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. The mTOR pathway has evolved to sense nutrient levels and control protein synthesis. An important target in the mTOR pathway is 4E-BP1 which under conditions of low nutrients is released from mTOR inhibition and becomes active. When active, 4E-BP1 competes with eIF4G on binding to eIF4E and inhibits cap-dependent translation. 4E-BP is mostly considered as a tumor suppressor, as it restricts protein synthesis and proliferation. We however argue that 4E-BP is essential for tumor cells survival under low glucose levels in the tumor and is therefore a possible druggable target.
Using Kaplan-Meier Estimator for human lung, breast, head and neck and brain cancer patients, we observed that 4EBP is over-expressed in many tumors and is associated with poor clinical prognosis. Moreover, using tumor and non-tumor cells we confirmed that 4E-BP1 promotes cell survival under glucose starvation by facilitating a metabolic switch to maintain cellular NADPH levels and REDOX balance. Likewise, 4EBP depletion results in reduced tumoroginicity. Our immediate goal is to target 4E-BP1 via multiple strategies including:
- A synthetic 4E-BP1 small molecule inhibitors.
- Oligonucleotide therapeutic targeting 4E-BP1.
- 4E-BP1 is not active under normal conditions and is being activated in nutrient starved cells such as in solid tumors. This suggests that its inhibitors will have a selective killing of tumor cells.
- 4E-BP1 inhibitors are predicted to be more active in poorly perfused tumors.
- 4E-BP1 is overexpressed in a number of tumors allowing screening patients most likely to respond.
- 4E-BP1 inhibitor may synergize with energy depleting compounds such as mitochondrial toxins, glucose uptake inhibitors and blood vessel inhibitors.
Provisional application will be filed on the identified compounds.
Dr. Barak Rotblat, NIBN and the Department of Life Sciences, Ben-Gurion University of the Negev, Israel.