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Our long-term goal is to identify and validate effective therapeutic targets for cancer and
Alzheimer’s Disease (AD). The seminar will focus on the crucial roles of Cdk5 kinase in the
pathogenesis of Alzheimer’s Disease and Aurora A kinase in breast cancer through the
applications of genetic and chemical tools developed in our laboratory.
We have developed a chemical genetic approach to identify the direct targets of kinases on a
proteome wide scale. Using an analog-sensitive Cdk5 kinase and an orthogonal radioactive
ATP analog, we unearthed multiple novel substrates of Cdk5 kinase in mouse brains. Using
these substrates as cues, we uncovered several neuronal death pathways that are triggered by
deregulated Cdk5 in neurotoxin-exposed neurons and in mouse models. Our previous work
revealed that Cdk5 deregulation causes Golgi fragmentation, oxidative stress and
mitochondrial dysfunction leading to neuronal death in Alzheimer’s disease model.
Another area of special interest to us is dissecting the roles of oncogenic kinases (Aurora A,
Aurora B, v-Src) and G Proteins in cancer. Aurora A is overexpressed in several types of
cancers: prostate, breast, ovarian, colorectal, gastric, pancreatic, hepatocellular, gliomas,
nonendometriod and aggressive non-Hodgkin’s lymphoma to name a few. Several small
molecule inhibitors against Aurora A are undergoing testing in mid- to late-stage clinical trials.
However, Aurora A inhibition in Phase II clinical trials has been associated with numerous
adverse side effects, suggesting that collateral inhibition of Aurora A in rapidly proliferating
normal tissues is the culprit. Therefore, selective targeting of disease-specific targets of Aurora
A in cancer could be a superior option for developing effective drugs and simultaneously
combating collateral toxicity. Our goal is to identify the direct oncogenic targets of Aurora A
kinase in highly aggressive castration-resistant prostate cancer and triple negative breast
cancer. We have documented that ablation of a novel Aurora A substrate using RNAi abrogates
tumor formation in nude mice, suggesting that it is a critical oncogenic effector of Aurora A
and a potential clinical target. Results from these studies have the potential to facilitate the
development of combination therapies using both Aurora A and substrate-targeted drugs. |