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在全身的扩散和生长引起的 身体。虽然局部癌症的 5 年生存率比过去有了显着提高 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，诊断后 10 个月时 4 期患者的中位生存期。 诊断患有晚期或转移性癌症的患者还被认为是晚期癌症 转移性病变对当前的治疗方案有抵抗力。新的治疗药物可以 有效治疗和强制消退晚期癌症或已确定的转移是迫切需要的 治疗方案中需要，但只有免疫检查点阻断疗法已显示出 能够延长一小部分 4 期癌症患者的生存期。因此，免疫疗法 迫切需要具有新的作用机制和对现有疗法的补充 增加美国有反应患者的比例并改善癌症生存指标 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对于免疫抑制至关重要 通过产生免疫抑制肿瘤微环境来促进实体瘤的进展。我们的 发现工作和最近发表的研究表明，这条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，但之前 由于缺乏效力和特异性，商业和学术界对该途径进行的药物尝试都失败了 和/或药理学特性较差。我们是第一批开发出先导化合物的团队 针对这一途径，显示出非凡的效力和特异性，同时避免了药理作用 其他药物开发项目的责任。重要的是，我们的疗法在治疗方面显示出希望 晚期和转移性癌症，其特点是低纳摩尔效力（<50 nM，100 倍） 比已发表的分子有所改进），无脱靶活性，代谢稳定性高，口服效果优异 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 通过药效学测定、剂量范围寻找研究和开发候选药物 具有免疫功能的癌症模型。该研究提案的结果将推进一流的 治疗转向临床测试，目的是治愈曾经被诊断为不治之症的患者。 具体来说，从该申请获得的功效和临床前数据将支持 2 期 SBIR 导致 IND 申请的研究。