Targeting Macrophages to Treat Soft Tissue Sarcomas

靶向巨噬细胞治疗软组织肉瘤

基本信息

批准号：
10760719
负责人：
Faith H Barnett
金额：
$ 39.9万
依托单位：
RESOLUTE SCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10760719
关键词：
Adolescent Adult American Cancer Society Antibodies Antibody-drug conjugates Antineoplastic Agents Behavior Biological Assay Body Weight Changes Body Weight decreased Bypass Canis familiaris Cell Line Cells Cessation of life Child Clinic Clinical Clinical Research Data Disease Dose Doxorubicin Drug Design Ewings sarcoma Excretory function Female Goals Good Manufacturing Process Guidelines Histologic Human Ifosfamide Insurance Carriers Investigational Drugs Lead Ligand Binding Ligands Liquid Chromatography Macrophage Malignant Fibrous Histiocytoma Malignant Neoplasms Mass Spectrum Analysis Maximum Tolerated Dose Measures Metabolism Methodology Methods Modeling Mus Nude Mice Oncology Operative Surgical Procedures Patients Pharmacotherapy Phase Price Process Property Radiation Rattus Receptor Cell Recovery Renal function Resistance Rodent Science Small Business Innovation Research Grant Soft tissue sarcoma Solid Neoplasm Survival Rate Therapeutic Toxic effect Toxicokinetics Toxicology Toxin Treatment outcome Tumor-associated macrophages United States Validation Vertebral column Work absorption anti-cancer cancer cell cancer subtypes cancer therapy cancer type chemical substitution chemotherapy clinical development cost dosage effectiveness evaluation efficacy study improved innovation leiomyosarcoma liver function male manufacture molecular subtypes mouse model novel novel strategies patient derived xenograft model pharmacokinetics and pharmacodynamics pre-Investigational New Drug meeting pre-clinical programs research clinical testing response sarcoma soft tissue subcutaneous success synovial sarcoma targeted treatment therapeutic target tumor tumor heterogeneity validation studies

项目摘要

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.

项目概要软组织肉瘤 (STS) 是一个广义术语，指始于软组织的多种癌症亚型。无论 STS 是什么亚型，在临床上都以相同的方式进行治疗，涵盖 50 多种组织学和病理学类型。分子亚型，每种亚型表现出不同的临床行为，目前尚无统一的治疗方法。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 Resolute 的模块化药物。设计允许配体、主链、连接体和有效负载的直接化学取代。商业化生产的成本将显着低于抗体和抗体药物偶联物（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。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 对抗癌功效的贡献在第二阶段，我们将与 RS-5 进行预研究新药 (IND) 和 IND 启用研究。通过额外的功效研究可能扩展到其他 STS 亚型成功的衡量标准。 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 的第一个临床适应症完成支持 RS-5 临床开发的 IND 研究。 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。