Targeting Translation Inhibition to Inhibit Tumor Adaptation to Metabolic Stress
It is known today that tumor cells reduce the rate of protein synthesis to adapt to the nutrient stress found in the tumor micro environment (TME). Using translation modifiers to prevent cells from suffering oxidative stress, tumors are protected from glucose starvation which is typical for TME. We aim to target translation factors essential for tumor cells survival under low glucose levels.
Using Kaplan-Meier Estimator for human lung, breast, head and neck and brain cancer patients, we have identified a translation modifier which is over-expressed in many tumors and is associated with poor clinical prognosis. Moreover, using tumor and non-tumor cells we confirmed that it promotes cell survival under glucose starvation by facilitating a metabolic switch to maintain cellular NADPH levels and REDOX balance. Liekwise, a depletion of said translation modifier results in reduced tumoroginicity. Our immediate goal is to target it via multiple strategies including:
- A synthetic small molecule inhibitors.
- Oligonucleotide therapeutic.
- A translation modifier which is not active under normal conditions and is being activated in nutrient starved cells such as in solid tumors. This suggest that its inhibitors will have a selective killing of tumor cells.
- Inhibitors are predicted to be more active in poorly perfused tumors.
- Target is over expressed in a number of tumors allowing screening patients most likely to respond.
- Inhibitors may synergize with energy depleting compounds such as mitochondrial toxins, glucose uptake inhibitors and blood vessel inhibitors.
Drafting of a new provisional application is in process.
Dr. Barak Rotblat, NIBN and the Department of Life Sciences, Ben-Gurion University of the Negev, Israel.