GDSC Graduate Student Ludia J. Pack Passes her Qualifying Exam!
Tuesday, October 5, 2021
GDSC Graduate Student Ludia Pack, passed her Qualifying Exam. Last year, Ludia joined the laboratory of Dr. Mark Noble. Ludia’s thesis research focuses on restoring Redox/Fyn/c-Cbl (RFC) pathway function as a therapeutic target in non-small cell lung cancers and ovarian cancers. Ludia's thesis proposal abstract can be read below. Congratulations Ludia!
Non-small cell lung cancers (NSCLCs) are the most lethal subtype of lung cancers, which are the number one cause of cancer-related death worldwide. Despite the development of numerous treatments, there is still no cure for NSCLCs. There are two major subcategories of NSCLCs: lung adenocarcinomas (LUADs) and lung squamous cell carcinomas (LUSCs). Although the molecular landscape of NSCLC is very heterogeneous, there are actionable pathways of interest that have led to the development of targeted therapies such as tyrosine kinase inhibitors. Similarly, if the tumor expresses high levels of programmed-death ligand 1 (PD-L1), immune checkpoint inhibitors are included in the therapeutic regimen. However, the current obstacles to the success of existing therapies result from the development of primary, adaptive, or secondary resistance, highlighting the need for more research and development of additional therapies. In addition, no targeted therapies exist for LUSCs.
Many of the targets of interest in both LUADs and LUSCs are targets that can be modulated by the E3 ubiquitin ligase known as Casitas B-lineage lymphoma (c-Cbl). C-Cbl is an important tumor suppressor, due to its capability of negatively regulating mitogenic pathways via ubiquitination of receptor tyrosine kinases as well as non-receptor tyrosine kinases. C-Cbl has also been shown to play a role in decreasing levels of PD-L1. Previous studies in our lab have discovered that c-Cbl can become super-activated via the Redox/Fyn/c-Cbl (RFC) pathway. The RFC pathway becomes activated by increases in intracellular oxidation, which leads to the phosphorylation of Fyn kinase, subsequently causing the phosphorylation and super-activation of c-Cbl, which leads to enhanced degradation of its targets. The lab found that c-Cbl can become inhibited by the rho-guanine nucleotide exchange factor ßpix, and that we can reverse this inhibition via an FDA approved antidepressant called CRA01 (for c-Cbl restorative agent -1).
The pathways of therapeutic interest in NSCLCs may be targetable by harnessing the RFC pathway. My proposal aims to determine if c-Cbl is inhibited in NSCLCs, whether CRA01 can restore c-Cbl function, and if activation of the RFC pathway is a viable strategy for treating cancer growth in vitro and in vivo. The second part of my proposal aims to determine if super-activation of c-Cbl leads to enhanced degradation of PD-L1, and whether this increased degradation leads to increased immune cell infiltration in immuno-competent mice, allowing for the development of a treatment strategy that tackles multiple aspects of NSCLC tumor biology.