Targeting Macrophages to Treat Soft Tissue Sarcomas

项目摘要 软组织肉瘤（STS）是一个广义的术语，用于描述始于软组织的多种癌症亚型。大多数STS 在临床上以相同的方式治疗，无论亚型如何。STS包括50多个组织学和 分子亚型，每种亚型显示不同的临床行为。目前没有统一的治疗方法 除了手术化疗和放疗之外的STS亚型。 Resolute Science Inc.正在开发一种新的STS疗法， to solid实体tumors肿瘤.靶向TAM以杀死相关癌症具有肿瘤不可知的优势 与靶向特定的癌细胞受体相比。这种方法绕过了肿瘤的担忧 与靶向每种癌症特定性质的治疗剂相关的异质性和进化的抗性 类型.我们的主要治疗药物RS-5具有良好的耐受性，并在多种肿瘤中表现出强大的抗癌疗效。 鼠肉瘤肿瘤模型，包括皮下（sc）和颅内（ic）HT 1080肉瘤细胞系 模型和多柔比星抗性患者来源的异种移植物（PDX）肉瘤模型。Resolute的模块化药物 设计允许配体、骨架、接头和有效载荷的直接化学取代。最后 商业生产成本将显著低于抗体和抗体-药物缀合物的成本 （ADC）可以显着降低患者和保险公司的癌症治疗价格。 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。 平台分子作为不同STS亚型的治疗，并进行研究前新药（IND）， 国家研究开发扶持性研究。我们的SBIR快速通道提案的第一阶段目标是验证一种亚型的选择 STS，未分化多形性肉瘤（UPS）作为RS-5的初始临床适应症。的量度 成功进入II期是：1）在阿霉素抗性UPS模型中建立RS-5的剂量反应，2） 在多柔比星初始PDX模型中建立等于或优于多柔比星的抗癌功效，3）证实 在雄性和雌性小鼠中的抗癌功效，4）确定MTM对抗癌功效的贡献， RS-5。在第二阶段，我们将进行临床试验前新药（IND）和IND使能研究， 通过额外的疗效研究可能扩展到其他STS亚型。衡量成功的标准是 II期是：1）证明RS-5在良好耐受剂量下的抗癌功效与 在至少1个额外的PDX模型中以良好耐受的剂量使用阿霉素，2）生物- 用于非临床毒理学种属和人类的分析方法，以及3）进行IND使能研究。 该快速通道提案的完成将使STS作为RS-5的首个临床适应症得到验证， 完成IND使能研究，以支持RS-5的临床开发。一旦完成，阶段 I和II工作将为RS-5获得I期临床试验批准提供快速途径。

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.