Targeting Macrophages to Treat Soft Tissue Sarcomas

项目概要 软组织肉瘤 (STS) 是一个广义术语，指的是始于软组织的多种癌症亚型。大多数STS 无论亚型如何，在诊所中都以相同的方式进行治疗。 STS 涵盖 50 多个组织学和 分子亚型，每种亚型都表现出不同的临床行为。目前尚无统一治疗方法 适用于手术、化疗和放疗之外的 STS 亚型。 Resolute Science Inc. 正在开发新型 STS 疗法，利用 TAM 处理和输送抗癌药物 至实体瘤。靶向 TAM 来杀死相关癌症具有与肿瘤无关的优势 与针对特定癌细胞受体的方法相比。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耐药性 类型。我们的主要治疗药物 RS-5 具有良好的耐受性，并在多种疾病中表现出强大的抗癌功效。 鼠肉瘤肿瘤模型，包括皮下 (sc) 和颅内 (ic) HT1080 肉瘤细胞系 模型和多柔比星耐药患者衍生的异种移植（PDX）肉瘤模型。 Resolute的模块化药物 设计允许对配体、主链、连接体和有效负载进行简单的化学取代。最后， 商业化生产的成本将显着低于抗体和抗体药物偶联物的成本 （ADC）可以显着降低患者和保险公司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，进一步证明 Resolute 的功效 平台分子作为不同 STS 亚型的治疗方法并进行预研究新药 (IND) 和 支持 IND 的研究。我们此 SBIR 快速通道提案的第一阶段目标是验证一个子类型的选择 STS、未分化多形性肉瘤 (UPS) 作为 RS-5 的初始临床适应症。的衡量标准是 成功进入 II 期是 1) 在阿霉素耐药 UPS 模型中建立 RS-5 的剂量反应，2) 在未使用阿霉素的 PDX 模型中建立与阿霉素相同或更好的抗癌功效，3) 证明 雄性和雌性小鼠的抗癌功效，4) 确定 MTM 对抗癌功效的贡献 RS-5 的那个。在第二阶段，我们将进行预研究新药 (IND) 和 IND 启用研究 通过额外的功效研究，有可能扩展到其他 STS 亚型。衡量成功的标准 II 期是 1) 证明 RS-5 在耐受性良好的剂量下具有与 在至少 1 个额外的 PDX 模型中以耐受良好的剂量阿霉素，2) 成功验证了生物- 非临床毒理学物种和人类的分析方法，以及 3) 进行 IND 支持研究。 该快速通道提案的完成将导致 STS 被验证为我们 RS-5 和的第一个临床适应症 完成 IND 支持研究以支持 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 I 期临床测试批准提供快速途径。

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.