A Novel Approach to Understand and Prevent the Evolution of Drug-Resistant Lung Cancer Cells: A Feasibility Study
Abstract
At present, lung cancer patients exhibiting cancers that have spread from other parts of the body are routinely treated with anti-cancer drugs. Although the cancer may respond well in many patients, the cancer returns later with a vengeance, often having become resistant to the original anti-cancer drug to which the cancer had responded earlier. This re-emergence of drug-resistant lung cancers is a major cause of death. The emergence of resistant forms of lung cancer is related to adaptive mechanisms that arise within the minority of cancer cells remaining in the patient s body upon surgical removal of the main lesions and/or upon generalized cancer chemotherapy. These cells, which, as a result of mutational changes, become drug-resistant, are selected because of such cell s ability to survive the drug and their proliferation abilities despite the presence of the drug. Therefore, if two anticancer drugs are used simultaneously, the rates of emergence of such resistant cells could be drastically reduced: If one in a thousand lung cancer cells responding to drug 1 adapts to drug 1, and so do 1 in a thousand cancer cells adapt to drug 2, then only one in a million cancer cells would become resistant to both drugs 1 and 2 if the cells are exposed to both drugs simultaneously. However, this is rarely feasible in a clinical setting, because severe toxic effects of anticancer drugs generally preclude their simultaneous use. Clinicians therefore alternate between two drugs. As a result, cells are slowly conditioned to be selected for resistance to one followed by the other drug, and so on, thus becoming resistant to both drugs. Using a novel approach, we have proposed an alternate paradigm for drug development, targeted to preventing the adaptation of cancer cells to drugs, and thus would undercut the major factor for death due to lung cancer. The approach utilizes state-of-the-art advances in genomic technology, including the use of a recently developed genome-wide gene-targeting technology coupled with massively parallel DNA sequencing, followed by computational modeling. If successful, this approach should benefit patients who have been treated for metastatic lung cancers and are the most vulnerable lung cancer patients to die from the disease. It is anticipated that if these experiments are successful, we will be in a position to proceed along a new paradigm of cancer treatment, in which a novel class of drugs with relatively low toxicity will be developed: drugs that do not by themselves target a cancer cell s ability to survive; therefore, are less toxic than are current anti-cancer drugs, but will target the adaptive strategies of drug-treated cancer cells. This proposal is the first articulation of this novel concept of cancer drug development. If successful, this work will pave the way for testing the discoveries in mouse models in future projects, and, if successful, clinical trials based on this novel concept could begin as early as 5 years after the completion of this project s goals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610170
Entities
People
- Animesh Ray
Organizations
- Keck Graduate Institute
- United States Army