Prospective Validation of Prognostic and Predictive Molecular tests in Mesothelioma

间皮瘤预后和预测分子检测的前瞻性验证

• 批准号: 10216184
• 负责人: RAPHAEL BUENO
• 金额: $ 30.21万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-07 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216184
• 关键词: Address; Algorithms; American Joint Committee on Cancer; Asbestos; Asbestos-Related Malignant Neoplasm; Biological Specimen Banks; Biopsy; Biopsy Specimen; Blood Tests; Cerebral Decortication; Cisplatin; Clinical; Clinical Data; Clinical Treatment; Clinical Trials; Clinical Trials Design; Collection; Communities; Complete Blood Count; Consensus; Consent; DNA; Data; Diagnosis; Diagnostic; Enrollment; Epithelial; Excision; Formalin; Freezing; Gene Expression; Genetic; Germ Lines; Goals; Grant; Histologic; Histology; Image; Immune response; Link; Long-Term Survivors; Lymphocyte; Malignant Neoplasms; Malignant Pleural Mesothelioma; Measures; Medical; Mesenchymal; Mesothelioma; Molecular; Molecular Diagnostic Testing; Morbidity - disease rate; Nature; Normal tissue morphology; Operative Surgical Procedures; Outcome; PF4 Gene; Paraffin Embedding; Pathologic; Pathological Staging; Pathology; Patient Selection; Patient-Focused Outcomes; Patients; Pemetrexed; Pharmaceutical Preparations; Plasma; Pleural; Pneumonectomy; Prognostic Factor; Prognostic Marker; Property; Prospective cohort; Publishing; Regimen; Research; Resources; Reverse Transcriptase Polymerase Chain Reaction; Risk; Serum; Specimen; Staging; Stratification; Survival Rate; TNM; Testing; Therapeutic; Training; Treatment Protocols; Treatment outcome; Tumor Volume; Unresectable; Validation; Vimentin; Work; base; bevacizumab; candidate marker; chemotherapy; chest computed tomography; cohort; design; exome sequencing; follow-up; genetic testing; improved; improved outcome; individualized medicine; lymph nodes; mortality; multimodality; neutrophil; novel; novel diagnostics; patient stratification; patient subsets; potential biomarker; predictive signature; predictive test; preservation; prognostic; prognostic assays; prognostic model; prognostic signature; prospective; recruit; research clinical testing; response; success; survival prediction; targeted treatment; therapy outcome; tool; transcriptome sequencing; treatment stratification; tumor; validation studies

Malignant pleural mesothelioma (MPM), a devastating asbestos-induced cancer, has <10% 5-yr survival. Treatments are few and limited. Aggressive surgery (extra-pleural pneumonectomy (EPP) or pleurectomy/decortication (PD)) followed by chemotherapy is effective in a subset of patients, yielding 20%-30% 5-yr survival, but identifying the patients who will benefit from this treatment is a significant challenge. Surgery of any type for MPM is associated with considerable morbidity and some mortality. The primary goal is to enhance and validate prognostic biomarkers and a robust risk score to identify only those patients who will be long-term survivors to undergo surgery. We previously developed and prospectively validated a 4-factor pathology staging score (MPS=MPM Prognostic Score) that is the best reliable prognostic test after surgery for MPM. We extended this effort to develop a pre-treatment clinical prognostic score to inform patients in their decisions regarding therapy. Herein we propose for multicenter clinical evaluation this risk score (MRiS = MPM Risk Score) based on 4 simple tests (Chest CT, CBC, 2 molecular tests on pleural biopsy). We will leverage 4 unique prospective patient cohorts (total: 1101 patients) with clinical data and specimens for the proposed work. These cohorts constitute a one-of-a-kind resource that also allows to generate, evaluate and validate new candidate biomarkers. In a recent study published in Nat. Genetics, we defined 4 robust, distinct and more homogeneous expression clusters consistent with the epithelial to mesenchymal transformation and demonstrated that expression cluster I (defined by CLDN15/VIM ratio) can be a surrogate for the histological- subtype-diagnosis in MRiS and we propose to expand this to the other clusters. We also constructed and validated a derivative of a simple existing blood test (neutrophil/lymphocyte ratio) that is prognostic and a part of MRiS representing the immune response. We hypothesize that 1) adding new genetic and clinical test information to our current prognostic models will enable more accurate allocation of MPM patients into more homogeneous pre-treatment subpopulations, allowing for rational assignment of therapies; 2) our new prognostic models can be successfully transferred to FFPE and be used clinically. The Aims are: 1. Prospectively validate a new pre-treatment prognostic algorithm to predict survival for MPM patients, by enrolling all new patients with MPM into a clinical trial where the MRiS is determined prior to treatment and outcome is measured by follow up. We will also: a. Determine test and specimens properties for the molecular tests in pleural biopsies; and b. Develop, explore and test new diagnostic, prognostic and predictive signatures for MPM based on expression clusters membership and response to specific therapies. 2. Transfer the molecular tests to FFPE preserved pleural biopsy samples and determine concordance, specimen and test properties of proposed molecular tests (MPT and expression cluster membership) using RT-PCR. 3. Prospectively validate MRiS as well as MPT and MPS in FFPE specimens from multi-center collections.

恶性胸膜间皮瘤 (MPM) 是一种由石棉诱发的毁灭性癌症，其 5 年生存率低于 10%。 治疗方法很少且有限。激进的手术（胸膜外全肺切除术 (EPP) 或 胸膜切除术/皮质剥脱术 (PD)）随后化疗对部分患者有效，有效率 20%-30% 5 年生存期，但确定哪些患者将从这种治疗中受益是一项重大挑战。外科手术 任何类型的 MPM 都与相当大的发病率和一定的死亡率相关。主要目标是 增强和验证预后生物标志物和强大的风险评分，以仅识别那些将要接受治疗的患者 长期幸存者接受手术。我们之前开发并前瞻性验证了 4 因素 病理分期评分（MPS=MPM 预后评分）是术后最可靠的预后测试 MPM。我们扩展了这项工作，开发了治疗前临床预后评分，以告知患者他们的情况 有关治疗的决定。在此，我们建议多中心临床评估使用该风险评分（MRIS = MPM 风险评分）基于 4 项简单测试（胸部 CT、CBC、2 项胸膜活检分子测试）。我们将利用4 独特的前瞻性患者队列（总计：1101 名患者）以及拟议工作的临床数据和标本。 这些群体构成了一种独一无二的资源，还可以生成、评估和验证新的 候选生物标志物。在最近发表在《Nat》上的一项研究中。遗传学，我们定义了 4 个稳健、独特等 与上皮间质转化一致的同质表达簇 证明表达簇 I（由 CLDN15/VIM 比率定义）可以替代组织学- MRiS 中的亚型诊断，我们建议将其扩展到其他集群。我们还建造并 验证了一种简单的现有血液测试（中性粒细胞/淋巴细胞比率）的衍生物，该测试具有预后意义，并且是 MRiS 代表免疫反应。我们假设 1) 增加新的基因和临床测试 我们当前的预后模型的信息将使 MPM 患者能够更准确地分配到更多 同质的治疗前亚群，允许合理分配治疗； 2）我们的新预测 模型可成功转移至FFPE并用于临床。目标是： 1. 前瞻性验证 一种新的治疗前预后算法，通过招募所有新患者来预测 MPM 患者的生存率 MPM 进入临床试验，其中 MRiS 在治疗前确定，并通过随访测量结果。 我们还将：确定胸膜活检分子测试的测试和样本特性；和 b.基于表达开发、探索和测试 MPM 新的诊断、预后和预测特征 集群成员资格和对特定疗法的反应。 2. 将分子测试转移到保存的 FFPE 中 胸膜活检样本并确定提议的分子测试的一致性、样本和测试特性 （MPT 和表达簇成员资格）使用 RT-PCR。 3. 前瞻性验证 MRiS 以及 MPT 和 来自多中心收藏的 FFPE 标本中的 MPS。

项目成果

Sequential binary gene ratio tests define a novel molecular diagnostic strategy for malignant pleural mesothelioma.

连续二元基因比率测试定义了恶性胸膜间皮瘤的新型分子诊断策略。

• 发表时间: 2013-05-01
• 作者: De Rienzo, Assunta;Richards, William G;Yeap, Beow Y;Coleman, Melissa H;Sugarbaker, Peter E;Chirieac, Lucian R;Wang, Yaoyu E;Quackenbush, John;Jensen, Roderick V;Bueno, Raphael
• 通讯作者: Bueno, Raphael

Large-scale analysis of BAP1 expression reveals novel associations with clinical and molecular features of malignant pleural mesothelioma.

BAP1 表达的大规模分析揭示了与恶性胸膜间皮瘤的临床和分子特征的新关联。

• 发表时间: 2021
• 作者: De Rienzo, Assunta;Chirieac, Lucian R;Hung, Yin P;Severson, David T;Freyaldenhoven, Samuel;Gustafson, Corinne E;Dao, Nhien T;Meyerovitz, Claire V;Oster, Michela E;Jensen, Roderick V;Yeap, Beow Y;Bueno, Raphael;Richards, William G
• 通讯作者: Richards, William G

Gene expression ratio test distinguishes normal lung from lung tumors in solid tissue and FNA biopsies.

基因表达比测试可区分实体组织和 FNA 活检中的正常肺与肺肿瘤。

• DOI: 10.1016/j.jmoldx.2013.11.008
• 发表时间: 2014-03-01
• 期刊: The Journal of molecular diagnostics : JMD
• 作者: A. De Rienzo;B. Yeap;E. Cibas;W. Richards;Lingsheng Dong;R. Gill;D. Sugarbaker;R. Bueno
• 通讯作者: R. Bueno

MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma.

MET 和 PI3K/mTOR 作为恶性胸膜间皮瘤的潜在组合治疗靶点。

• 发表时间: 2014
• 影响因子: 3.7
• 作者: Kanteti, Rajani;Dhanasingh, Immanuel;Kawada, Ichiro;Lennon, Frances E;Arif, Qudsia;Bueno, Raphael;Hasina, Rifat;Husain, Aliya N;Vigneswaran, Wickii;Seiwert, Tanguy;Kindler, Hedy L;Salgia, Ravi
• 通讯作者: Salgia, Ravi

Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations.

恶性胸膜间皮瘤的综合基因组分析可识别复发突变、基因融合和剪接改变。

• 发表时间: 2016-04
• 影响因子: 30.8
• 作者: Bueno, Raphael;Stawiski, Eric W;Goldstein, Leonard D;Durinck, Steffen;De Rienzo, Assunta;Modrusan, Zora;Gnad, Florian;Nguyen, Thong T;Jaiswal, Bijay S;Chirieac, Lucian R;Sciaranghella, Daniele;Dao, Nhien;Gustafson, Corinne E;Munir, Kiara J;H
• 通讯作者: H