Targeting Macrophages to Treat Soft Tissue Sarcomas

项目总结 软组织肉瘤(STS)是一个宽泛的术语，指起源于软组织的多种亚型癌症。大多数STS 在临床上以同样的方式治疗，而不考虑亚型。STS涵盖了50多个组织学和 分子亚型，每一种都表现出不同的临床行为。目前还没有统一的治疗方法 适用于手术、化疗和放疗以外的STS亚型。 RESOLUTE科学公司正在开发使用TAMS加工和输送抗癌药物的新型STS疗法 到实体肿瘤。靶向TAMs杀死相关癌症的优势是肿瘤不可知 与靶向特定的癌细胞受体相比。这种方法绕过了对肿瘤的担忧 与针对每种癌症特定特性的治疗相关的异质性和进化的耐药性 打字。我们的先导疗法RS-5耐受性良好，并在多种药物中显示出强大的抗癌效果。 小鼠肉瘤模型，包括皮下(Sc)和颅内(Ic)肉瘤细胞系HT1080 模型和阿霉素耐药患者来源的异种移植瘤(PDX)模型。索列特(氏)模块化药物 设计允许对配体、主干、连接体和有效载荷进行直接的化学替代。最后， 商业化生产的成本将大大低于抗体和抗体-药物结合物 (ADC)，这可以显著降低患者和保险公司的这种癌症治疗的价格。 快速通道计划的总体目标是进行研究，进一步显示Resolute的疗效 平台分子用于不同STS亚型的治疗，并进行预研新药(IND)和 支持IND的研究。此SBIR快速通道计划的第一阶段目标是验证选择的一个子类型 在STS中，未分化多形性肉瘤(UPS)是RS-5的初步临床指征。衡量的标准 成功进入第二阶段是1)在阿霉素耐药的UPS模型中建立RS-5的剂量反应，2) 在阿霉素-初始PDX模型中建立与阿霉素相同或更好的抗癌效果，3)演示 雄性和雌性小鼠的抗癌作用，4)确定MTM对抗癌作用的贡献 RS-5。在第二阶段，我们将进行研究前新药(IND)和启用IND的研究， 通过额外的疗效研究有可能扩展到其他STS亚型。成功的衡量标准是 第二阶段为1)在耐受性良好的剂量下表现出与RS-5相当或更好的抗癌效果 阿霉素在至少1个额外的PDX模型中具有良好的耐受性，2)成功的生物验证 非临床毒理学物种和人类的分析方法，以及3)进行IND使能研究。 完成这项快速通道提案将使STS成为我们的第一个RS-5和 完成支持IND的研究，以支持RS-5的临床开发。一旦完成，该阶段 I和II工作将为RS-5获得第一阶段临床试验的批准提供一条快速途径。

PROJECT SUMMARY Soft tissues sarcomas (STS) is a broad term for multiple subtypes of cancer that start in soft tissues. Most STS are treated in the same way in the clinic regardless of the subtype. STS encompasses over 50 histologic and molecular subtypes, with each displaying variable clinical behavior. There is currently no unifying treatment for STS subtypes beyond surgery, chemotherapy, and radiation. Resolute Science Inc. is developing novel STS therapy by using TAMs to process and deliver anti-cancer agents to solid tumors. Targeting TAMs to kill the associated cancer has the advantage of being tumor-agnostic compared to that of targeting a specific cancer cell receptor. This approach bypasses concerns of tumor heterogeneity and evolved resistance associated with therapeutics that target specific properties of each cancer type. Our lead therapeutic, RS-5, is well-tolerated and demonstrated strong anti-cancer efficacy across multiple murine sarcoma tumor models, including the subcutaneous (sc) and intracranial (ic) HT1080 sarcoma cell line model and a doxorubicin-resistant patient derived xenograft (PDX) sarcoma model. Resolute’s modular drug design allows for straightforward chemical substitutions of ligand, backbone, linker, and payloads. Finally, the cost of commercial manufacturing will be significantly lower than that of antibodies and antibody-drug conjugates (ADCs) which could significantly reduce the price of this cancer treatment for patients and insurers. The overall goal of the Fast-Track program is to conduct studies that further show the efficacy of Resolute’s platform molecule as therapy for different STS subtypes and perform pre-Investigational New Drug (IND) and IND-enabling studies. Our Phase I goal for this SBIR Fast-Track proposal is to validate the choice of one subtype of STS, Undifferentiated Pleomorphic Sarcoma (UPS) as an initial clinical indication for RS-5. The measure of success to advance to Phase II is 1) establish dose response of RS-5 in a doxorubicin-resistant UPS model, 2) establish anti-cancer efficacy equal or better than doxorubicin in a doxorubicin-naive PDX model, 3) demonstrate anti-cancer efficacy in both male and female mice, 4) establish contribution of MTM to anti-cancer efficacy from that of RS-5. In Phase II, we will perform pre-Investigational New Drug (IND) and IND-enabling studies with potential expansion into other STS subtypes through additional efficacy studies. The measure of success for Phase II is 1) demonstrate comparable or better anti-cancer efficacy of RS-5 at a well-tolerated dose to that of doxorubicin at a well-tolerated dose in at least 1 additional PDX model, 2) the successful validation of bio- analytical methods for nonclinical toxicology species and humans, and 3) conduct IND-enabling studies. Completion of this Fast-Track proposal will result in validation of STS as our first clinical indication for RS-5 and completion of the IND-enabling studies to support the clinical development of RS-5. Once completed, the Phase I and II work will provide a rapid path for RS-5 to obtain approval for Phase I clinical testing.