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

NCT ID: NCT01596374

Last Updated: 2013-12-11

Basic Information

• Recruitment Status: UNKNOWN
• Total Enrollment: 2000 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2011-08-31

Brief Summary

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.

Conditions

Cancer

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: RETROSPECTIVE

Eligibility Criteria

Inclusion Criteria

• Patients with cancer

• Minimum Eligible Age: 21 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National University Hospital, Singapore

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Nationa University Hospital

Singapore, , Singapore

Site Status: RECRUITING

Countries

Singapore

Central Contacts

Ross Soo, MBBS

Role: CONTACT

Phone: +65 6779 5555

Email: Ross_Soo@nuhs.edu.sg

Facility Contacts

Ross Soo, MBBS

Role: primary

Other Identifiers

2011/01714

Identifier Type: -

Identifier Source: org_study_id