Studies on Lineage Plasticity in Prostate Cancer
前列腺癌谱系可塑性的研究
基本信息
- 批准号:10722935
- 负责人:
- 金额:$ 27.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:ATAC-seqAdenocarcinomaAdvisory CommitteesAndrogen ReceptorBRAF geneBiologicalBiopsyCRISPR/Cas technologyCancer ModelCancer PatientCancerousCellsChemicalsClinicalCollaborationsCombined Modality TherapyCompetenceDNADataDoxycyclineDrug CombinationsDrug resistanceEnvironmentEpidermal Growth Factor ReceptorEstrogen receptor positiveEventEvolutionFDA approvedFGFR1 geneFGFR3 geneFibroblast Growth Factor ReceptorsFundingFutureGeneticGenetic Models for CancerGenitourinary systemGenomicsGoalsGrantHistologyHumanKineticsKnockout MiceLeadLungMAP Kinase GeneMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMediatingMemorial Sloan-Kettering Cancer CenterMentorsModelingMolecularMorphologyMusNOD/SCID mouseNeurosecretory SystemsOncogenicOncologyOrganoidsOutcomePIK3CG genePathway interactionsPatient-Focused OutcomesPatientsPharmaceutical PreparationsPhosphorylationPhysiciansPositioning AttributePredictive FactorProcessProstateProtein IsoformsProto-Oncogene Proteins c-aktRB1 geneRNARandomizedReceptor SignalingResearchResearch PersonnelResistanceResourcesSTAT1 geneSTAT3 geneSafetySamplingScienceSignal PathwaySignal TransductionTP53 geneTestosteroneTherapeuticTimeTrainingTranslationsTransplantationTumor Suppressor GenesTumor WeightsXCL1 genecancer cellcastration resistant prostate cancercomputerized toolsefficacy evaluationenzalutamidein vivoinhibitormalignant breast neoplasmmelanomamouse modelmultiple omicsmutantnoveloverexpressionpharmacologicprogramsreceptor expressionresistance mechanismsingle-cell RNA sequencingsubcutaneoussuccesssynergismtargeted agenttargeted cancer therapytherapy resistanttranscription factortranscriptome sequencingtumor
项目摘要
PROJECT SUMMARY
Despite the remarkable successes of targeted cancer therapies, certain cancers, including lung, breast, and
prostate cancer and melanoma, invariably become resistant to therapy. One mechanism of secondary
resistance—lineage plasticity—arises when cells transition into aggressive states, and, in the case of prostate
cancer, acquire a neuroendocrine histology. This results in a rapid downhill course for a subset of the so–termed
castrate–resistant prostate cancer (CRPC) patients. This, in essence, not only poses a clinical challenge, but
also confronts us with a wide–open biological question—what are the molecular underpinnings of lineage
plasticity, and importantly, can the process be reversed? We have very recently documented that the activation
of JAK/STAT and FGFR signaling pathways promote lineage plasticity and result in complete insensitivity to
androgen receptor signaling inhibitors (ARSIs) [*Chan, *Zaidi, et al., Science, 2022, PMID: 35981096, *co–
first authors]. Importantly, we found that FDA–approved inhibitors of JAK/STAT (ruxolitinib) and FGFR
(erdafitinib) synergize to reverse lineage plasticity and restore ARSI sensitivity. We therefore hypothesize that
signals downstream of JAK/STAT and FGFR, including novel transcription factors, interact to promote lineage
plasticity, and their timed perturbation can reverse plasticity and ARSI insensitivity. Thus, in Specific Aim 1, to
study how FGFR signals synergize with JAK/STAT to impart plasticity, we will use chemical inhibitors and
CRISPR–Cas9 to delete specific molecules in TP53/RB1–null mouse and human tumor organoids. Specific
Aim 2 will focus on further deconvoluting the molecular complexity of lineage plasticity through unbiased single
cell paired RNA and ATAC (multiome) sequencing in murine organoids. We expect to identify novel transcription
factors and study their DNA accessibility post–TP53/RB1 deletion across the evolution of lineage plasticity, with
and without ruxolitinib and/or erdafitinib. In Specific Aim 3, in proof–of–concept in vivo studies, we will examine
the efficacy of combined treatment with ruxolitinib plus erdafitinib in reversing lineage plasticity and restoring
ARSI sensitivity. For this, the ruxolitinib+erdafitinib combination will be studied in NOD SCID mice grafted either
with TP53/RB1–null murine organoids, orthotopically, or with the human tumoroid MSK–PCA3, subcutaneously.
These studies will not only inform future therapeutic strategies to subvert drug resistance in CRPC patients but
should also provide a unique platform for my Training Aims. Under the tutelage of my primary mentor, Dr.
Charles Sawyers, and my Advisory Committee, I expect to enhance my competencies in advanced computation,
cancer modeling and genetic editing, and bedside translation. Together with the rich scientific environment and
vast array of resources at MSKCC, my research and training should position me to achieve my goal of becoming
an independently funded physician–investigator in genitourinary oncology by the end of this grant period.
项目总结
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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SAMIR ZAIDI其他文献
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{{ truncateString('SAMIR ZAIDI', 18)}}的其他基金
Genomic and Functional Architecture of Congenital Heart Disease
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8986651 - 财政年份:2014
- 资助金额:
$ 27.77万 - 项目类别:
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