Exploiting Cancer Metabolism and Drug Efflux with Bystander-Assisted Immunotherapy

通过旁观者辅助免疫疗法利用癌症代谢和药物流出

• 批准号: 10227793
• 负责人: Rock Mancini
• 金额: $ 34.34万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227793
• 关键词: ABCB1 gene; ATP-binding cassette transport; Active Biological Transport; Address; Agreement; Allografting; Antineoplastic Agents; Area; Binding; Biodistribution; Biological Models; Cancer Patient; Cancer cell line; Carrier Proteins; Cell Survival; Cells; Coculture Techniques; Cohort Studies; Coupling; Data; Development; Diffusion; Disseminated Malignant Neoplasm; Drug Efflux; Drug Transport; Drug resistance; Enzyme Tests; Enzymes; Exhibits; Extracellular Space; Goals; Immune; Immune response; Immune system; Immunocompetent; Immunomodulators; Immunotherapeutic agent; Immunotherapy; In Vitro; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Metabolic; Metabolic Pathway; Metabolism; Methods; Modality; Multi-Drug Resistance; Mus; Outcome; Pharmaceutical Preparations; Phenotype; Predisposition; Process; Prodrugs; Progression-Free Survivals; RNA Interference; Reporting; Research; Resistance development; Specificity; Structure; Techniques; Testing; Therapeutic; Toxic effect; Tumor Volume; Vision; Work; acquired drug resistance; anti-cancer; anti-cancer therapeutic; base; cancer cell; cancer drug resistance; cancer immunotherapy; cancer therapy; cancer type; chemotherapy; conventional therapy; cytotoxic; design; drug metabolism; immunogenicity; in vivo; in vivo Model; inhibitor/antagonist; mortality; mouse model; multidrug resistant cancer; nanomedicine; novel drug class; novel therapeutics; overexpression; programs; prostate cancer model; refractory cancer; side effect; small molecule; synthetic enzyme; tumor metabolism; tumor microenvironment; tumorigenesis

ABSTRACT. Two hallmarks of drug resistance in cancers are irregular metabolism and drug efflux. In multidrug- resistant cancers, both of these processes disarm the efficacy of chemotherapeutics, ultimately resulting in de- creased chemotherapeutic efficacy and increased mortality. Several strategies in development attempt to miti- gate the effects of drug resistance by modulating specific metabolic pathways or disrupting drug efflux. Specifi- cally, these strategies include inhibitors, interference RNAs, and nanomedicine approaches. However, a funda- mental challenge to these strategies is the off-target toxicity that arises from disrupting metabolism or drug efflux mediated by P-glycoprotein (P-gp), as these mechanisms are also critical to a number of healthy processes throughout the body. To address this, our long-term objective is to develop a therapeutic strategy that exploits both of these mechanisms of drug resistance in tandem to generate a therapeutic anti-cancer immune repsonse. Our central hypothesis is that rationally designed prodrugs can co-opt cancer cell metabolism and drug efflux to cause an anti-cancer immune response via a mechanism of action we have termed Bystander Assisted Immu- noTherapy (BAIT). In BAIT, an enzyme-directed prodrug is first metabolized to an immunotherapeutic metabolite by the irregular metabolism of multidrug-resistant cancer cells. Next, the immunotherapeutic is transported, via P-gp-mediated drug efflux, to the extracellular space. This results in the activation of bystander immune cells in local proximity, which initiate an anti-cancer immune response. Because BAIT requires tandem metabolism and drug efflux, we anticipate a uniquely enhanced specificity for multidrug-resistant phenotypes that exhibit both of these processes. To develop rationally designed BAIT prodrugs, we first identify small-molecule immunothera- peutics that are susceptible to drug efflux. In concurrent studies, we also develop synthetic enzyme-directing groups that modulate the activity of immunotherapeutics and are specifically removed by enzymes expressed in the irregular metabolism of multidrug-resistant cancer cells. Combining these two research areas, we generate enzyme-directed BAIT prodrugs that confer immunogenicity to multidrug-resistant cancers. In-vitro, this is con- firmed in co-cultures of immune cells and cancer cell lines that express these metabolic enzymes and P-gp. In- vivo, we use a murine model system for prostate cancer (TRAMP-C2 allograft) to demonstrate that BAIT pro- drugs result in lowered toxicity, decreased tumor volume, and increased progression-free survival, relative to conventional immunotherapeutics in immunocompetent mice. Taken together, we envision that this research will establish BAIT as a therapeutic strategy that is enhanced, rather than disarmed, by drug resistance. It is our long-term vision that this strategy could be widely applicable to multidrug-resistant cancers that evade the action of conventional therapies through altered metabolisms and drug efflux.

摘要。癌症耐药的两个特征是代谢不规律和药物外排。在多