Elucidation and targeting of paracrine cascades in PDAC
PDAC 中旁分泌级联的阐明和靶向
基本信息
- 批准号:10518098
- 负责人:
- 金额:$ 98.55万
- 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:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:AlgorithmsAllograftingBehaviorBiological ModelsBlocking AntibodiesBloodBlood specimenCCR1 geneCD8-Positive T-LymphocytesCellsClinicalClinical ServicesClinical TrialsCoculture TechniquesCommunicationComplexComputational algorithmCytotoxic ChemotherapyDataData SetDesmoplasticDiffusionDissectionDrug CombinationsDrug Delivery SystemsEffector CellElectronic Medical Records and Genomics NetworkElementsEndotheliumErinaceidaeFibroblastsGenetic TranscriptionGenetically Engineered MouseGrowthHeterogeneityHospitalsHumanImmunosuppressionImmunotherapyIndividualIntercellular FluidInterceptInvestigationKPC modelLeadLigandsLinkLogicLymphocyteLymphoidMalignant Epithelial CellMalignant NeoplasmsMalignant neoplasm of pancreasMediatingMetabolicMethodsModelingMyelogenousMyeloid CellsMyeloid-derived suppressor cellsMyofibroblastNew YorkOlives - dietaryOutcome StudyPaintPancreasPancreatic Ductal AdenocarcinomaParacrine CommunicationPathway AnalysisPathway interactionsPatientsPerfusionPhenotypePopulationPresbyterian ChurchPrimary Cell CulturesRecombinant ProteinsRegimenRegulationReportingResourcesRoleSHH geneSamplingSeriesSignal TransductionSliceSpleenStromal CellsStromal NeoplasmSystemSystems BiologyTechniquesTestingTherapeuticTherapeutic AgentsTherapeutic InterventionTissue SampleTissuesToxic effectTumor TissueValidationWorkanalytical toolangiogenesisbasecancer cellcell typechemokineclinical translationcomputational suitecomputerized toolsconditioningcytotoxicdrug efficacyfunctional outcomesimmunosuppressedimprovedin vivoinhibitorinnovationmembermouse modelmultidisciplinarymutantnoveloverexpressionpancreatic ductal adenocarcinoma cellpancreatic ductal adenocarcinoma modelpancreatic neoplasmparacrinepre-clinicalreceptorresponsesingle cell technologysingle-cell RNA sequencingtargeted agenttargeted treatmenttooltreatment responsetumortumor microenvironment
项目摘要
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies due largely to their lack
of response to current cytotoxic, targeted, and immune therapies. PDAC tumor tissues harbor an expansive,
desmoplastic stroma that both suppresses angiogenesis and limits perfusion and diffusion. Consequently,
delivery of therapeutic agents through systemic administration is impeded, lowering drug efficacy and
increasing general toxicity. Indeed, multiple components of the PDAC stroma support its survival and growth,
for example by conditioning a locally immunosuppressed microenvironment that facilitates tumor survival.
Conversely, we previously showed that at least some elements of the tumor stromal restrain PDAC growth and
progression, for example Hedgehog pathway-responsive myofibroblasts. Early attempts to modulate the PDAC
stroma in order to facilitate drug delivery failed upon clinical translation. Post-clinical trials ultimately
demonstrated that stromal remodulation upon inhibition of individual pathways can lead to unpredictable
consequences in multiple additional cell types. Based on these data, we hypothesize that individual paracrine
pathways typically link together to form “paracrine cascades” that propagate through multiple pathways and
cell types. We advance that reconstructing these paracrine cascades offers both the opportunity to better
understand the consequences of therapeutic intervention and also to infer candidate targets that act on a
broad range of cell types within the PDAC TME to enact stromal remodulation.
In order to test this, we will make use of a series of innovative systems biology tools built by members of
our transdisciplinary team. These include a suite of algorithms leveraging the computational field of regulatory
network analysis, as well as technically innovative techniques for studying outcomes in single cell datasets.
Moreover, we will acquire unique dataset from samples collected by members of our multidisciplinary clinical
service at the Pancreas Center of New York Presbyterian Hospital. These include acquiring human PDAC
tumor interstitial fluid and generating matched sets of tumor, normal pancreas, spleen, and blood samples from
PDAC patients. We will also routinely utilize fresh PDAC tissue samples to make tumor “explants” a novel ex
vivo model system for the short-term, medium throughput study of PDAC. This new model system enables the
dissection of complex multi-cellular phenotypes in ways that are not possible through study of intact tumors or
co-cultures of purified cell types
Using these approaches, we will reconstruct the network of paracrine cascades in PDAC and validate
selected candidates experimentally. We will also test a specific candidate pathway uncovered through study of
the Hh pathway that connects myofibroblasts to myeloid derived suppressor cells and cytotoxic lymphocytes.
We expect that the proposed studies will provide an expansive understanding of paracrine crosstalk in PDAC
and also provide multiple valuable resources and techniques to the PSRC consortium.
摘要
项目成果
期刊论文数量(0)
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Gulam Abbas Manji其他文献
Gulam Abbas Manji的其他文献
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{{ truncateString('Gulam Abbas Manji', 18)}}的其他基金
Targeting cell regulatory states to complement MEK/autophagy inhibition in pancreatic cancer
靶向细胞调节状态以补充胰腺癌中的 MEK/自噬抑制
- 批准号:
10587719 - 财政年份:2022
- 资助金额:
$ 98.55万 - 项目类别:
Phase 2 study of combination therapy with PLX3397 and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors
PLX3397和西罗莫司联合治疗恶性周围神经鞘肿瘤中肿瘤相关巨噬细胞的2期研究
- 批准号:
10364636 - 财政年份:2017
- 资助金额:
$ 98.55万 - 项目类别:
Phase 2 study of combination therapy with PLX3397 and sirolimus to target tumor-associated macrophages in malignant peripheral nerve sheath tumors
PLX3397和西罗莫司联合治疗恶性周围神经鞘肿瘤中肿瘤相关巨噬细胞的2期研究
- 批准号:
9444352 - 财政年份:2017
- 资助金额:
$ 98.55万 - 项目类别:
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