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
基本信息
- 批准号:10502177
- 负责人:
- 金额:$ 40.26万
- 依托单位:
- 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:2022-07-01 至 2027-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffinityAnabolismAntimetabolitesAttenuatedAutomobile DrivingAutophagocytosisBindingBladderBreastCatabolic ProcessCell LineCell ProliferationCell surfaceClinicalColonColorectal CancerCulture MediaDevelopmentDiseaseDrug resistanceEndocytosisEngineeringEnzymesExtracellular MatrixFluorouracilGene ExpressionGenesGlucosamineGlucuronic AcidsGlycosidesGoalsGrowthGrowth FactorHeparan Sulfate ProteoglycanHeparin LyaseHeparitin SulfateHomeostasisInvestigational DrugsKRAS oncogenesisLesionLungLysosomesMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of pancreasMalignant neoplasm of prostateMalignant neoplasm of urinary bladderManualsMeasuresMediatingMediator of activation proteinMetabolicMetabolismMethodsModificationMonomeric GTP-Binding ProteinsNational Cancer InstituteNatural regenerationNeoplasm MetastasisNutrientOncogenicOutcomePancreatic Ductal AdenocarcinomaPathway interactionsPatientsPlasmidsProcessProductionPrognosisProstateProteinsRecombinantsRecurrenceResearchResistanceSalmonella typhimuriumSignal TransductionSignaling MoleculeSourceStressStructureTestingTherapeuticTherapeutic AgentsTherapeutic Use StudyTumor TissueVertebral columnWorkXenograft Modelbasecancer therapyclinical translationclinically relevantconventional therapycostcytokinedepolymerizationdesign and constructionexperienceextracellulargemcitabineheparanaseheparinase IIIin vivoineffective therapiesinhibitormacromoleculemalignant breast neoplasmmicrobialmortalitymouse modelmutantneoplastic cellneovascularizationnovelnovel strategiespancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpatient derived xenograft modelpromoterreceptorresponsestandard of caresyndecantargeted agenttargeted treatmenttherapeutic targettherapy resistanttumortumor growthtumor metabolismtumor microenvironmenttumor progressiontumorigenicvector
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('EDWIN MANUEL', 18)}}的其他基金
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 - 财政年份:2022
- 资助金额:
$ 40.26万 - 项目类别:
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:
10652633 - 财政年份:2022
- 资助金额:
$ 40.26万 - 项目类别:
Utilizing Hybrid Antigen-Presenting Neutrophils to Prime WT1-Specific Immune Responses as Therapy for Acute Leukemia
利用混合抗原呈递中性粒细胞引发 WT1 特异性免疫反应作为急性白血病的治疗方法
- 批准号:
10533378 - 财政年份:2021
- 资助金额:
$ 40.26万 - 项目类别:
Utilizing Hybrid Antigen-Presenting Neutrophils to Prime WT1-Specific Immune Responses as Therapy for Acute Leukemia
利用混合抗原呈递中性粒细胞引发 WT1 特异性免疫反应作为急性白血病的治疗
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10373124 - 财政年份:2021
- 资助金额:
$ 40.26万 - 项目类别:
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