Microbial- based targeting of major extracellular matrix components for improved therapy of pancreatic cancer

基于微生物的主要细胞外基质成分靶向以改善胰腺癌的治疗

• 批准号: 10701792
• 负责人: EDWIN MANUEL
• 金额: $ 35.79万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701792
• 关键词: Antibodies; Antineoplastic Agents; Attenuated; Cancer Etiology; Cancer Patient; Cessation of life; Characteristics; Clinical; Collagen; Combined Modality Therapy; Culture Media; Data; Deposition; Desmoplastic; Developing Countries; Diameter; Distal; Dose; Drug Delivery Systems; Encapsulated; Engineering; Enzymes; Epithelium; Extracellular Matrix; Extracellular Matrix Degradation; Frequencies; Goals; Hyaluronan; Hyaluronic Acid; Hyaluronidase; Immune; Immunotherapy; Incidence; Infiltration; Investigational Drugs; Legal patent; Malignant Neoplasms; Malignant neoplasm of pancreas; Manuals; Measures; Mesenchymal; Methods; Myofibroblast; National Cancer Institute; Neoplasm Metastasis; Pancreatic Ductal Adenocarcinoma; Patients; Penetration; Perfusion; Permeability; Pharmaceutical Preparations; Plasmids; Play; Primary Neoplasm; Production; Public Health; Publishing; Recombinants; Regenerative capacity; Regimen; Research; Role; Salmonella; Salmonella typhimurium; Serious Adverse Event; Solid; Solid Neoplasm; Surface; Survival Rate; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Tumor Burden; Tumor Promotion; Tumor Tissue; Tumor-infiltrating immune cells; Vascularization; Work; advanced disease; cancer therapy; candidate identification; chemotherapy; clinical translation; clinically relevant; collagenase; comparative efficacy; conventional therapy; cost; density; design and construction; experience; immune cell infiltrate; immune checkpoint blockade; improved; innovation; interstitial; macromolecule; manufacture; microbial; mortality; mouse model; novel; novel strategies; pancreatic ductal adenocarcinoma model; pressure; prevent; promoter; protein expression; remediation; side effect; smoothened signaling pathway; standard of care; systemic toxicity; therapy resistant; tumor; tumor growth; vector

PROJECT SUMMARY Therapeutic resistance is a major contributor to high lethality in pancreatic ductal adenocarcinoma (PDAC). A prominent feature of PDAC is desmoplasia, the formation of fibrous tissue that not only plays a critical role in reducing drug perfusion but also in limiting anti-tumor immune cell infiltration and function. The fibrous tissue is primarily composed of the extracellular matrix (ECM) components hyaluronan (HA) and collagen (CN). Previous methods to target these major ECM components have caused severe systemic side effects in patients and, thus, finding a safe, effective approach to disrupt the PDAC ECM and improve drug delivery remains a critical unmet need. Our long-term goal is to develop tumor-specific, microbial-based agents that express functional ECM- degrading enzymes. This novel strategy will remediate tumor desmoplasia, minimize systemic toxicity, and maximize the penetration and efficacy of therapeutics against primary PDAC tumors, as well as distal metastases. The objective of this proposal is to determine the utility of attenuated Salmonella typhimurium (ST)-based agents, engineered to express the ECM-degrading enzymes hyaluronidase (ST-HAse) and collagenase (ST-CNase), in triggering collapse of dense tumor stroma and in enhancing therapeutic efficacy in clinically-relevant models of PDAC. The rationale underlying this proposal is that successful completion of these studies will identify a feasible, tumor-targeting approach to ameliorate desmoplasia in PDAC, which will enable anticancer agents to achieve their greatest therapeutic effects. Our central hypothesis is that degrading both HA and CN in PDAC using tumor-specific ST vectors will induce the greatest stromal collapse, ultimately leading to enhanced penetration and efficacy of therapeutic treatment. This central hypothesis will be tested in relevant models of PDAC by pursuing three specific aims: (1) Determine the effect of dual ST-HAse/CNase treatment on the antitumor efficacy of standard-of-care chemotherapy; (2) Determine the impact of dual ST-HAse/CNase treatment on efficacy of immune checkpoint blockade therapy; and (3) Develop and characterize recombinant STs expressing HAse and CNase under tumor-inducible promoters. The use of tumor-colonizing ST and tumor-inducible bacterial promoters to express ECM-degrading enzymes is an innovative strategy to limit the effects of stromal degradation to tumor tissues. Furthermore, simultaneously degrading HA and CN will result in greater tumor permeability than targeting either component alone. The results of this work will have a significant impact for PDAC patients, because it is predicted to yield an agent(s) that can, in the short-term, be optimized for manufacturing and Investigational New Drug (IND)-enabling studies and, in the long-term, become a first-in-class, microbial-based agent used to significantly improve drug permeability of desmoplastic primary and metastatic tumors that are inaccessible to conventional therapy.

项目摘要 治疗性耐药性是胰腺导管腺癌（PDAC）高致死性的主要因素。一个 PDAC的突出特征是Desmoplasia，这是纤维组织的形成，不仅在 减少药物灌注，但也限制了抗肿瘤免疫细胞浸润和功能。纤维组织是 主要由细胞外基质（ECM）组成透明质酸（HA）和胶原蛋白（CN）组成。以前的 针对这些主要ECM组件的方法对患者产生了严重的全身副作用，因此 寻找一种安全有效的方法来破坏PDAC ECM并改善药物输送仍然是一个关键 需要。我们的长期目标是开发表达功能性ECM-的肿瘤特异性，基于微生物的药物 降解酶。这种新颖的策略将补救肿瘤脱木质，最大程度地减少全身毒性，并 最大化治疗剂对原发性PDAC肿瘤的渗透和功效以及远端 转移。该提议的目的是确定鼠伤寒沙门氏菌的效用 基于（ST）的代理，设计为表达ECM降解酶透明质酸酶（ST-hase）和 胶原酶（ST-CNase），在触发致密肿瘤基质的崩溃和增强治疗疗效中 PDAC的临床相关模型。该提议的基本原理是成功完成 研究将确定一种可行的，涉及肿瘤的方法，以改善PDAC中的脱木质，这将使能够实现 抗癌药以达到其最大的治疗作用。 我们的中心假设是，使用肿瘤特异性ST载体在PDAC中降低HA和CN将诱导 最大的基质崩溃，最终导致治疗治疗的渗透率和功效增强。 该中心假设将通过追求三个特定目的在PDAC的相关模型中进行测试：（1）确定 双 - 圣酶/CNase处理对护理标准化疗的抗肿瘤功效的影响； （2） 确定双重ST-das-ass/CNase治疗对免疫检查点阻滞治疗功效的影响； （3）在肿瘤诱导症下发展并表征表达大麻和CNase的重组STS 发起人。 使用肿瘤 - 殖民化的ST和肿瘤诱导的细菌启动子来表达ECM降解酶是 限制基质降解对肿瘤组织的影响的创新策略。此外，同时 与单独靶向任何一个分量相比，降解HA和CN的肿瘤渗透性将导致更大的肿瘤通透性。结果 这项工作将对PDAC患者产生重大影响，因为预计它会产生一种代理商 在短期内，可以针对制造和研究新药（IND）进行优化，并确保研究 从长远来看，成为一类基于微生物的剂，用于显着改善药物渗透性 传统疗法无法访问的脱糖原发性和转移性肿瘤