Induced Tumor Cell Heterogeneity by the Sleeping Beauty Transposon System to Generate an Improved Model of Drug Resistance
Abstract
Many human lung cancers have a single gene that is critical for its growth and survival, and these genes are referred to as oncogenes. Many oncogenes can be inhibited by targeted drugs. Matching the oncogenes in patients tumors with the correct oncogene-targeted drug has given rise to the concept of precision medicine and has markedly improved outcomes in patients, but has not led to a cure for advanced disease. A feature of human cancer, including lung cancer, is diversity or complexity at the genetic level. This diversity means that an individual cancer is comprised of many different cancer cells, some of which are likely to be resistant to any give cancer drug. While laboratory models such as immortal cancer cell lines derived from human cancers often replicate the oncogenes seen in human cancers, they do not faithfully represent the genetic diversity observed in a patient s tumor burden. This makes treating or curing these models too simple. The goal of this project is to replicate the diversity of human tumors using established cell lines with well-defined oncogenes by artificially inducing widespread and random genetic alterations using a novel technology called transposons. We aim to show that it is more difficult to treat or cure these new diverse cell lines because they harbor a key feature of human cancers -- genetic diversity. In this proposal, we will test this concept using four types of cancer cells harboring four different oncogenes (ALK, ROS1, RET, and EGFR) that comprise about 25% of human lung adenocarcinoma. We believe that this technology will be applicable to any type of cancer cell line. Ultimately, these new diverse cell lines can be used to understand why it is difficult to eliminate all cancer cells with a single drug and thus leading to combination strategies that can overcome this barrier.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510181
Entities
People
- Robert Doebele
Organizations
- United States Army
- University of Colorado Denver