Targeting SEMA3C in Castration Resistant Prostate Cancer

靶向 SEMA3C 治疗去势抵抗性前列腺癌

• 批准号: 8555013
• 负责人: MARTIN GLEAVE
• 金额: $ 19.09万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 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/8555013
• 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; 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; neuronal cell body; new therapeutic target; novel; plexin; pre-clinical; pressure; prostate cancer model; receptor; response; sulfated glycoprotein 2; tumor; tumor growth; tumor progression

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 re-activation 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 3C (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 MDVS100 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 MDVS100 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 MDVS100 or ABI in LNCaP or LUCaP35CR models, respectively. Aim 2 will characterize the functional role of SEMA3C on MDVS100 treatment resistance and define cross-talk between SEMA3C signaling and AR activity in MDVS100 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) MDVS100; 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/II clinical trial of SEMA3C soma domain (SD) Fc fusion protein inhibitor in men with CRPC and examine the utility of serum SEMA3C as a clinical biomarker.

这项更新应用建立在我们之前研究的主题上，机制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）轴的再激活以及应激激活的细胞保护伴侣和生长因子信号通路。随着新的强效AR通路抑制剂如MDV3100和阿比特龙（ABI）被批准用于CRPC，对这些药物的耐药性的出现代表了下一个主要的临床挑战。最近，我们在CRPC和mdv3100后复发肿瘤中发现了信号蛋白3C （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生长因子，我们发现其与PTEN缺失、聚簇蛋白过表达、AR蛋白水平和转录活性调节有关。这些发现将SEMA3C与PTEN缺失和AKT和AR活性增加联系起来，这是驱动CRPC和MDVS100治疗抗性的两个关键途径。SEMA3C可以提高去势条件下PCa细胞的存活率，我们已经开发了两种新的SEMA3C抑制剂，可以延缓CRPC的进展。我们的总体目标是确定SEMA3C促进去势和MDVS100治疗耐药的机制，并开发临床前机制和抗癌活性数据，以支持新型SEMA3C抑制剂在CRPC中的首次人体临床试验。Aim 1将分别定义在LNCaP或LUCaP35CR模型中，CRPC和MDVS100或ABI治疗后SEMA3C信号通路的变化。目的2将描述SEMA3C在MDVS100治疗抗性中的功能作用，并定义SEMA3C信号和AR活性在MDVS100敏感和难治性CRPC中的串扰。目的3将测试新型SEMA3C融合蛋白和反义抑制剂在CRPC临床前模型中的体内活性，作为A)单药治疗；B)结合i) MDVS100；ii)多西他赛，iii) AR伴侣蛋白Hsp27 （OGX-427）或Hsp90 （PF-04928473）的抑制剂。从实验室到床边的Aim 4将在CRPC男性患者中进行SEMA3C体细胞结构域（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。