Youssel Kriko
Research Mentor(s): Nathan Merrill
Mentor Department: Internal Medicine
Authors: Youssel Kriko, Habib Serhan, Hasan Zbib, Rhea Raghavan, Hamadi Madhi, Liwei Bao, Xu Cheng, Sofia Merajver, Nathan Merrill
Session: Session 5 (2:00pm – 2:50pm)
Presentation Type: Poster 76
Abstract
Cancer continues to be one of the top causes of death globally, and improvements in therapeutic approaches are desperately needed. In this study, we investigate two forms of breast cancer that are the most aggressive and difficult to treat: inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) brain metastases (BM). As models, we used tumor-derived cancer cell lines. Following expansion in culture, these cells were subjected to extensive pharmacological testing, including both combination regimens and single-agent treatments. Using computer tools, the results were methodically examined to assess two crucial parameters with single-agent treatments: potency and efficacy. Compounds with moderate potency and/or efficacy were selected as candidates for testing in combination to determine synergy, additivity, or antagonism. In IBC, we have identified two classes of compounds that are suitable to test in combination. The first class is compounds that target the B-cell lymphoma 2 (BCL2) family proteins and the second is compounds that target the mitogen-activated protein kinase kinase (MAPKK or MEK) protein. Testing compounds from these classes in combination yielded synergy which was more powerful in IBC cell lines than non-IBC ones. Targeting these two proteins together has been tested in previously published studies in other cancers as well. In TNBC BM, we built upon a study previously published by our lab (Serhan et al, NPJ Breast Cancer, 2024). We tested the combinations of the chemotherapeutic SN-38 with ND-646 and Firsocostat, inhibitors of the enzyme that catalyzes the rate-limiting step in fatty acid synthesis, acetyl-CoA carboxylase (ACC), Testing combinations of these compounds yielded synergy in vitro. We observed synergy specifically between SN-38 and ND-646 as well as SN-38 and Firsocostat, using lower concentrations of SN-38 and higher concentrations of ND-646 and Firsocostat. In the future, we plan to test the combinations mentioned above in in vivo models to validate the in vitro results. We also plan to perform mechanistic studies to understand how these drug combinations work together favorably. Our work aims to provide new treatment options for patients with IBC or TNBC BM, who are desperately in need.
