Over the last two years, patients diagnosed with cancer at the Massachusetts General Hospital (MGH) have been the beneficiaries of the successful implementation of a clinical, high-throughput tumor genotyping platform. This has helped transform cancer diagnosis from a purely morphologic assessment to a prospective molecular analysis. Knowledge of the mutational status of an individual tumor means that clinicians can decide on the treatment that is best for that patient. Furthermore, the matching of experimental therapeutics to the patients most likely to respond accelerates the adoption novel therapies and advances patient care. The overall objective of this proposal is to design and develop a robust clinical assay to detect ROS1 rearrangements in lung cancer. Building on the lessons learned from our successful implementation of diagnostics to detect chromosomal rearrangements involving the ALK gene, we will identify, test, validate, and implement the optimal ROS1 assay platform. We will test the feasibility of using a variety of assay platforms including fluorescence in situ hybridization, immunohistochemistry and PCR for clinical application. This objective will be achieved in two aims: (1) To establish assays for assessing ROS1 rearrangements in non-small cell lung carcinoma and (2) to perform ROS1 assay comparisons of sensitivity and specificity in a larger NSCLC cohort. This proposal will allow the timely implementation of novel ROS1 diagnostics that will enable the efficient identification of a subset of lung cancer patients that may benefit from new small molecule inhibitors that target the ROS1 kinase. This project will serve as a model for development and clinical implementation of diagnostics for the benefit of patients, and will be used to disseminate knowledge and expertise to the academic field of clinical lung cancer diagnostics in general.
Detailed knowledge of the genetic changes in a cancer patient's tumor is now important for patient care. In the era of personalized cancer therapy, targeted agents or smart drugs are routinely matched to a patient based largely on the genetic profile of their tumor. We propose to develop a clinical biomarker assay to identify a newly-described genetic alteration in lung cancer involving the ROS1 gene. This assay will enhance the chances that clinical trials of targeted ROS1 inhibitors will be successful, and will improve the chances that the patients with ROS1 alterations will receive optimal therapy.
| Shim, Hyo Sup; Kenudson, Mari-; Zheng, Zongli et al. (2015) Unique Genetic and Survival Characteristics of Invasive Mucinous Adenocarcinoma of the Lung. J Thorac Oncol 10:1156-62 |
| Shaw, Alice T; Ou, Sai-Hong I; Bang, Yung-Jue et al. (2014) Crizotinib in ROS1-rearranged non-small-cell lung cancer. N Engl J Med 371:1963-71 |
| Zheng, Zongli; Liebers, Matthew; Zhelyazkova, Boryana et al. (2014) Anchored multiplex PCR for targeted next-generation sequencing. Nat Med 20:1479-84 |
| Awad, Mark M; Katayama, Ryohei; McTigue, Michele et al. (2013) Acquired resistance to crizotinib from a mutation in CD74-ROS1. N Engl J Med 368:2395-401 |
| Bergethon, Kristin; Shaw, Alice T; Ou, Sai-Hong Ignatius et al. (2012) ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 30:863-70 |
