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.

项目摘要（参见说明）：该更新应用程序建立在我们之前研究的主题之上，从机械上定义和治疗靶向驱动去势抵抗性前列腺癌 (CRPC) 进展的途径。 CRPC 归因于雄激素受体 (AR) 轴的重新激活以及应激激活的细胞保护伴侣和生长因子信号通路。随着 MDV3100 和阿比特龙 (ABI) 等新型强效 AR 通路抑制剂在 CRPC 中获得批准，对这些药物的耐药性的出现代表了下一个重大的临床挑战。最近，我们发现 CRPC 和 MDV3100 后复发肿瘤中 Semaphorin 30 (SEMA3C) 信号通路的激活。 SEMA3C 是一种与癌症转移和化疗耐药相关的分泌性生长因子，我们发现它与 PTEN 缺失、簇蛋白过度表达以及 AR 蛋白水平和转录活性的调节有关。这些发现将 SEMA3C 与 PTEN 缺失以及 AKT 和 AR 活性增加联系起来，这是驱动 CRPC 和 MDV3100 治疗耐药的 2 个关键途径。 SEMA3C 可增强去势条件下 PCa 细胞的存活率，我们开发了 2 种新型 SEMA3C 抑制剂，可延缓 CRPC 进展。我们的总体目标是确定 SEMA3C 促进去势和 MDV3100 疗法耐药的机制，并开发临床前机制和抗癌活性数据，以支持新型 SEMA3C 抑制剂治疗 CRPC 的首次人体临床试验。目标 1 将定义 CRPC 中以及 LNCaP 或 LUCaP35CR 模型中分别用 MDV3100 或 ABI 治疗后 SEMA3C 信号通路的变化。目标 2 将描述 SEMA3C 对 MDV3100 治疗耐药性的功能作用，并定义 MDV3100 敏感与难治性 CRPC 中 SEMA3C 信号传导和 AR 活性之间的串扰。目标 3 将测试新型 SEMA3C 融合蛋白和反义抑制剂在 CRPC 临床前模型中作为单一疗法的体内活性； B) 与 i) MDV3100 组合； ii) 多西他赛，以及 iii) AR 伴侣蛋白 Hsp27 (OGX-427) 或 Hsp90 (PF-04928473) 的抑制剂。床边目标 4 将在患有 CRPC 的男性中进行 SEMA3C sema 结构域 (SD) Fc 融合蛋白抑制剂的 I/II 期临床试验，并检查血清 SEMA3C 作为临床生物标志物的效用。