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Targeting SEMA3C in Castration Resistant Prostate Cancer

靶向 SEMA3C 治疗去势抵抗性前列腺癌

基本信息

批准号：
8933575
负责人：
MARTIN GLEAVE
金额：
$ 20.07万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-19 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8933575
关键词：
Adhesions Aftercare Androgen Receptor Androgens Antisense Oligonucleotides Apoptosis Automobile Driving Binding Biological Biological Markers Castration Cell Line Cell Proliferation Cell Survival Cell surface Chimeric Proteins Clinical Clinical Trials Data Dominant-Negative Mutation Dose Drug Kinetics ERBB2 gene Epidermal Growth Factor Receptor FDA approved Fc domain Gene Expression Generations Growth Factor Human In Vitro Instruction LNCaP Legal patent Ligands Link MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Mediating Messenger RNA Modeling Molecular Chaperones Neoplasm Metastasis PTEN gene Pacific Northwest Pathway interactions Peptides Pharmaceutical Preparations Pharmacodynamics Phase Phase I Clinical Trials Phase II Clinical Trials Phosphorylation Phosphotransferases Pre-Clinical Model Proteins Proto-Oncogene Proteins c-akt Proto-Oncogenes Receptor Gene Receptor Protein-Tyrosine Kinases Recurrence Recurrent tumor Refractory Regulation Resistance Role Semaphorins Serum Shapes Signal Pathway Signal Transduction Stress Testing Withdrawal abiraterone arm bench to bedside cancer therapy castration resistant prostate cancer cell growth clinically relevant docetaxel feeding improved in vivo inhibitor/antagonist loss of function mRNA Expression malignant breast neoplasm man meetings men migration new therapeutic target novel plexin pre-clinical pressure prostate cancer model receptor response sulfated glycoprotein 2 tumor tumor growth tumor progression

项目摘要

PROJECT SUMMARY (See instructions): This renewal application builds on themes of our previous studies mechanistically defining & therapeutically targeting pathways driving castration-resistant prostate cancer (CRPC) progression. CRPC is attributed to reactivation of the androgen-receptor (AR) axis along with stress-activated cytoprotective chaperone and growth factor signaling pathways. With new potent AR pathway inhibitors like MDV3100 and abiraterone (ABI) approved in CRPC, emergence of resistance to these agents represents the next major clinical challenge. Recently, we identified activation of the Semaphorin 30 (SEMA3C) signaling pathway in CRPC and post-MDV3100 recurrent tumors. SEMA3C is a secreted growth factor associated with cancer metastasis and chemoresistance that we found associated with PTEN loss, clusterin over-expression, and regulation of AR protein levels and transcriptional activity. These findings link SEMA3C with PTEN loss and increased AKT & AR activity, 2 key pathways driving CRPC and MDV3100 treatment resistance. SEMA3C enhances PCa cell survival under castrate conditions, and we have developed 2 novel SEMA3C inhibitors that delay CRPC progression. Our overall aim is to define mechanisms of SEMA3C in promoting resistance to castration and MDV3100 therapies, and to develop preclinical mechanistic and anti-cancer activity data to support a first-in-man clinical trial of a novel SEMA3C inhibitor in CRPC. Aim 1 will define changes in SEMA3C signaling pathway in CRPC and after treatment with MDV3100 or ABI in LNCaP or LUCaP35CR models, respectively. Aim 2 will characterize the functional role of SEMA3C on MDV3100 treatment resistance and define cross-talk between SEMA3C signaling and AR activity in MDV3100 sensitive vs refractory CRPC. Aim 3 will test in vivo activity of novel SEMA3C fusion protein and antisense inhibitors in preclinical models of CRPC as A) monotherapy; and B) in combination with i) MDV3100; ii) docetaxel, and iii) inhibitors of AR chaperone proteins Hsp27 (OGX-427), or Hsp90 (PF-04928473). The bench to bedside Aim 4 will conduct a Phase l/ll clinical trial of SEMA3C sema domain (SD) Fc fusion protein inhibitor in men with CRPC and examine the utility of serum SEMA3C as a clinical biomarker.

项目概述（见说明）：