This project addresses how a chaperone molecule called grp94 controls breast cancer. Preliminary studies have revealed that grp94 orchestrates a number of important pathways for cancer development and progression, including the pathway of transforming growth factor beta (TGFβ). Findings from this proposal should lead to a better understanding of the biological and clinical significance of grp94-TGFβ interaction and eventual development of novel cancer therapeutics for breast cancer.
This project will address an unmet research and medical need by developing novel chemical tools to enable a spatiotemporal investigation of grp94-regulated cancer mechanisms in endogenous cancer phenotypes. This chemical biology/pharmacology approach complements the genetic and structural approaches of other research components in this integrated program. Importantly, it will help address the biology of grp94 in the cellular environment where grp94 is limited but not absent, and this also aims to improve the drug-like characteristics of grp94 ligands towards the ultimate goal of identifying leads with therapeutic potential for clinical translation.
This project attempts to understand the structure and function of grp94, a master-activator protein that helps other proteins in the cell become active. Given that many grp94-dependent proteins have been implicated in cancers, the ability to selectively stop their function by stopping their master activator, grp94, could open a powerful new route to treating cancer. Stopping the activity of grp94 requires that we understand what it looks like, how it works and what makes it unique; to achieve this understanding, we will visualize the 3-dimensional structure of grp94, identify, and test the structural features that make grp94 special, and ultimately use this knowledge to design drug inhibitors that have fewer side effects.