Prof. Vincenzo Ciminale, MD

Research topic

Mitochondria, cancer cell metabolism, reactive oxygen species, leukemia.

Background

Intracellular reactive oxygen species (ROS) constitute a homeostatic “rheostat” whose perturbation can lead to cell death. Cancer cells generally have increased ROS levels compared to normal cells. According to the ROS rheostat model, a further increase in ROS could engage death pathways in cancer cells while sparing normal cells, which have a lower ROS set-point. In line with this hypothesis, our previous studies revealed that HTLV-1, the causative agent of adult T-cell leukemia (ATL), codes for p13, a mitochondrial protein that increases mitochondrial ROS production and sensitizes transformed T-cells to death signals without harming normal T-cells. Based on these findings, we have set out to investigate ROS homeostasis in acute T-lymphoblastic leukemia (T- ALL) and devise ROS-based strategies to kill transformed cells.

Research achievements

We are testing drugs that increase mitochondrial ROS production with strategies to block scavenging pathways whose activity might otherwise blunt the efficacy of ROS- inducers. Treatments are tested in vitro on T-ALL cell lines and short-term cultures of primary T- ALL xenografts. We are characterizing the ROS set-point of the T-ALL leukemia-initiating cell (LIC) subpopulation to test whether ROS modulators might deplete their self-renewal capacity. ROS-enhancing treatments are combined with drugs that engage cell death pathways (e.g. TRAIL). Effective treatments will tested in vivo in mice inoculated with HTLV-1-transformed cells and T-ALL xenografts.

Conclusions and perspectives

Approximately 25% of T-ALL have a dismal prognosis as these patients are refractory to current therapies; our studies will provide leads for the development of innovative therapies for treating patients with refractory T-ALL.