According to the Centers for Disease Control, lung cancer accounts for more US-deaths (~170,000) than breast cancer, prostate cancer, and colon cancer combined. Although between 85-90% of all lung cancer deaths are directly attributable to tobacco use, it is not known exactly when and how normal lung cells become malignant. In fact, more lung cancers presently arise in former smokers than in active smokers. We have hypothesized that lung cancers may arise from stem or progenitor cell populations, a concept that dates back at least a quarter of a century. We have spent the last 20 months developing methods to isolate and characterize such cells from clinical specimens, and have identified putative lung cancer initiating cells (LCIC). This proposal seeks to exploit our ongoing effort at LCIC-isolation with a strategy to jointly develop strategies for the treatment of lung cancer. Thus, as we identify cells that possess LCIC properties, we will determine whether there are factors in their tumor-environment that enable these cells to survive, and factors which may impair the immune response of the patient to their tumor. In our experiments, we will seek to neutralize such survival and immune suppressive factors, and determine whether these measures enable us to induce an effective anti-tumor response by vaccinating against lung cancer initiating cells.
Statement of Benefit to California:
The American Cancer Society estimates that lung cancer presently accounts for more California-deaths (~14,500) than breast cancer, prostate cancer, and colon cancer combined. Approximately 15,650 new cases of lung cancer are annually diagnosed among men and women in California. Although the vast majority of these cases are directly attributable to tobacco use, more lung cancers presently arise in former smokers than in active smokers.
To develop better targeted and more effective preventative and/or treatment strategies, we first have to develop a better understanding of how lung cancer develops. For the past 20 months, we have embarked on a project that seeks to test the hypothesis whether lung cancers may arise from stem or progenitor cell populations, a concept that dates back at least a quarter of a century.
Because we have been able to identify putative lung cancer initiating cells (LCIC) in primary clinical specimens, we want to couple that ongoing effort with an immunotherapeutic strategy against these cells for the treatment of lung cancer. Specifically, as we identify putative LCIC in clinical specimens (Malignant Pleural Effusions or MPE), we will screen their tumor microenvironment (TME) for factors that are jointly LCIC-survival factors and immunomodulatory, which curtail the patient’s anti-tumor immune responses.
In this proposal, we have designed approaches to screen and validate the properties of such factors in the MPE-TME, and then to neutralize these factors to measure whether more effective anti-tumor responses can be restored in both in vitro and in vivo models using vaccination approaches against LCIC cells. Upon the completion of our aims, we will have better characterized specific factors in the MPE-TME that sustains LCIC in patients, and whether the neutralization of these specific factors engenders effective immune responses in a novel humanized animal model of lung cancer.
The identification of such factors and will enable the development of more effective preventative and treatment strategies for the leading cause of cancer-mortality in the world.