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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结