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.

项目摘要软组织肉瘤（STS）是从软组织开始的多种癌症亚型的广义术语。大多数ST 无论亚型如何，在诊所中以相同的方式进行治疗。 STS包括超过50个组织学和分子亚型，每个显示可变的临床行为。目前没有统一的治疗对于超出手术，化学疗法和放射线的STS亚型。 Resolute Science Inc.正在通过使用TAM处理和提供抗癌剂来开发新型的STS治疗到实体瘤。靶向TAM杀死相关的癌症的优势是肿瘤敏捷与靶向特定的癌细胞受体相比。这种方法绕过了对肿瘤的关注与治疗相关的异质性和进化的抗性，靶向每种癌症的特定特性类型。我们的铅疗法RS-5具有良好的耐受性，并且在多个方面表现出强大的抗癌效率鼠肉瘤肿瘤模型，包括皮下（SC）和颅内（IC）HT1080肉瘤细胞系模型和阿霉素耐药的患者衍生异种移植（PDX）肉瘤模型。坚定的模块化药物设计允许配体，骨干，连接器和有效载荷的直接化学替代。最后，商业制造的成本将大大低于抗体和抗体 - 药物缀合物的成本（ADC）可以显着降低患者和保险的癌症治疗价格。 Fast-Track计划的总体目标是进行研究，以进一步表明Resolute的效率平台分子作为不同STS亚型的疗法，并进行投影前新药（IND）和辅助研究。我们的SBIR快速提议的I阶段目标是验证选择一种亚型在STS中，未分化的多形性肉瘤（UPS）是RS-5的初始临床指示。测量在抗霉素的UPS模型中，成功晋升为II期的成功是1）建立RS-5的剂量反应，2）在阿霉素不接受PDX模型中，建立抗癌效率等于或更好的阿霉素，3）证明雄性和雌性小鼠的抗癌效率，4）建立MTM对抗癌效率的贡献 RS-5。在第二阶段，我们将进行投资前的新药（IND）和辅助研究通过其他效率研究，潜在扩展到其他STS亚型。成功的衡量 II阶段是1）在耐受性良好的剂量下，RS-5的抗癌效率可比或更好的抗癌效率在至少1个额外的PDX模型中，阿霉素剂量良好，2）成功验证生物非临床毒理学物种和人类的分析方法，以及3）进行指定的研究。完成此快速提案的完成将导致STS确认为我们的第一个RS-5和完成辅助研究以支持RS-5的临床发展。完成后，阶段 I和II的工作将为RS-5提供快速路径，以获得I期临床测试的批准。