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The current areas of study

1. Our new project concerns the mechanism of development of drug resistance in cancer. We focus on the common drug irinotecan, which inhibits topoisomerase 1, leading to DNA breaks. Surprisingly, upon acquiring resistance, cancer cells accumulate hundreds of thousands of mutations mostly in non-coding regions. These mutations specifically block the interaction of topoisomerase 1 with chromosomes, thus reducing the probability of DNA breaks upon the irinotecan exposure. Currently, we study how to avoid development of the resistance.  We collaborate with chemists to develop irinotecan analogs that suppress generation of the resistance mutations. 

Our current research address:

(1)  Can we avoid development of the irinotecan resistance by preventing generation of these mutations?

(2)  How the resistance mutations are generated with inhibitors of topoisomerase 2 and other common drugs?


2. In another translational project, we are developing methods for fast genetic screens to identify genes that modulate responses to drugs. Currently used pooled shRNA or CRISPR screens are plagued with false hits. We are applying a novel DNA barcoding system to enable identification of true and false hits, which will dramatically improve the screens. Application of this novel screening system for the identification of genes that affect drug responses will help designing novel drug combinations, developing biomarkers of drug responses or establishing the nature of side effects.​


3. Over the years, research in the lab has focused on understanding molecular mechanisms underlying the central role of the heat shock protein Hsp70 in cancer. We have found that Hsp70 regulates tumor initiation and metastasis via modulation of cancer-related signaling pathways. This signaling function of Hsp70 is mediated by a scaffold protein BAG3. In collaboration with medicinal chemists, we further developed small molecules that specifically target this regulatory function of Hsp70 by disrupting its complex with BAG3.

Our current research addresses:

How does Hsp70 regulate signaling pathways? 

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4. In a distinct project we study a process of aggregation of abnormal polypeptides. When chaperone and protein degradation machinery fail to handle abnormal proteins, they aggregate and cause cell toxicity, which may give rise to various disorders. As the last line of defense, special machinery has evolved that transports these toxic aggregates to a centrosome location via microtubules, which leads to the relief of toxicity.

Our current research address:

(1) What cellular components control protein aggregation?

(2) How do signaling pathways regulate protein aggregation?


Our Grants


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