Koong Laboratory

The Koong Lab is supported by an experienced research team. We have previously shown that the IRE1alpha-XBP1 pathway, a key component of the unfolded protein response (UPR), was activated by hypoxia and endoplasmic reticulum (ER) stress. Since identifying IRE1alpha-XBP1 as a potential therapeutic target in cancer, our laboratory has completed a high throughput small molecule screen of >120,000 compounds for inhibitors of this pathway. The current research directions in the lab include:

Targeting the IRE1alpha-XBP1 branch of the UPR: We identified a class of compounds that selectively inhibit IRE1alpha and demonstrate potent anti-cancer activity. We developed several computational biology methods of analyzing the drug screening data to improve the efficiency of drug discovery. We also completed a genome-wide siRNA screen to identify other genes that are required for the activation of IRE1alpha. Studies investigating the mechanisms of IRE1alpha activation will lead to the development of novel cancer therapeutics targeting this pathway.

The role of metabolic cell death in tumor response to radiation therapy (RT): Recently, we also identified a novel regulatory function of IRE1alpha in cellular sensitivity to ferroptosis, an iron-dependent form of non-apoptotic cell death, suggesting that targeting this pathway pharmacologically may be a novel therapeutic approach for alleviating tissue damages due to excessive ferroptosis, as well as for improving cancer therapy (Jiang et al. Nature Communications 2024). We expanded our research to the broader topic of metabolic cell death, cell death due to metabolic imbalances of tumor cells (Mao, et al. Nature Reviews Cancer 2025) including ferroptosis, cuproptosis and disulfdptosis, in tumor responses to treatment, especially RT.

Interplay between hypoxia, Cancer-Associated Fibroblasts (CAFs) and macrophages in PDAC tumor microenvironment: M2 macrophages suppress anti-tumor T cell responses, which leads to favorable conditions for tumor growth. Previously we found that this effect was HIF-2a (HIF2) dependent and could be reversed with a small molecule inhibitor of HIF-2a called PT2399, a preclinical version of belzutifan, an FDA-approved HIF-2a inhibitor for use in VHL-mutant renal cell carcinoma (Garcia et al. Gastroenterology 2022). We are actively working to identify the paracrine factor(s) mediating this polarization effect on macrophages. We envision that by using our combination of in vivo mouse modeling and in vitro cell/organoid culture systems we will determine the role of hypoxia in various cell types within the PDAC tumor microenvironment, with the goal to identify potentially druggable targets, such as the fibroblast-macrophage signaling axis.

Combination of mutant KRAS/pan-RAS inhibition with RT in pancreatic cancer treatment: Dr. Koong's clinical interest is in the treatment of gastrointestinal malignancies, particularly pancreatic cancer (pancreatic ductal adenocarcinoma, or PDAC). He has pioneered the use of stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) for pancreatic cancer. The translational focus of the Koong Laboratory is to identify cancer biomarkers that facilitate clinical decision making, as well as more effective therapeutic strategies to improve SBRT. More recently, we have been testing the combination of mutant KRAS/pan-RAS inhibitors in clinical development with SBRT in pre-clinical PDAC models.

Principal Investigator

Albert C. Koong, M.D., Ph.D., FACR, FASTRO
Professor and Head, Division of Radiation Oncology
Chair, Department of Radiation Oncology
Olga Keith and Harry Carothers Wiess Distinguished University Chair in Cancer Research

Office: 713-563-2300

@ACKoongMDPhD