Research Portfolio

Funding Opportunities

Join our Mailing List
Join our mailing list to be notified of new funding opportunities.

Your Email

To receive information about funding opportunities, events, and program updates.

Novel Susceptibility Factors in Lung Cancer Evolution

Institution: Stanford University
Investigator(s): Ashby Morrison, Ph.D.
Award Cycle: 2010 (Cycle 19) Grant #: 19XT-0124 Award: $400,000
Subject Area: Cancer
Award Type: Exploratory/Developmental Award

Initial Award Abstract
A primary cause of lung cancer is mutation caused by exposure to toxins that damage DNA, particularly those found in tobacco smoke. One especially potent carcinogen in tobacco smoke is the chemical benzo(a)pyrene diolepoxide, or BPDE. BPDE structurally attaches to DNA, contributing to subsequent mutation of the DNA sequence. Enough mutations in genes critical for a cell’s normal function can lead to cancer. However, not all DNA sequences in a cell are equally susceptible to BPDE, with some being recognized as “hotspots” for BPDE-induced mutation and others rarely if ever targeted by the chemical. A major goal of our research proposed here is to establish which DNA sequences are more often attacked by BPDE and why. Determination of this could reveal ways in which susceptibility to BPDE could be reduced or even eliminated, leading to possible new ways to prevent lung cancer. One possible reason for the specificity of BPDE action lies in the actual state of DNA within a cell nucleus. By itself, DNA is a long molecule with its characteristic double-helix structure. However, in a cell DNA is part of an extensive complex with a large number of protein molecules. This massive complex of DNA and protein is called chromatin. Chromatin is necessary for several functions including packaging the large DNA molecules of the human genome in the relatively small nucleus, and protecting the DNA from damaging agents. Indeed, we hypothesize that chromatin status is a determining factor in DNA’s susceptibility to BPDE-induced damage. Previous research has revealed several genes and related genetic “pathways” that are important in lung cancer development. One of the most significant of these is the retinoblastoma (RB) gene pathway. As suggested by the name, RB was first identified as playing a major role in retinal cancer. However, it was soon found to be inactivated in a very large number of human cancers, including lung cancer. Indeed, it has been suggested that RB pathway inactivation is a fundamental requirement for lung cancer development. Interestingly, a major function of RB is to modulate chromatin structure. It does so by regulating the activity of enzymes that modify the protein components of chromatin. These modifications serve, amongst other purposes, to determine the degree of DNA packaging in chromatin. Therefore, depending on the type and number of modifications, chromatin can be in a relatively more open or closed state. Provocatively, loss of RB function, which is invariably found in lung cancer, leads to a more open state of chromatin. This has lead us to hypothesize that loss of RB pathway function in lung cells renders them more susceptible to carcinogens, such as BPDE, due to changes in chromatin structure. We will address this hypothesis with the following approaches: (1) Identify the chromatin structure of lung cells after RB loss; (2) Establish the BPDE susceptibility in lung cells after RB loss; and (3) Determine BPDE susceptibility and cancer potential of lung cells after modulation of chromatin structure. Using normal human lung cells, we will experimentally disrupt RB function and determine the effects of RB loss on chromatin structure and DNA susceptibility to BPDE-induced damage. These studies will enable us to correlate chromatin structure with damage susceptibility. Finally, we propose that modulating chromatin structure can revert the increased susceptibility to DNA damage and cancer potential observed in cells lacking RB. In conclusion, we believe these investigations will contribute significantly to the identification of the molecular determinants of lung cancer and aid in the understanding of RB function in lung cancer, thus illuminating new avenues for cancer detection, prevention and treatment.