Elucidating and Targeting tumor dependencies and drug resistance determinants at the single cell level
Elucidating and Targeting tumor dependencies and drug resistance determinants at the single cell level
批准号:
10505333
负责人:
ANDREA CALIFANO
金额:
$99.12万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-09-21 至 2027-08-31
关键词:
AcuteAddressAdultBiological AssayBiological MarkersBreast AdenocarcinomaCLIA certifiedCancer PatientCategoriesCellsClinicalClinical TrialsCollaborationsCombined Modality TherapyData SetDependenceDesmoplastic Small Round Cell TumorDevelopmentDissectionDrug TargetingDrug resistanceGeneticGenetic TranscriptionGlioblastomaGoalsHealthImmunotherapyIndividualMaintenanceMalignant Childhood NeoplasmMalignant NeoplasmsMalignant neoplasm of prostateMediatingMethodologyMolecularMutateMutationNetwork-basedNeuroblastomaNeuroendocrine TumorsOncogenesOncoproteinsPathway interactionsPatientsPediatric NeoplasmPharmaceutical PreparationsPharmacologyPopulationProgression-Free SurvivalsProstateProstate AdenocarcinomaProteinsRelapseReporter GenesResearch PersonnelReverse engineeringRoleSignal TransductionSliceTestingThe Cancer Genome AtlasTissuesTumor SubtypeValidationbasebiomarker developmentcancer cellcancer geneticscancer pharmacologycohortdesigndrug sensitivityfallsfollow-upimprovedneoplastic cellnovelpatient derived xenograft modelresistance mechanismresponsesarcomasingle-cell RNA sequencingsuccesstargeted treatmenttherapeutic targettherapeutically effectivetranscription factortumortumorigenesis
中文摘要
癌症靶点主要分为两大类:一类是癌蛋白,由于其在肿瘤中的直接作用而引发肿瘤的必要性
英文摘要
Cancer targets fall into two major categories: oncoproteins that elicit tumor essentiality due to their direct role in
tumorigenesis or tumor maintenance (oncogene dependencies) and proteins that elicit synthetic lethality with
oncogene mutations but are not themselves mutated (non-oncogene dependencies). Unfortunately, clonal
selection and inherent cancer cell plasticity—as well as the ability of cancer cells to undergo adaptation and
reprogramming to drug resistant states, following treatment—are currently challenging the concept of
individual proteins as effective therapeutic targets for an entire tumor mass—especially if identified from
bulk tissue analyses. Indeed, despite several successes, only 5% – 11% of cancer patients benefit from
targeted therapy, based on progression free survival, often with no substantial overall survival differences; while
promising, immune therapy is also subject to selective response and relapse. To address these challenges, our
proposal will study a more universal class of mutation-agnostic, non-oncogene dependencies implemented
by tightly-autoregulated sets of Master Regulator (MR) proteins that we have called Tumor Checkpoint (TC)
modules. We have shown that MR proteins mechanistically implement a tumor cell’s transcriptional state by
canalizing the effect of mutations and aberrant signals in their upstream pathways. As such, within the context
of a transcriptionally-distinct tumor subtype, they represent largely mutation-agnostic dependencies. Our
proposal will thus focus on the elucidation and pharmacological targeting of MRs and TC-modules at the
single cell level, within molecularly distinct, yet co-existing tumor subpopulations. This will lead to design
of successful combination therapy approaches and will help elucidate and pharmacologically target mechanisms
of drug resistance and cell adaptation. To accomplish these goals, we will extend a highly successful, network-
based framework developed by our CTD2 Center, for the elucidation, validation, and pharmacological targeting
of MR proteins and TC-modules. Indeed, we have shown that genetic or pharmacological targeting of this new
class of tumor dependencies can induce collapse of TC-module activity and induce loss of tumor viability in a
wide range of malignancies, ranging from glioblastoma, neuroblastoma, and neuroendocrine tumors, to prostate
and breast adenocarcinoma, among many others. In particular, analysis of 25 TCGA cohorts has identified 112
transcriptionally distinct tumor subtypes, each one regulated by a distinct subtype-specific TC-module, which
was independent of patient-specific mutations. These methodologies are especially relevant in rare, aggressive
tumors—including several pediatric malignancies—where cohort size may be too small to support correlative
analyses. Critically, these studies have led to the development of two NY/CA Dpt. of Health approved, CLIA-
compliant tests, OncoTarget and OncoTreat, whose predictions have spurred several clinical trials. These
approaches will be extended to elucidate TC-module dependencies and to develop drug sensitivity biomarkers
at the single cell level.
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会议论文
Administrative Core
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批准号:10729384
-
项目类别:
-
资助金额:$5.4万
-
财政年份:2023
-
负责人:ANDREA CALIFANO
-
依托单位:
Center for Cancer Systems Therapeutics (CaST)
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批准号:10729383
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项目类别:
-
资助金额:$175.41万
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财政年份:2023
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负责人:ANDREA CALIFANO
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依托单位:
Drug Mechanism of Action-based targeting of tumor subpopulations
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批准号:10729387
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项目类别:
-
资助金额:$47.94万
-
财政年份:2023
-
负责人:ANDREA CALIFANO
-
依托单位:
Elucidating and Targeting tumor dependencies and drug resistance determinants at the single cell level
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批准号:10709574
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项目类别:
-
资助金额:$95.62万
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财政年份:2022
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负责人:ANDREA CALIFANO
-
依托单位:
Structural and Functional Biology-based analysis of non-oncogene cancer dependencies
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批准号:10401148
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项目类别:
-
资助金额:$50.0万
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财政年份:2021
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负责人:ANDREA CALIFANO
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依托单位:
Systematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer Medicine
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批准号:9977981
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项目类别:
-
资助金额:$129.94万
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财政年份:2017
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负责人:ANDREA CALIFANO
-
依托单位:
Systematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer Medicine
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批准号:10204929
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项目类别:
-
资助金额:$120.19万
-
财政年份:2017
-
负责人:ANDREA CALIFANO
-
依托单位:
Systematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer Medicine
-
批准号:9750650
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项目类别:
-
资助金额:$114.5万
-
财政年份:2017
-
负责人:ANDREA CALIFANO
-
依托单位:
Systematic Identification and Pharmacological Targeting of Tumor Dependencies for Precision Cancer Medicine
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批准号:9362806
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项目类别:
-
资助金额:$116.45万
-
财政年份:2017
-
负责人:ANDREA CALIFANO
-
依托单位:
Centers for Cancer Systems Therapeutics (CaST)
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批准号:9976471
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项目类别:
-
资助金额:$204.16万
-
财政年份:2016
-
负责人:ANDREA CALIFANO
-
依托单位:
Centers for Cancer Systems Therapeutics (CaST)
-
批准号:10021243
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项目类别:
-
资助金额:$6.83万
-
财政年份:2016
-
负责人:ANDREA CALIFANO
-
依托单位:
Centers for Cancer Systems Therapeutics (CaST)
-
批准号:9328002
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项目类别:
-
资助金额:$199.17万
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财政年份:2016
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负责人:ANDREA CALIFANO
-
依托单位:
Centers for Cancer Systems Therapeutics (CaST)
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批准号:9752983
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项目类别:
-
资助金额:$206.55万
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财政年份:2016
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负责人:ANDREA CALIFANO
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依托单位:
An Administrative Core for the CaST Center
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批准号:9186388
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项目类别:
-
资助金额:$26.66万
-
财政年份:2016
-
负责人:ANDREA CALIFANO
-
依托单位:
Centers for Cancer Systems Therapeutics (CaST)
-
批准号:9186387
-
项目类别:
-
资助金额:$199.19万
-
财政年份:2016
-
负责人:ANDREA CALIFANO
-
依托单位:
Predicting Cancer Cell Response to Endogenous and Exogenous Perturbations at the Single Cell Level
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批准号:10698176
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项目类别:
-
资助金额:$95.73万
-
财政年份:2015
-
负责人:ANDREA CALIFANO
-
依托单位:
Elucidating the dependencies of tumor initiating and drug-resistant niches in human malignancies by genome- wide molecualr profiling of single cells
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批准号:9319711
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项目类别:
-
资助金额:$95.23万
-
财政年份:2015
-
负责人:ANDREA CALIFANO
-
依托单位:
Elucidating the dependencies of tumor initiating and drug-resistant niches in human malignancies by genome- wide molecualr profiling of single cells
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批准号:10219168
-
项目类别:
-
资助金额:$95.23万
-
财政年份:2015
-
负责人:ANDREA CALIFANO
-
依托单位:
Elucidating the dependencies of tumor initiating and drug-resistant niches in human malignancies by genome- wide molecualr profiling of single cells
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批准号:9979775
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项目类别:
-
资助金额:$95.23万
-
财政年份:2015
-
负责人:ANDREA CALIFANO
-
依托单位:
Elucidating the dependencies of tumor initiating and drug-resistant niches in human malignancies by genome- wide molecualr profiling of single cells
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批准号:9127182
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项目类别:
-
资助金额:$95.23万
-
财政年份:2015
-
负责人:ANDREA CALIFANO
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依托单位:
海外基金