Current Research Projects in the Koumenis Lab
Since 2002, we have been systematically dissecting the role of the Unfolded Protein Response (UPR) and the Integrated Stress Response (ISR) in primary and metastatic tumor growth. We are also leveraging this knowledge to develop novel anti-cancer treatments.
Elucidating the role of the ISR in oncogene-driven tumorigenesis & metastasis
The Integrated Stress Response (ISR) is a developmentally conserved process that promotes cell homeostasis, particularly to unfolded proteins in the endoplasmic reticulum and to nutrient and hypoxic stress. One area of interest is how oncogenic activation-exemplified by the protooncogene c-Myc activates the ISR and how it is co-opted by tumors to drive Myc-dependent tumorigenesis and metastasis in a tumor cell-intrinsic manner.
Investigating the ISR in tumor stroma as a driver in tumorigenesis & metastasis
While it has been well-established that the ISR plays primarily a pro-tumorigenic role in a tumor cell-autonomous manner, its role in the tumor microenvironment remains largely unexplored. We have uncovered a key role for the ISR effector ATF4 (a leucine zipper transcription factor) in activated cancer associated fibroblasts (CAFs) and promoting tumor angiogenesis. We are currently investigating this role by employing scRNA-seq analysis, transgenic mouse models and various cell biology approaches, such as EM, confocal microscopy, etc.
Screening for novel inhibitors of the ISR
Our work and that of other groups has firmly established a significant role for the ISR in tumor progression and metastasis. We are employing cell-based and biochemical screening assays to screen curated small molecule libraries to identify novel therapeutics to interfere with this process as effective anti-tumor modalities. Additionally, we are interested in testing these compounds or existing ISR inhibitors with established modalities such as chemotherapy and radiotherapy.
We are studying the impact of radiation on normal cells and tissues. We are developing novel modalities and technologies to improve the therapeutic window of radiotherapy
Developing physiologically-relevant animal models to study radiation-induced normal tissue effects to facilitate clinical translation of novel therapeutics and modalities
Animal models are key to understanding the molecular processes underlying the effects of ionizing radiation to critical normal tissues and organs and in developing clinically actionable biomarkers of toxicity. We have been developing mouse models which more closely mimic incidental radiation deposition to intestinal and cardiac tissues. We are also testing novel radioprotectors and radiation delivery modalities which spare normal tissues as well as to test the prognostic value of imaging modalities to predict response to therapy.
Testing the ability fo untra high-dose rate radiotherapy (FLASH-RT) to spare normal tissues and control tumor growth
FLASH radiotherapy represents a relatively recent and highly exciting area of research with strong clinical promise. The current evidence suggests that FLASH radiotherapy delivered in the form of electron, proton or other particles at doses exceeding 60 Gy/sec can spare normal tissues but is equipotent as conventional radiation (1 Gy/min or less) in controlling the growth of tumors. We are employing expertise in radiobiology and radiation physics to test the ability of FLASH-Proton RT to improve the therapeutic window and usher in new human clinical trials.