Ana Patricia da Silva Gomes, PhD

Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many of the patients do not respond to these treatments or relapse following an initial response. The preclinical research and clinical trials that has led to the development and approval of current anti-lung cancer therapies largely ignore the age of the patient; even though aging is the main risk factor for lung cancer with 70 as the average age at the time of diagnosis. Our research program was based on the hypothesis that organismal reprogramming that occurs as an individual ages makes lung tumors in the aged host more conducive to withstand chemotherapies. Through the support provided by the ALA we were able to demonstrate that in fact age-induced circulatory changes are sufficient to protect lung cancer cells against a wide range of chemotherapies. We were able to trace this effect to the chronic accumulation of the stress hormone cortisol. Our data show that cortisol by itself is able to mimic the same effects as observed with old serum. Moreover, our data also show that inhibiting cortisol’s actions re-sensitizes lung cancer cells to chemotherapies. Mechanistically, our data support the paradigm that cortisol acts to promote resistance to chemotherapies in lung cancer cells via upregulation of a specific family of proteins. Together, our work thus far has demonstrated a critical role for age-induced cortisol accumulation in circulation as a driver of resistance to chemotherapies in lung cancer and support the need for studies testing the potential benefit of inhibiting cortisol’s actions to potentiate the anti-cancer effect of chemotherapies in old patients. On the second funding period of this award, we propose to evaluate this new research strategy in pre-clinical murine models as well as to perform in depth mechanistic studies to precisely determine the link between age-induced cortisol and the age-induced resistance to chemotherapies in lung cancer.

Update: Through the support provided by the ALA we were able to demonstrate that age-driven circulatory changes promote resistance to standard of care chemotherapies in lung cancer and narrow this effect to the chronic accumulation of the stress hormone cortisol that occurs during aging. Our data show that cortisol acts on lung cancer cells through its cognate receptor, the glucocorticoid receptor, to promote resistance to several classes of chemotherapies. Together these data support the overall hypothesis of this research program and suggests that glucocorticoid receptor inhibitors, such as the FDA approved mifepristone, might be of interest to sensitize old patients to chemotherapies.