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.

项目摘要： 大多数癌症死亡是由整个次级肿瘤的传播和生长引起的 身体。虽然局部癌症的5年生存率在最后一个 四十年的药物开发，晚期或转移性癌症患者的存活率 疾病仍然是糟糕的，在诊断后10个月后，第4阶段患者的中位生存期。 此外，被诊断为晚期或转移性癌症的患者被认为是终端 转移性病变对当前的治疗选择有抵抗力。可以 有效地治疗和强制治疗高级癌症或已建立转移的回归是紧急的 在治疗曲目中需要 在一小部分患有4期癌症的患者中延长生存的能力。因此，免疫疗法 迫切需要采用新颖的作用机理和对当前疗法的互补性 增加反应患者的百分比并改善联合的癌症生存指标 国家。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 由两种互补酶驱动的免疫抑制信号通路，这对 通过产生免疫抑制肿瘤微环境，实体瘤的进展。我们两个 发现工作和最近发表的研究表明，该途径是一个关键节点 多种癌症类型的进展，例如肉瘤，黑色素瘤和乳腺癌，但事先 由于缺乏效力，特异性，商业和学术尝试这一途径失败了 和/或药理学特性不佳。我们是第一个开发铅化合物的小组 在这种避免药理学的同时，在这种途径上表现出非凡的效力和特异性 其他药物开发计划的负债。重要的是，我们的疗法在治疗方面表现出希望 高级和转移性癌症的特征是低纳摩尔效力（<50 nm，100倍 改善了发表的分子），没有脱靶活动，高代谢稳定性，出色的口服 药代动力学特性和有希望的体内毒理学。在这里，我们建议提名 通过药效分析，剂量范围的发现研究和 免疫能力的癌症模型。该研究建议的结果将提高一流 治疗临床测试的治疗，目的是治愈曾经被诊断为无法治愈的患者。 具体而言，从本应用程序获得的功效和临床前数据将支持阶段2 SBIR 导致IND应用的研究。