Targeting colorectal cancer stem cells with ALDH1B1 antagonists
使用 ALDH1B1 拮抗剂靶向结直肠癌干细胞
基本信息
- 批准号:10640894
- 负责人:
- 金额:$ 43.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-06-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:Adherent CultureAftercareAngiogenesis InhibitorsAntimitotic AgentsBiochemicalBiochemistryBiological AssayCancer BiologyCancer EtiologyCancer ModelCell LineCell MaintenanceCell modelCellsCellular biologyCessation of lifeChemicalsChemoresistanceClinicalClustered Regularly Interspaced Short Palindromic RepeatsColon CarcinomaColorectal CancerComplementComplexDevelopmentDiagnosisDifferentiation and GrowthDiseaseDrug TargetingEnzymesEpidermal Growth Factor ReceptorExhibitsGastroenterologyGenesGoalsGuanidinesImmunodeficient MouseImmunotherapyIn VitroIncidenceIndividualIntestinesInvestigationInvestigational DrugsKnock-outLeadLife StyleLipid PeroxidationMalignant NeoplasmsMediatingMetabolicMetabolic PathwayMetabolismMitochondriaMolecularMusMutagenesisNeoplasm MetastasisNormal tissue morphologyOncogenicOperative Surgical ProceduresOutcomePathway interactionsPatientsPeriodicityPharmaceutical ChemistryPopulationPreventive screeningPropertyProtein IsoformsRelapseReportingResearchResectedRetinaRoentgen RaysRoleSignal TransductionStructureSurvival RateSynthesis ChemistryTherapeuticTimeTretinoinTumor PromotionTumorigenicityWorkXenograft ModelXenograft procedureabsorptionaldehyde dehydrogenasesantagonistcancer cellcancer stem cellcancer subtypescancer therapychemotherapeutic agentchemotherapycolon cancer cell linecolon cancer patientscolon growthcolorectal cancer progressioncolorectal cancer treatmenteffective therapyimprovedin vivoinhibitorinsightlipid metabolismmetastatic colorectalmolecular subtypesneoplastic cellnew therapeutic targetoxidationpharmacologicpre-clinicalresponsescaffoldself renewing cellstem cell biologystem cell biomarkersstem cell functionstem cell populationstem cell survivalstem cellsstemnessstructural biologytherapeutic targettooltranscriptometranscriptomic profilingtumortumor growthtumor xenografttumorigenesiswestern dietyoung adult
项目摘要
Colorectal cancer is the third most common malignancy in the world, with approximately 1.4 million new cases
and 700,000 deaths each year. Global incidence rates are expected to escalate 60% by 2030 as Western diets and
lifestyles become more common, and colorectal cancer is afflicting increasing numbers of young adults. Despite
preventative screening and surveillance, approximately 20% of colorectal cancer patients have metastatic disease at
the time of diagnosis, and 40-50% of early-stage patients will relapse after treatment. Unfortunately standard colorectal
cancer therapies such as anti-mitotic agents, epidermal growth factor receptor antagonists, and angiogenesis inhibitors
are largely ineffectual against late-stage disease. As a result, the 5-year survival rates for these patients is only 12%.
It is now widely believed that eliminating cancer stem cells (CSCs) is the key to durable clinical responses, as
these self-renewing cells drive tumor relapse, chemoresistance, and metastasis. Our project strives to achieve this
goal by investigating and pharmacologically targeting metabolic pathways that are unique to colorectal cancer CSCs.
Our work builds on recent reports that aldehyde dehydrogenase 1B1 (ALDH1B1) is expressed in intestinal stem cell
and required for the growth of colon cancer-derived spheroid cultures and xenografts. Our findings support a role for
ALDH1B1 in colorectal CSC maintenance, and we have developed the first known ALDH1B1-selective antagonists.
We have also solved the first X-ray crystal structures of ALDH1B1 and ALDH1B1-inhibitor complexes, uncovering the
molecular basis of antagonist action and gaining insights for further compound development. Our latest lead
compounds can inhibit the viability of colorectal cancer spheroids, with minimal effects on adherent cultures or non-
cancerous cells. In addition, our preliminary studies indicate that ALDH1B1 inhibitors can suppress the growth of colon
cancer xenografts in mice.
We are now investigating the mechanisms by which ALDH1B1 promotes colorectal cancer (Aim 1). We will
explore the potential roles of this mitochondrial enzyme in colorectal CSC maintenance, chemoresistance, and
invasiveness, using cell lines that are representative of various colorectal cancer subtypes. We will also determine
whether oncogenic ALDH1B1 function involves the oxidation of retinal and/or lipid peroxidation products, and we will
elucidate the ALDH1B1-dependent transcriptome. In parallel with these mechanistic studies, we will use medicinal
chemistry, biochemical assays, and cellular models to develop ALDH1B1 inhibitors with optimized potency, selectivity,
and pharmacological properties (Aim 2). We will then evaluate the activities of ALDH1B1 inhibitors in colorectal cancer
xenograft models (Aim 3). Together, these investigations will deepen our understanding of ALDH1B1 function and
colorectal CSC biology. They will also generate new chemical tools for studying ALDH1B1-dependent pathways,
reveal the therapeutic potential of pharmacological ALDH1B1 inhibition, and provide valuable leads for the
development of ALDH1B1-targeting drugs.
结直肠癌是世界上第三大最常见的恶性肿瘤,大约有140万新病例
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JAMES K CHEN其他文献
JAMES K CHEN的其他文献
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{{ truncateString('JAMES K CHEN', 18)}}的其他基金
Targeting colorectal cancer stem cells with ALDH1B1 antagonists
使用 ALDH1B1 拮抗剂靶向结直肠癌干细胞
- 批准号:
10407067 - 财政年份:2021
- 资助金额:
$ 43.19万 - 项目类别:
Targeting colorectal cancer stem cells with ALDH1B1 antagonists
使用 ALDH1B1 拮抗剂靶向结直肠癌干细胞
- 批准号:
10299142 - 财政年份:2021
- 资助金额:
$ 43.19万 - 项目类别:
Development of allosteric HIPK4 inhibitors as non-hormonal male contraceptives
开发变构 HIPK4 抑制剂作为非激素男性避孕药
- 批准号:
10470960 - 财政年份:2019
- 资助金额:
$ 43.19万 - 项目类别:
Development of allosteric HIPK4 inhibitors as non-hormonal male contraceptives
开发变构 HIPK4 抑制剂作为非激素男性避孕药
- 批准号:
10018041 - 财政年份:2019
- 资助金额:
$ 43.19万 - 项目类别:
Development of allosteric HIPK4 inhibitors as non-hormonal male contraceptives
开发变构 HIPK4 抑制剂作为非激素男性避孕药
- 批准号:
10673682 - 财政年份:2019
- 资助金额:
$ 43.19万 - 项目类别:
Development of allosteric HIPK4 inhibitors as non-hormonal male contraceptives
开发变构 HIPK4 抑制剂作为非激素男性避孕药
- 批准号:
10456372 - 财政年份:2019
- 资助金额:
$ 43.19万 - 项目类别:
Gli1-selective inhibitors of the Hedgehog signaling pathway
Hedgehog 信号通路的 Gli1 选择性抑制剂
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9100825 - 财政年份:2015
- 资助金额:
$ 43.19万 - 项目类别:
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