Neurofibromatosis type 2 (NF2) is a multiple tumor-forming disease of the nervous system. Bilateral vestibular schwannomas (VS) are diagnostic for NF2, occurring in 95% of the patients. These tumors cause hearing loss and life-threatening brain stem compression. VS commonly require repeated invasive surgeries to remove or debulk the tumors. The outcome of these surgeries is often deafness, loss of balance, and facial paralysis. Identifying new therapeutic targets for drug development in NF2 that are present in tumors but not in normal cells is imperative to prevent and control tumor growth.

This research project studies novel mechanisms by which tyrosine nitration, an oxidative modification to proteins that occurs in pathological conditions, regulates cell metabolism in NF2 to favor tumor growth. We found that tyrosine nitration indeed regulates the way schwannoma-related cells produce energy to survive. In agreement, preventing nitration of proteins in these cells selectively reduces their survival. The long-term goal of this project is to develop drugs that specifically inhibit these oxidized proteins. We aim to target key modified proteins that are not present in normal Schwann cells and control Schwannoma growth. This will maximize the therapeutic efficacy and minimizing the risk of affecting healthy cells by specifically targeting tumor cells.

I recently identified an oxidized protein as a key regulator of the oxygen consumption and energy levels in tumor cells. Nitrated heat shock protein 90 (Hsp90) is an oxidatively modified form of Hsp90. While Hsp90 is essential to normal cell functioning, nitrated Hsp90 is detected only in pathological conditions. I showed that nitrated Hsp90 decreases the cellular oxygen demand, increasing the resistance of tumor cells to low oxygen conditions such as those found in schwannomas. Because this protein is not modified in normal cells and regulates the energy requirements of tumor cells, nitrated Hsp90 constitutes an exceptional target to develop drug therapies focalized specifically on tumor cells. We detected nitrated Hsp90 in human NF2-related schwannoma cells but not in normal Schwann cells. Importantly, recent evidence shows that Hsp90 inhibitors have promising antitumor activity in NF2-related schwannomas. Currently, five inhibitors of Hsp90 are undergoing clinical trials for malignant peripheral nerve sheath tumors and for several cancers. Tumor cells die at concentrations of these inhibitors that do not affect normal cells. A plausible explanation is that nitration of Hsp90, a process that does not occur in normal cells, makes this protein more susceptible to inhibition, thus affecting mainly tumor cells. I found that one of the parental inhibitors of Hsp90, the natural antibiotic geldanamycin, binds to nitrated Hsp90 with higher affinity than to unmodified Hsp90, further supporting this important concept.

Hsp90 is not the only protein undergoing nitration in pathological conditions. In addition to nitrated Hsp90, we detected several other nitrated proteins in schwannoma cell culture models that are not present in normal Schwann cells. We found that preventing tyrosine nitration in human NF2-related schwannoma cells decreased cell survival, implying that one or more of these modified proteins may indeed promote schwannoma growth. Identifying the nitrated proteins playing relevant roles in tumor growth is essential for the development of new molecular-targeted therapies. The completion of this project will help to develop tumor-directed, more effective therapies for this devastating disease.