Clinical Relevance of ROS (V-ros UR2 Sarcoma Virus Oncogene Homolog) Aberrations in Solid Tumours

Alterations involving the ROS (v-ros UR2 sarcoma virus oncogene homolog 1) gene such as mutations, overexpression and gene rearrangements has been implicated in carcinogenesis and has been demonstrated to be a relevant target for ALK inhibitors. While emerging reports have demonstrated the role of ROS rearrangement in non-small cell lung cancer and cholangiocarcinoma, the functional significance of ROS dysregulation in solid tumors remain largely unstudied. The investigators aims are: (1) To characterize the frequency of ROS gene fusion, ROS protein overexpression and ROS gene mutations in cell lines and tumors from patients with hepatocellular carcinoma, colorectal, gastric, breast, ovarian, cholangiocarcinoma and non-small cell lung cancer, (2) To identify novel ROS gene variants in human solid tumors harboring ROS aberrations using next generation sequencing (NGS), (3) To determine the functional relevance of novel ROS gene variants identified with NGS, (4) To characterize the sensitivity of cells with functionally relevant ROS aberrations using ROS tyrosine kinase inhibitors. ROS fusions and protein overexpression will be screened in a panel of cell lines and primary tumors using Fluorescence In-situ Hybridization and immunohistochemistry respectively. Targeted next-generation sequencing will be applied to identify ROS variants in matching cancer types demonstrating high levels of gene fusion and protein overexpression. Functional characterization of novel ROS variants will be performed by silencing (shRNA) and overexpressing candidate cell lines with the respective ROS mutations/fusions, and evaluating their effects on biological functions including cell proliferation, migration, invasion and apoptosis, as well as sensitivity against ROS/ALK inhibitors. The investigators anticipate findings from this study will improve the investigators understanding of aberrant ROS signaling in an expanded group of cancer types, and potentially identifying a larger group of cancer patients that will benefit from ROS targeted therapy.

Further insight of the role of ROS receptor tyrosine kinase will confirm it as a therapeutic target in human solid tumors and hence expand the indication of crizotinib and other dual ALK/ ROS inhibitors. Furthermore, given the rarity of ROS fusion receptor tyrosine kinase in reported cancers, defining the epidemiology of ROS aberrations in other unreported cancers harboring ROS pathway activation is essential to properly design future clinical trials of ROS inhibitors. The validation of ROS receptor tyrosine kinase will also provide a new therapeutic target in the treatment of cancer and expand the role of novel targeted agents. Findings from this study will further the investigators knowledge on the oncogenic functions of the ROS and the application of ROS inhibitors in an extended group of solid tumors.

Study Overview

• Status: Unknown
• Conditions: Cancer

• Study Type: Observational
• Enrollment (Anticipated): 2000

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore
    • Recruiting
    • Nationa University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Department of Pathology, NUH Tissue Repository, The samples collected for the study are leftover clinical samples and the patients have consented for their samples to be used for research.

Description

Inclusion Criteria:

- Patients with cancer

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description
Characterize the frequency of ROS gene fusion, ROS protein overexpression and ROS gene mutations in cell lines and tumors	To characterize the frequency of ROS gene fusion, ROS protein overexpression and ROS gene mutations in cell lines and tumors from patients with hepatocellular carcinoma, colorectal, gastric, breast, ovarian, cholangiocarcinoma and non-small cell lung cancer

Secondary Outcome Measures

Outcome Measure
Identify novel ROS gene variants in human solid tumors harboring ROS aberrations using next generation sequencing (NGS)
Determine the functional relevance of novel ROS gene variants identified with NGS
Characterize the sensitivity of cells with functionally relevant ROS aberrations using ROS tyrosine kinase inhibitors

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Anticipated): July 1, 2014

Study Registration Dates

• First Submitted: April 2, 2012
• First Submitted That Met QC Criteria: May 10, 2012
• First Posted (Estimate): May 11, 2012

Study Record Updates

• Last Update Posted (Estimate): December 11, 2013
• Last Update Submitted That Met QC Criteria: December 10, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Other Study ID Numbers: 2011/01714