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

项目总结： 大多数癌症死亡是由继发性肿瘤的扩散和生长 身体。虽然局限性癌症的5年存活率在过去的几年里有了显著的提高 经过四十年的药物开发，晚期或转移性癌症患者的存活率 疾病仍然很糟糕，确诊后10个月，4期患者的中位生存期为10个月。 被诊断为晚期或转移性癌症的患者进一步被认为是晚期 转移性病变对目前的治疗方案具有抵抗力。新的治疗剂可以 有效地治疗和加强晚期癌症或已确定的转移的消退是当务之急 在治疗方案中需要，但只有免疫检查点阻断疗法显示 能够延长一小部分4期癌症患者的生存时间。因此，免疫疗法 有了新的作用机制和对现有疗法的补充，迫切需要 提高有反应的患者百分比并改善美国的癌症生存指标 各州。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 实体肿瘤的进展通过产生免疫抑制的肿瘤微环境。我们的 发现工作和最近发表的研究表明，这条途径是 多种癌症类型的进展，如肉瘤、黑色素瘤和乳腺癌 由于缺乏效力、特异性，商业和学术上对该途径的药物尝试都以失败告终 和/或较差的药理特性。我们是第一个开发出先导化合物的组织 对这一途径表现出非凡的效力和特异性，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，我们的疗法在治疗方面显示出了希望。 晚期和转移性癌症，其特点是低纳摩尔效力(&lt；50 NM，100倍 比已发表的分子更好)，没有偏离目标的活性，高代谢稳定性，极好的口服 药代动力学特性和有希望的体内毒理学。在这里，我们建议提名一名 通过药效学分析、剂量范围发现研究和 免疫活性癌症模型。这项研究提案的结果将是一流的 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。 具体地说，从这项应用中获得的疗效和临床前数据将支持第二阶段SBIR 学习导致IND申请。

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.