Project 1: Tumor Microenvironment Initiators of the Metastatic Cascade in High-Risk Prostate Cancer
项目1:高危前列腺癌转移级联的肿瘤微环境启动因素
基本信息
- 批准号:10555400
- 负责人:
- 金额:$ 38.86万
- 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:3-DimensionalAdjuvant StudyAndrogen ReceptorBiologicalBiological MarkersBiological ModelsCancer and Leukemia Group BCell Differentiation processCell ProliferationCellsClinical TrialsCombined Modality TherapyComplexDNA Sequence AlterationDataData SetDiseaseDissectionEarly DiagnosisEngineeringEvaluationFOLH1 geneFailureFibroblastsGenetic TranscriptionGenomicsGoalsHeterogeneityImageImmuneIn complete remissionIncidenceInvadedLesionLymphaticLymphovascularMRI ScansMacrophageMagnetic Resonance ImagingMalignant NeoplasmsMalignant neoplasm of prostateMapsMetabolismMetastatic/RecurrentModelingMoldsMolecularMolecular AnalysisMultifocal LesionMutationNeoadjuvant TherapyNeoplasm MetastasisNewly DiagnosedOperative Surgical ProceduresOutcomePTEN genePathologicPatientsPermeabilityPhenotypePopulationPositron-Emission TomographyPre-Clinical ModelProstateProstatectomyProstatic NeoplasmsRandomizedReceptor SignalingResistanceSamplingScanningSliceSpecimenStromal CellsTP53 geneTechnologyTestingTumor Cell InvasionUniversitiesWisconsinWorkabirateroneadvanced prostate cancerarmbiomarker developmentcell typecohortdigitaldocetaxeldrug developmentexome sequencinghigh riskhormone therapyimmune cell infiltrateinhibitorlymphatic Invasionlymphatic vesselmenmicrophysiology systemmigrationmolecular phenotypeneoplastic cellnovelnovel therapeutic interventionpatient populationphase II trialphase III trialpotential biomarkerprospectiveprostate cancer cellprostate cancer metastasisprostate cancer riskradiological imagingresponsesuccesstechnology platformtherapeutic targettherapy resistanttooltranscriptome sequencingtranscriptomicstumortumor DNAtumor growthtumor microenvironment
项目摘要
PROJECT SUMMARY
There is an increasing incidence of men with newly diagnosed prostate cancer (PC) presenting with locally
advanced or metastatic disease, a population that comprises >60% of the men who die from the disease. The
failure of early detection has led to the initiation of multiple clinical trials testing neoadjuvant therapies in an
attempt to cure these patients. Analysis of pre-treatment samples from neoadjuvant trials have identified genomic
alterations that associate with a treatment resistance. More recent studies indicate the tumor microenvironment
(TME) can initiate the metastatic cascade. However, it remains unclear how and when genomic alterations co-
opt different cell types in a complex 3-dimensional TME to initiate the metastatic cascade. We have recently
found that activated fibroblasts and macrophage sub-populations induce lymphovascular sprouting and
permeability. Based on these data sets, we hypothesize that somatic alterations in tumor DNA co-opt
stromal and immune cells in the TME to promote invasion and intravasation of lympho-vascular
channels. To test this hypothesis, we have three cohorts of patients with high-risk prostate cancer (surgery
alone, neoadjuvant Abiraterone, and neoadjuvant chemohormonal therapy) that undergo PSMA PET/MRI scans
prior to surgery. This scan is used to develop 3D mold of the prostate to perform whole mount sectioning and
dissection of multi-focal PC for multi-plex molecular analysis. Samples from these specimens are used to create
patient-specific “TMEs on a Chip” using a humanized Micro-Physiologic System (MPS) of the prostate with
surrounding lympho-vasculature. This novel model system allows culture of patient tumor cells and stromal cells
to identify the factors that induce lymphatic permeability and culminate in tumor invasion and intravasation.
Success in these studies will identify the biologic interactions in the TME that can initiate the metastatic cascade
as potential biomarkers and therapeutic targets for men with high-risk, locally advanced PC. In Aim 1 we will
perform whole exome and transcriptome sequencing, across 3D whole mount sections identified by PSMA
PET/MRI, in untreated patients to evaluate heterogeneity and determine the impact of neoadjuvant ARSIs and
docetaxel across 3D multifocal PC. In Aim 2, we extend spatial mapping with PSMA PET/MRI and IHC data to
perform transcriptional Digital Spatial Profiling (DSP) on whole-mount sections collected in Aim 1. This
integration will test whether distinct CAF and immune cell infiltrates associate with genomic alterations in a spatial
configuration of cells invading regional lymphovascular channels. In Aim 3, we use LumeNEXT MPS technology
to create humanized lymphatic vessels cultured in patient-specific humanized prostate TMEs, with genomically
engineered PC cells, that reflect the molecular and cellular signatures identified in Aims 1 and 2. When
completed, the outcome of this work will advance the field by helping us to understand how prostate cancer
metastasizes for both biomarker and drug development.
项目总结
项目成果
期刊论文数量(0)
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