The September 2019 “VTPP Science in action” article comes from Dr. Mahsa Zarei. The article “Tumors with TSC mutations are sensitive to CDK7 inhibition through NRF2 and glutathione depletion” was published in the Journal of Experimental Medicine, September 10, 2019. The article describes the effects of a novel therapy for Tuberous sclerosis complex (TSC). TSC is an autosomal dominant tumor predisposition syndrome characterized by tumor development in the brain, heart, kidney, and lungs caused by germline loss-of-function mutations in either TSC1 or TSC2. In TSC tumors loss of the TSC1/TSC2 protein complex leads to activation of mTORC1, suggesting targets downstream of mTOR may offer attractive treatment options. The article has the potential to open new treatment directions, and can be found at

Dr. Zarei’s article (link included above and below) provides important new data that begins to decipher the mechanism by which TSC1- or TSC2-null cells, in contrast to their wild-type counterparts, are sensitive to pharmacological inhibition of CDK7. The manuscript goes on to demonstrate that in cells lacking TSC1 or TSC2 the sensitivity to CDK7 inhibition significantly reduced glutathione levels and increased reactive oxygen species that was the result of decreased expression of NRF2 and glutathione biosynthesis genes. The data are exciting as they provide a rationale to explain how the anti-tumor effects are manifest. Zarei’s lab went on to show using a TSC1-null bladder cancer xenograft model in vivo that treatment with a covalent CDK7 inhibitor (THZ1,) significantlymarked reduced tumor volume and tumor regrowth. In sum, the data demonstrate that THZ1 inhibits growth and induces cell death in a TSC-dependent manner, providing a strong rationale for the use of this approach in the treatment of these devastating tumors. The compelling data (summarized in the putative mechanism Figure 6) argue for the anticancer activities of THZ1 and the effect on glutathione biosynthesis. These agents represent a promising new therapeutic opportunity in TSC, a tumor with limited treatment options.

The entire paper can be found at:

Not only is VTPP Science making an impact in the scientific literature, but also in the advancement of science in India. Dr. Long (Currently a Indo-US GETin visiting fellow) has developed a hands-on Workshop “CRISPR Editing in Mammalian Cells and Embryos” that will run November 4-9 in the ICAR-Central Institute for Research on Buffaloes (CIRB), Hisar, Haryana, India. The program has been swamped with registration applications and Dr. Long is headlining the workshop.