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Principal Investigator: Scott M. Dehm
Organization: UNIVERSITY OF WISCONSIN-MADISON
Fiscal Year: 2024
Award: $625,914
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
The last decade has seen a significant increase in the number of FDA approved treatments for men
with metastatic castrate resistant prostate cancer (mCRPC). Even greater improvements in survival
were observed for men with metastatic castration sensitive PC (mCSPC) treated with chemotherapy or
androgen receptor signaling inhibitors compared to hormone therapy alone (Despite these advances
in mCSPC, median OS for men with mCRPC remains less than two years and cross-resistance to
therapies within the same class (e.g. Enzalutamide and Abiraterone) occurs in >90% of patients, limiting
effective treatments in mCRPC to agents with OS improvements ranging from only 2-4 months. There
is a critical need to identify new agents that can eliminate resistant disease5. Understanding the
molecular associations driving resistance may identify new therapeutic sensitivities in these aggressive
cancers to improve quality and quantity of life for men with mCRPC. Translational research studies
focused on understanding the underlying mechanisms driving treatment resistance in CRPC have
identified a wide range of genomic, epigenomic and transcriptional alterations. Approximately 15-20%
of patients with mCRPC develop lineage plasticity, with small cell neuroendocrine CRPC (SCNPC)
representing the most aggressive subtype. However, the field lacks consensus definitions for the
diverse lineage plasticity phenotypes observed in mCRPC, and few therapeutic targets have been
developed to date. In this study, we propose Trop-2 (Trophoblastic cell-surface antigen) as a high value
target for therapy of mCRPC with an antibody-drug conjugate Sacituzumab Govitecan (SG). We
hypothesize that ARSI-resistant phenotypes in mCRPC can be identified through integrated solid
tumor and liquid biopsy analysis and targeted therapeutically with SG. To test this hypothesis, we
propose to study Trop-2 regulation in pre-clinical and clinical specimens and test this agent in a
prospective Phase II clinical trial for ARSI-resistant mCRPC. In Aim 1, we will conduct molecular-spatial
analysis of Trop-2 expression in mCRPC PDX tissues as well as solid tumor and liquid biopsies from
patients with CSPC, CRPC and SCNPC In Aim 2, we will evaluate solid tumor and liquid biopsies
collected longitudinally from patients with mCRPC treated with SG in a prospective Phase II trial. Aim
2 will characterize chromatin enhancer profiles in the TACSTD2 gene encoding Trop-2 to identify
factors regulating Trop-2 levels in prostate cancer. We will test if Trop-2 levels determine sensitivity to
SG therapy, and identify SG-based combination regimens that enhance therapeutic efficacy in vitro
and in vivo.
Terms: <AR gene><Androgen Metabolism><Androgen Receptor><Antibody-drug conjugates><Automobile Driving><Biological><Biological Markers><Biopsy><Blood><Blood Reticuloendothelial System><Body Tissues><Bypass><Cancer Patient><Cancers><Castration><Cell Surface Antigens><Cell surface><Chromatin><Clinical><Clinical Trials><Combined Modality Therapy><Consensus><DNA Rearrangement><Dihydrotestosterone Receptor><Disease><Disease Resistance><Disorder><Endocrine Therapy><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial Cells><FDA approved><Future><GA733><Gastrointestinal Tumor-Associated Antigen 1, 40-KD Glycoprotein><Gene Amplification><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Rearrangement><Gene Transcription><Generations><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Goals><Hormonal Therapy><Human><Immunologic Surface Markers><Immunological Surface Markers><In Vitro><Life><M1S1><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Medical><Membrane Component, Chromosome 1, Surface Marker 1><Metastatic Prostate Cancer><Modern Man><Molecular><Molecular Analysis><Multimodal Therapy><Multimodal Treatment><Mutation><Mutation Analysis><NR3C4><Neoplasm Circulating Cells><Neuroendocrine Cell><New Agents><PARP Inhibitor><PARP-1 inhibitor><PARPi><Pathway interactions><Patient Selection><Patients><Phase 2 Clinical Trials><Phase II Clinical Trials><Phenotype><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) polymerase 1 inhibitor><Progression-Free Survivals><Prostate CA><Prostate Cancer><Prostate Carcinoma Metastatic><Prostate malignancy><Prostatic Cancer><RNA Expression><Radiography><Receptor Signaling><Regimen><Regulation><Research Specimen><Resistance><Roentgenography><SMAX1><Sampling><Solid Neoplasm><Solid Tumor><Specimen><Surface Antigens><Surgical Castration><TACSTD2><TACSTD2 gene><Taxotere><Testing><Therapeutic><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Alteration><Translational Research><Translational Science><Treatment Efficacy><Trophoblastic Cell><Tumor-Associated Calcium Signal Transducer 2><Variant><Variation><Xtandi><abiraterone><advanced prostate cancer><analyze gene expression><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen receptor gene><androgen resistance in prostate cancer><androgen resistant prostate cancer><bio-markers><biologic><biologic marker><biomarker><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><chemotherapy><circulating neoplastic cell><circulating tumor cell><clinical efficacy><combination therapy><combined modality treatment><combined treatment><constitutive expression><constitutive gene expression><docetaxel><docetaxol><driving><effective therapy><effective treatment><enzalutamide><epigenetically><epigenomics><gene expression analysis><gene expression assay><genome mutation><hormone refractory prostate cancer><hormone therapy><improved><in vivo><inhibitor><intervention efficacy><liquid biopsy><malignancy><men><multi-modal therapy><multi-modal treatment><natural gene amplification><neoplasm/cancer><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><pharmacodynamic biomarker><pharmacodynamic marker><phase 2 trial><phase II protocol><phase II trial><pre-clinical><pre-clinical study><preclinical><preclinical study><predictive biomarkers><predictive marker><predictive molecular biomarker><programs><prospective><prostate cancer resistant to androgen><radioligand><radiologic imaging><radiological imaging><research study><resistance mechanism><resistance to disease><resistance to therapy><resistant><resistant disease><resistant mechanism><resistant to disease><resistant to therapy><response><single cell proteins><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><taxane><therapeutic efficacy><therapeutic resistance><therapeutic target><therapy efficacy><therapy resistant><transcriptional profiling><translation research><translational investigation><treatment resistance><treatment strategy><tumor>