Molecular regulation and expression of Trop-2 in advanced prostate cancer: Identifying optimal therapeutic niches

晚期前列腺癌中 Trop-2 的分子调控和表达：确定最佳治疗领域

• 批准号: 10735996
• 负责人: Scott M. Dehm
• 金额: $ 69.51万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10735996
• 关键词: AR gene; Androgen Metabolism; Androgen Receptor; Antibody-drug conjugates; Automobile Driving; Biological; Biological Markers; Biopsy; Blood; Bypass; Cancer Patient; Castration; Cell surface; Chromatin; Clinical; Clinical Trials; Combined Modality Therapy; Consensus; Disease; Disease Resistance; Enhancers; Epigenetic Process; Epithelial Cells; FDA approved; Future; Gene Amplification; Gene Expression Profiling; Gene Rearrangement; Generations; Genetic Transcription; Genomics; Goals; Human; In Vitro; Life; Malignant Neoplasms; Malignant neoplasm of prostate; Medical; Metastatic Prostate Cancer; Molecular; Molecular Analysis; Mutation; Mutation Analysis; Neoplasm Circulating Cells; Neuroendocrine Cell; New Agents; Pathway interactions; Patient Selection; Patients; Phase II Clinical Trials; Phenotype; Poly(ADP-ribose) Polymerase Inhibitor; Progression-Free Survivals; Receptor Signaling; Regimen; Regulation; Resistance; Sampling; Solid Neoplasm; Specimen; Surface Antigens; TACSTD2 gene; Testing; Therapeutic; Tissues; Transcription Alteration; Translational Research; Treatment Efficacy; Trophoblastic Cell; Variant; abiraterone; advanced prostate cancer; castration resistant prostate cancer; chemotherapy; clinical efficacy; constitutive expression; docetaxel; effective therapy; enzalutamide; epigenomics; hormone therapy; improved; in vivo; inhibitor; liquid biopsy; men; novel; novel therapeutics; pharmacodynamic biomarker; phase II trial; pre-clinical; preclinical study; predictive marker; programs; prospective; radioligand; radiological imaging; research study; resistance mechanism; response; single cell proteins; targeted treatment; taxane; therapeutic target; therapy resistant; treatment strategy; tumor

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.

项目总结/文摘