experimental study; immune checkpoint; immune checkpoint blockade; immunoregulation; improved; in vivo; inhibitor; innovation; lead candidate; malignant breast neoplasm; melanoma; monocyte; nanomolar; neoplastic cell; next generation; novel; novel therapeutics; oral immunotherapy; patient subsets; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; research clinical testing; response biomarker; sarcoma; scaffold; tool; tumor; tumor-immune system interactions

Project Summary: The majority of cancer deaths are caused by dissemination and growth of secondary tumors throughout the body. While the 5-year survival rate for localized cancers has dramatically improved over the last four decades of drug development, the survival rates for cancer patients with advanced or metastatic disease remains abysmal, with median survival of Stage 4 patients at 10 months following diagnosis. Patients diagnosed with advanced or metastatic cancers are furthermore considered terminal as metastatic lesions are resistant to current therapeutic options. New therapeutic agents that can effectively treat and enforce regression of advanced cancers or established metastases are urgently needed in the therapeutic repertoire, yet only immune checkpoint blockade therapies have shown the ability to prolong survival in a small subset of patients with Stage 4 cancer. Therefore, immunotherapies with novel mechanisms of action and complementarity to current therapies are urgently needed to increase the percentage of responding patients and improve cancer survival metrics in the United States. Our academic collaborators as well as other leading academic laboratories have identified an immunosuppressive signaling pathway driven by two complementary enzymes that is critical to the progression of solid tumors by generating an immunosuppressive tumor microenvironment. Both our discovery work and recently published studies demonstrate this pathway is a critical node in the progression of multiple cancer types such as sarcoma, melanoma and breast cancer, yet prior commercial and academic attempts to drug this pathway have failed due to lack of potency, specificity and/or poor pharmacological properties. We are the first group to have developed lead compounds against this pathway that show exceptional potency and specificity while avoiding the pharmacologic liabilities of other drug development programs. Importantly, our therapies show promise in treating advanced and metastatic cancers and are characterized by low nanomolar potency (<50 nM, a 100-fold improvement over published molecules), no off-target activity, high metabolic stability, excellent oral pharmacokinetic properties and promising in vivo toxicology. Here we propose to nominate a development candidate through pharmacodynamic assays, dose-range finding studies and immunocompetent cancer models. The results of this research proposal will advance a first-in-class therapy toward clinical testing with the aim of curing patients who were once diagnosed as incurable. Specifically, the efficacy and preclinical data obtained from this application will support Phase 2 SBIR studies leading to an IND application.

项目概要： 大多数癌症死亡是由继发性肿瘤的扩散和生长引起的。 身体虽然局部癌症的5年生存率在过去几年中有了显着提高， 经过四十年的药物开发，晚期或转移性癌症患者的生存率 疾病仍然很糟糕，在诊断后10个月，4期患者的中位生存期。 此外，诊断为晚期或转移性癌症的患者被认为是晚期， 转移性病变对当前的治疗选择具有抗性。新的治疗药物， 迫切需要有效治疗晚期癌症或已确定转移并使其消退 在治疗谱中需要，但只有免疫检查点阻断疗法显示出 能够延长一小部分4期癌症患者的生存期。因此，免疫疗法 具有新的作用机制和对当前疗法的补充， 提高应答患者的百分比，改善美国癌症患者的生存指标 States.我们的学术合作者以及其他领先的学术实验室已经确定了一个 由两种互补酶驱动的免疫抑制信号传导途径，这对免疫抑制的发生至关重要。 通过产生免疫抑制性肿瘤微环境来抑制实体瘤的进展。我们的 发现工作和最近发表的研究表明，这一途径是一个关键节点， 多种癌症类型的进展，如肉瘤、黑色素瘤和乳腺癌，但先前 由于缺乏效力、特异性，对这一途径进行药物治疗的商业和学术尝试都失败了 和/或不良的药理学性质。我们是第一个开发出先导化合物的团队 针对这一途径，显示出特殊的效力和特异性，同时避免了药理学上的 其他药物开发项目的责任。重要的是，我们的疗法在治疗 晚期和转移性癌症，其特征在于低纳摩尔效力（<50 nM，100倍于100 nM）。 相对于公开的分子的改进），无脱靶活性，高代谢稳定性，优异的口服 药代动力学特性和有前景的体内毒理学。在此，我们建议提名一位 通过药效学试验、剂量范围探索研究和 免疫活性癌症模型。这项研究提案的结果将推动一流的 治疗转向临床试验，目的是治愈曾经被诊断为不治之症的患者。 具体而言，从本申请中获得的疗效和临床前数据将支持2期SBIR 导致IND申请的研究。