Development of Microbial-Based Therapies to Suppress Macropinocytosis in Kras-Driven Cancers

开发基于微生物的疗法来抑制 Kras 驱动的癌症中的巨胞饮作用

• 批准号: 10502177
• 负责人: EDWIN MANUEL
• 金额: $ 40.26万
• 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: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10502177
• 关键词: Affinity; Anabolism; Antimetabolites; Attenuated; Automobile Driving; Autophagocytosis; Binding; Bladder; Breast; Catabolic Process; Cell Line; Cell Proliferation; Cell surface; Clinical; Colon; Colorectal Cancer; Culture Media; Development; Disease; Drug resistance; Endocytosis; Engineering; Enzymes; Extracellular Matrix; Fluorouracil; Gene Expression; Genes; Glucosamine; Glucuronic Acids; Glycosides; Goals; Growth; Growth Factor; Heparan Sulfate Proteoglycan; Heparin Lyase; Heparitin Sulfate; Homeostasis; Investigational Drugs; KRAS oncogenesis; Lesion; Lung; Lysosomes; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Malignant neoplasm of urinary bladder; Manuals; Measures; Mediating; Mediator of activation protein; Metabolic; Metabolism; Methods; Modification; Monomeric GTP-Binding Proteins; National Cancer Institute; Natural regeneration; Neoplasm Metastasis; Nutrient; Oncogenic; Outcome; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Plasmids; Process; Production; Prognosis; Prostate; Proteins; Recombinants; Recurrence; Research; Resistance; Salmonella typhimurium; Signal Transduction; Signaling Molecule; Source; Stress; Structure; Testing; Therapeutic; Therapeutic Agents; Therapeutic Use Study; Tumor Tissue; Vertebral column; Work; Xenograft Model; base; cancer therapy; clinical translation; clinically relevant; conventional therapy; cost; cytokine; depolymerization; design and construction; experience; extracellular; gemcitabine; heparanase; heparinase III; in vivo; ineffective therapies; inhibitor; macromolecule; malignant breast neoplasm; microbial; mortality; mouse model; mutant; neoplastic cell; neovascularization; novel; novel strategies; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; patient derived xenograft model; promoter; receptor; response; standard of care; syndecan; targeted agent; targeted treatment; therapeutic target; therapy resistant; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor progression; tumorigenic; vector

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with dismal prognosis. A near-universal oncogenic driver of PDAC is the constitutive activation of the small GTPase protein Kras, which induces multiple downstream signaling cascades that together facilitate rapid cell proliferation, metastasis and therapeutic resistance. To surmount the high energy demands of these activities, Kras also triggers metabolic adaptations to promote nutrient scavenging from extracellular sources, such as through macropinocytosis. Macropinocytosis is a process by which extracellular material is non-specifically engulfed and then degraded in lysosomes to produce end-products utilized by tumor cells for biosynthesis. This process essentially confers resistance to a myriad of anabolic inhibitors. Syndecan-1 is a heparan sulfate proteoglycan (HSPG) upregulated on the surface of cells that serves as the key mediator of macropinocytosis in PDAC and other Kras-driven cancers that includes bladder, lung, prostate, colon and breast. In addition to mediating macromolecular transport, HSPGs can be found in the tumor extracellular matrix (ECM) binding to and regulating the interaction of numerous signaling molecules (e.g. growth factors and cytokines) with their cognate receptors. The pro-tumorigenic activities of HSPGs are exquisitely regulated by enzymatic modification of their heparan sulfate (HS) moieties. Mammalian heparanases employ hydrolytic cleavage of the beta-(1,4)-glycosidic bond between glucuronic acid and glucosamine to promote the release of growth factors and enzymes involved in ECM remodeling, invasion and metastasis. In contrast to mammalian heparanases, bacterial heparinase III (HepIII) depolymerizes HSPGs through a unique beta-elimination mechanism that cleaves at the alpha-(1,4)- glycosidic bond. Various studies have confirmed HepIII modification of HSPGs suppresses neovascularization, macropinocytosis, tumor growth and metastasis. However, the inability to restrict HepIII activity to tumor tissue has long prohibited its use as a therapeutic agent. Using attenuated, tumor-targeting Salmonella typhimurium (ST) vectors, we have developed the first recombinant ST expressing functional HepIII (ST-HepIII) through a tightly regulated, inducible promoter. We have confirmed the ability of ST-HepIII to suppress high-affinity HS interactions, macropinocytosis, and growth of Kras-mutant tumors. In this application, we will: 1) Determine the impact of ST-HepIII treatment on metabolite availability and metabolic-associated gene pathways in vivo; 2) Determine anti-tumor efficacy of anabolic inhibitors in combination with ST-HepIII; and 3) Develop and characterize recombinant STs expressing HepIII under tumor-inducible promoters for greater clinical feasibility. Completing these aims will allow us to develop a novel class of tumor-targeting agents capable of suppressing a metabolic process essential to the survival of PDAC and other Kras-driven cancers. Our agents may be used to counteract acquired resistance to standard-of-care therapies that target cooperative anabolic processes and positively impact survival for patients with difficult-to-treat cancers.

胰导管腺癌（Pancreatic ductal adencarcinoma， PDAC）是一种侵袭性很强的疾病