mRNA Translation Is a Therapeutic Vulnerability Necessary for Bladder Epithelial Transformation
This week, we profile a recent publication in JCI Insight from Sujata Jana (pictured, left) in the laboratory of Andrew Hsieh (pictured, right) at Fred Hutch.
Can you provide a brief overview of your lab’s current research focus?
Our laboratory studies the process of mRNA translation in normal cell physiology and disease. We are particularly interested in understanding how the protein and RNA components of the translation machinery interface to enable gene-specific translation. Our central hypothesis is that deregulation of translationally regulated gene networks can initiate and drive disease phenotypes such as tumorigenesis and cancer progression. Ultimately, we aim to use our fundamental discoveries to inform the design of precision therapeutics that can modulate protein synthesis and positively impact patient outcomes.
What is the significance of the findings in this publication?
Bladder cancer in 4th most common cancer in men (8th in women) and yet is significantly understudied at a mechanistic level. We wanted to leverage our extensive experience dissecting the translation regulatory network to answer a simple question. Is efficient protein synthesis necessary for bladder cancer formation and progression? This is a particularly important question from a therapeutics perspective because a positive result could represent a new druggable target in an intractable disease. Using a series of genetic models, we found that efficient protein synthesis is vital for bladder cancer initiation and progression but dispensable for normal bladder function. This is mediated in part by a protein called eukaryotic initiation factor 4E (eIF4E). Importantly, using both mouse and human models of advanced bladder cancer and an eIF4E inhibitor currently in clinical trials called eFT508 we found that tumors with highly active eIF4E are very sensitive to this promising drug.
What are the next steps for this research?
There are really two avenues of research that are of interest to our lab. First, our data provide the preclinical rationale for testing eFT508 in patients with bladder cancer. From our work, it appears that ~30% of patients could respond to this drug, but this remains to be seen in a well-controlled Phase 2 clinical trial. Second, we found that 63% of human bladder cancer do not exhibit changes to eIF4E suggesting that there are other important translation-base mechanisms to discover. To this end, we have other projects that are mechanistically exploring this question in-depth.
This work was funded by:
This research was supported by the National Institutes of Health (R37 CA230617, R01 DK119270, R01 GM135362), a Burroughs Wellcome Fund Career Award of Medical Scientists, the Emerson Collective, the Robert J. Kleberg Jr. and Helen C. Kleberg Foundation, the Matthews family, Nancy and Dick Bernheimer, Dan Stinchomb, the Thomas and Patricia Wright Memorial Fund and eFFECTOR Therapeutics, Inc.