Laboratory Research

            The major focus of Dr. Koong’s laboratory is to investigate hypoxia regulated signaling pathways that contribute to tumor growth and resistance to anti-cancer therapy.  His laboratory has shown that the Ire1-XBP1 pathway, a key component of the unfolded protein response (UPR), was activated by hypoxia and endoplasmic reticulum (ER) stress. Since identifying Ire1-XBP1 as a potential therapeutic target in cancer, Dr. Koong’s laboratory has completed a high throughput small molecule screen of >120,000 compounds for inhibitors of this pathway.  He has identified a class of compounds that selectively inhibits Ire1 and demonstrates potent anti-cancer activity (Papandreou et al., Blood 2010).  To further accelerate the preclinical evaluation of other compounds targeting this pathway, his laboratory has also developed an XBP1-luciferase transgenic mouse in which luciferase activity is detectable only when XBP1 is activated (Spiotto et al., Cancer Res 2009). He has completed a genome wide siRNA screen to identify other genes that are required for the activation of Ire1.  Studies investigating the mechanisms Ire1 activation will lead to the development of novel cancer therapeutics targeting this pathway.  More recently, his laboratory has developed several computational biology methods of analyzing the drug screening data to improve the efficiency of drug discovery.

            As part of Dr. Koong's clinical studies, plasma samples are collected from patients for the purposes of identifying novel biomarkers predictive of disease state and outcomes following therapy. This database of over 1000 samples has been used to identify novel biomarkers in pancreatic cancer. Initially, we developed the proximity ligation assay (PLA) as a method to analyze specific protein levels between pancreatic cancer patients and age-matched controls. PLA relies upon a pair of antibodies linked to an oligonucleotide. When these antibodies bind in close enough proximity to a sufficiently abundant substrate, the corresponding local oligonucleotide concentration increases significantly, allowing for hybridization of a connecting oligonucleotide and formation of a target specific amplicon. This unique molecular “barcode” serves as a primer for PCR amplification and can be multi-plexed for simultaneous detection of multiple different proteins. This technology was used to demonstrate the increased sensitivity and specificity of this assay compared to traditional ELISA methods. Next, a panel of 20 biomarkers was identified to develop a biomarker “signature” for pancreatic cancer. More recently, the change in this biomarker signature was analyzed  following therapy as a method to predict outcome and response to therapy.