Malignant pleural mesothelioma (MPM) is a rare but deadly malignancy. Therapy is often inadequate and most clinical trials with new chemotherapy regimens have not shown added benefit possibly due to tumor and stage heterogeneity. Surgery has been shown to improve survival in some patients with early disease, but identifying those patients most likely to benefit remain a significant challenge. Staging is also limited, essentially requiring a major surgical resection to determine the accurate pathological stage. What is truly lacking at this time is a comprehensive universally agreed-upon pre-treatment staging strategy to allow more rational treatment stratification and comparison of patients across clinical trials. Previously, we proposed specific predictive tests for MPM which were validated in a prospective clinical trial of 120 consecutive patients undergoing surgery and the test properties in terms of what constitute adequate specimens were established as well. The data obtained in this trial allowed for a comprehensive analysis of multiple predictive parameters which were all independent in this patient cohort and included in addition to the MPM predictive test, the lymph node status, histological subtype and the tumor volume. By combining these four parameters, we were able to quite accurately stratify patients into groups that had highly statistically significant and quite distinct survival expectations. Most importantly, all these variables can be determined through radiographic and minimally invasive staging procedures prior to decision on therapy. We propose to test this molecular-based staging model in a prospective clinical trial and to extend the results to the analysis of minimally invasive biopsies and formalin-fixed, paraffin-embedded tissues. To accomplish our objectives we will use discarded human tumor and control tissues.
Specific Aim 1 : To determine in a prospective clinical trial whether pre-treatment staging for patients with MPM which includes CT for measuring tumor volume, cervical mediastinoscopy to determine lymph node status as well as pleural biopsy for histological subtype diagnosis and determination of the predictive gene ratio test can predict survival.
Specific Aim 2 : To determine in a prospective clinical trial whether image-guided FNA in patients with MPM enhances diagnosis compared with cytology and allow for an accurate application of the MPM predictive test.
Specific Aim 3 : To determine whether the MPM diagnostic and predictive gene ratio tests can yield equivalent results in paraffin embedded and frozen specimens from the same patients.
The results of the experiments contained within this proposal will seek to validate in a prospective clinical trial a new combined minimally invasive molecular-pathological and clinical, pre-treatment staging system for mesothelioma, a highly lethal cancer with >99% 5-year mortality. Should this approach be validated, it can become a standard of care in the US and more importantly help identify more homogeneous groups of patients for treatment trials, thus enhancing improvement in survival.
|Bueno, Raphael; Stawiski, Eric W; Goldstein, Leonard D et al. (2016) Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet 48:407-16|
|De Rienzo, Assunta; Archer, Michael A; Yeap, Beow Y et al. (2016) Gender-Specific Molecular and Clinical Features Underlie Malignant Pleural Mesothelioma. Cancer Res 76:319-28|
|Baldini, Elizabeth H; Richards, William G; Gill, Ritu R et al. (2015) Updated patterns of failure after multimodality therapy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 149:1374-81|
|Tempany, Clare M C; Jayender, Jagadeesan; Kapur, Tina et al. (2015) Multimodal imaging for improved diagnosis and treatment of cancers. Cancer 121:817-27|
|Opitz, Isabelle; Bueno, Raphael; Lim, Eric et al. (2014) Biomolecular and clinical practice in malignant pleural mesothelioma and lung cancer: what thoracic surgeons should know. Eur J Cardiothorac Surg 46:602-6|
|Kanteti, Rajani; Dhanasingh, Immanuel; Kawada, Ichiro et al. (2014) MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma. PLoS One 9:e105919|
|Sugarbaker, David J; Richards, William G; Bueno, Raphael (2014) Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients. Ann Surg 260:577-80; discussion 580-2|
|De Rienzo, Assunta; Yeap, Beow Y; Cibas, Edmund S et al. (2014) Gene expression ratio test distinguishes normal lung from lung tumors in solid tissue and FNA biopsies. J Mol Diagn 16:267-72|
|De Rienzo, Assunta; Richards, William G; Yeap, Beow Y et al. (2013) Sequential binary gene ratio tests define a novel molecular diagnostic strategy for malignant pleural mesothelioma. Clin Cancer Res 19:2493-502|
|De Rienzo, Assunta; Dong, Lingsheng; Yeap, Beow Y et al. (2011) Fine-needle aspiration biopsies for gene expression ratio-based diagnostic and prognostic tests in malignant pleural mesothelioma. Clin Cancer Res 17:310-6|
Showing the most recent 10 out of 17 publications