GPCR Signaling in SCCHN: Integration with EGFR

SCCHN 中的 GPCR 信号转导：与 EGFR 整合

• 批准号: 9276624
• 负责人: Jennifer Rubin Grandis
• 金额: $ 28.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9276624
• 关键词: Address; Aspirin; Binding; Biological Markers; CXCR3 gene; Cell Line; Clinical; Clinical Treatment; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Development; Diagnosis; Dinoprostone; Disease; Enzymes; Epidermal Growth Factor Receptor; Erlotinib; FDA approved; Family; Funding; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Gene Amplification; Gene Mutation; Growth; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Human; Human Papillomavirus; Ligands; Malignant Neoplasms; Mediating; Modeling; Mus; Mutate; Mutation; Non-Steroidal Anti-Inflammatory Agents; Oncogenic; PDPK1 gene; PIK3CA gene; Pathway interactions; Patients; Phosphatidylinositols; Phosphotransferases; Placebo Control; Pre-Clinical Model; Predictive Value; Prevention strategy; Prostaglandin-Endoperoxide Synthase; Proto-Oncogene Proteins c-akt; Randomized; Receptor Activation; Receptor Inhibition; Receptor Signaling; Regulatory Pathway; Reporting; Role; Secondary Prevention; Signal Transduction; Subgroup; Sulindac; Testing; Transactivation; actionable mutation; antitumor effect; autocrine; cohort; cyclooxygenase 2; epidemiology study; inhibitor/antagonist; molecular targeted therapies; mutant; novel; pre-clinical; predictive marker; prevent; public health relevance; receptor expression; response; targeted agent; therapeutic biomarker; tumor

DESCRIPTION (provided by applicant): Head and neck squamous cell carcinomas (HNSCC) are frequently lethal and predictive biomarkers to guide therapy are lacking. EGFR targeting was FDA-approved in 2006 for HNSCC. EGFR signaling is activated by direct stimulation and transactivation by G-protein-coupled receptors (GPCR). We previously identified GPCR- induced activation of phosphoinositide-3-kinase (PI3K) both upstream and downstream of EGFR. Co-targeting of PI3K in combination with EGFR inhibition was associated with enhanced antitumor effects in HNSCC preclinical models. We recently completed a randomized, placebo-controlled, window-of-opportunity clinical trial where treatment with erlotinib plus the GPCR inhibitor/NSAID sulindac significantly reduced tumor proliferation. Aspirin, like sulindac, inhibit cyclooxygenase (COX) and GPCR signaling. A recent study in colon cancer reported that aspirin use in patients whose tumors harbored PIK3CA mutations was associated with significantly longer survival compared with patients whose tumors contained wild-type (WT) PIK3CA. We have now determined the mutational profile of HNSCC and find PIK3CA genetic alterations in nearly 25% of tumors. Preliminary results indicate that PIK3CA mutation enhances sensitivity to NSAID treatment. As NSAIDs are well tolerated, this provides an immediate opportunity to implement potentially effective approaches for PIK3CA mutant HNSCC. We developed novel HNSCC models to identify oncogenic "driver" mutations in this cancer. In addition, we can assess PIK3CA mutation and amplification in human HNSCC tumors to be grown as heterotopic tumorgrafts in mice and in a HNSCC cohort with known NSAID use. This project will elucidate the role of PIK3CA alterations in mediating sensitivity to NSAIDs, alone or in combination with EGFR blockade in HNSCC.

描述(申请人提供)：头颈部鳞状细胞癌(HNSCC)通常是致命的，缺乏指导治疗的预测性生物标志物。2006年，FDA批准EGFR靶向治疗HNSCC。EGFR信号是通过G蛋白偶联受体直接刺激和反式激活而激活的。我们以前发现了GPCR诱导的肌醇磷脂-3-激酶(PI3K)在EGFR的上游和下游的激活。在HNSCC临床前模型中，联合靶向PI3K和抑制EGFR与增强抗肿瘤效果相关。我们最近完成了一项随机、安慰剂对照的机会窗临床试验，在该试验中，厄洛替尼联合GPCR抑制剂/非甾体抗炎药舒林酸治疗显著减少了肿瘤的增殖。阿司匹林和舒林酸一样，可以抑制环氧合酶(COX)和GPCR信号转导。最近一项关于结肠癌的研究报告称，与肿瘤中含有野生型(WT)PIK3CA的患者相比，肿瘤中含有PIK3CA突变的患者使用阿司匹林可显著延长生存期。我们现在已经确定了HNSCC的突变情况，并在近25%的肿瘤中发现了PIK3CA基因改变。初步结果表明，PIK3CA突变增强了对非甾体抗炎药治疗的敏感性。由于非甾体抗炎药的耐受性良好，这为PIK3CA突变体HNSCC提供了实施潜在有效方法的直接机会。我们开发了新的HNSCC模型来识别这种癌症的致癌“驱动”突变。此外，我们可以评估PIK3CA突变和扩增在人类HNSCC肿瘤中的突变和扩增，这些肿瘤将作为小鼠异位肿瘤移植生长，并在已知使用非类固醇抗炎药的HNSCC队列中生长。本项目将阐明PIK3CA改变在HNSCC中单独或联合EGFR阻断在调节NSAIDs敏感性中的作用。

项目成果

Targeting GPCR-mediated p70S6K activity may improve head and neck cancer response to cetuximab.

• DOI: 10.1158/1078-0432.ccr-10-3406
• 发表时间: 2011-08-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Bhola NE;Thomas SM;Freilino M;Joyce S;Sahu A;Maxwell J;Argiris A;Seethala R;Grandis JR
• 通讯作者: Grandis JR

Systematic prediction of human membrane receptor interactions.

• DOI: 10.1002/pmic.200900259
• 发表时间: 2009-12
• 期刊: PROTEOMICS
• 影响因子: 3.4
• 作者: Qi, Yanjun;Dhiman, Harpreet K.;Bhola, Neil;Budyak, Ivan;Kar, Siddhartha;Man, David;Dutta, Arpana;Tirupula, Kalyan;Carr, Brian I.;Grandis, Jennifer;Bar-Joseph, Ziv;Klein-Seetharaman, Judith
• 通讯作者: Klein-Seetharaman, Judith

HGF/Met Signaling in Head and Neck Cancer: Impact on the Tumor Microenvironment.

• DOI: 10.1158/1078-0432.ccr-16-0951
• 发表时间: 2016-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Hartmann S;Bhola NE;Grandis JR
• 通讯作者: Grandis JR