Daniel McGrail, PhD

Cleveland Clinic Lerner Research Institute

Lung Cancer

Pilot Grant | Bruce Hollenbeck VeloSano Pilot Grant in Memory of Janet Hollenbeck

Molecular mediators of disparate outcomes in African American patients with lung cancer

For many years, experimental therapeutic development was disproportionately evaluated in male subjects at both the clinical and pre-clinical level, leading to some therapeutics that were not effective for half of the population. However, the scientific community has increasingly come to appreciate the importance of sex as a biological variable and it is now required to be included for federally funded research. We hypothesize that genetic ancestry is the next evolution of this paradigm. Minorities are often massively under-represented in clinical trials, and this exclusion could lead to therapeutics not effective for their genetic composition.

Lung cancer is currently the leading cause of cancer deaths in the United States. African Americans are disproportionately impacted by lung cancer, even though they do not smoke more than Americans of European ancestry. In order to improve outcomes for African American patients with lung cancer, we need to ensure we have effective therapeutic regimens.

Using cancer cell lines cultured in a lab, we found numerous molecular differences between lung cancer cell lines of African and European ancestry, which were mirrored in patient tumors. Several of these observed molecular differences were in signaling pathways commonly therapeutically targeted in cancer, and corresponded with altered sensitivity to cancer therapeutics both in cell lines and in patients.

Here, we first seek to understand how altered signaling leads to lung tumors of African ancestry poorly responding to clinically-approved therapy with EGFR inhibitors. Next, we will evaluate novel therapies that may offer increased anti-tumor efficacy in tumors of African ancestry, as well as potential synergistic combinations with current standards of care. If successful, these studies could identify improved therapeutic strategies for African Americans who are disproportionately affected by lung cancer. Moreover, this study could serve as proof-of-concept to expand this framework to other cancer types.

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