Posted November 6, 2015
Konstantina Stankovic, M.D., Ph.D., Massachusetts Eye and Ear Infirmary and Harvard Medical School
Neurofibromatosis type 2 (NF2) is a rare genetic disorder caused by a mutation in the Merlin gene. Clinical manifestations of NF2 can include non-malignant tumors, malignant brain tumors, headaches, visual defects, and hearing loss. Current treatment is essentially limited to surgical tumor removal. As a surgeon scientist taking care of NF2 patients, Dr. Konstantina Stankovic of Massachusetts Eye and Ear Infirmary and Harvard Medical School is profoundly aware of the potentially debilitating consequences of this disease and the pressing need to develop better therapies. Pharmacologic treatment of NF2 is a major unmet medical need. The hallmark of NF2 is bilateral vestibular schwannomas (VSs), a usually slow-growing tumor that develops from the balance nerves supplying the inner ear. VSs typically cause hearing loss, but if the tumor becomes large, it can press against nearby essential brain structures which can ultimately lead to death.
The main drug that has demonstrated success in clinical trials thus far is bevacizumab, which inhibits vascular endothelial growth factor (VEGF), an important signaling protein that promotes the growth of new blood vessels. Although effective in 54% of patients, bevacizumab can have serious adverse effects such as kidney failure. Dr. Stankovic's research aims to identify and develop effective drugs with minimal side effects to treat VS and NF2 by using VS as a model NF2 tumor.
With funding from a Neurofibromatosis Research Program Fiscal Year 2013 New Investigator Award, Dr. Stankovic and her team have used a bioinformatic approach to analyze all genes that have been implicated in human VS growth and have identified inflammation as playing a prominent role in tumor biology. They have specifically identified a pro-inflammatory transcription factor, called nuclear factor kappa B (NFκB), to be abnormally activated in human VS. Although novel in NF2 and VS, NFκB is known to play a major role in various other tumors. The research team used NFκB inhibitors that are novel to the NF2 and VS fields (BAY 11, an experimental drug, and curcumin, a dietary supplement) to show that inhibition of the NFκB pathway can prevent growth and promote death of VS cells. Unlike many drugs in clinical trials against NF2 today, curcumin is extremely well tolerated, inexpensive and effective against several malignancies.
Dr. Stankovic is also enthusiastic about exploring a possible therapeutic role of curcumin in a clinical trial. Pre-clinical studies in mice are underway to determine whether combination therapy with curcumin and bevacizumab together can be more potent than either drug alone. The team is also interested to determine whether such cocktail therapy would reduce the potential toxicity of bevacizumab.
1. Dilwali S, Briët MC, Kao SY, Fujita T, Landegger LD, Platt MP, Stankovic KM. Preclinical validation of anti-nuclear factor-kappa B therapy to inhibit human vestibular schwannomas growth. Mol Oncol. 2015 Aug;9(7):1359-70
2. Dilwali S, Kao SY, Fujita T, Landegger LD, Stankovic KM. Nonsteroidal anti-inflammatory medications are cytostatic against human vestibular schwannomas. Transl Res. 2015 Jul;166(1):1-11
3. Dilwali S, Roberts D, Stankovic KM. Interplay between VEGF-A and cMET signaling in human vestibular schwannomas and Schwann cells. Cancer Biol Ther. 2015;16(1):170-5.