Combinatorial Therapies for Neurofibroma and MPNST Treatment and Prevention
Abstract
Plexiform neurofibromas are a major cause of morbidity in NF1 patients, and malignant peripheral nerve sheath tumors (MPNSTs) are the most common malignancy and leading cause of death in these patients. Few therapeutic options are available to patients with plexiform neurofibromas or MPNSTs. At present, surgery is the only effective means of treating patients with these tumors. If the tumors cannot be completely resected, there is little that we can do. Radiation therapy is not used for plexiform neurofibromas; it can control MPNST growth locally, but has no effect on the long-term survival of patients with this malignancy. Drugs that are effective against plexiform neurofibromas and MPNSTs have not been developed. It is thus essential that we identify new drugs that will work in patients with plexiform neurofibromas and MPNSTs. Tamoxifen and trifluoperazine may represent such drugs. Tamoxifen has been used to treat breast cancer since the early 1970s because it is effective (70% response rate), well tolerated, and has minimal toxicity. Trifluoperazine has similarly been used to treat schizophrenia, a condition that often presents initially in teens, for several decades and it is also well tolerated. We have found that both tamoxifen and trifluoperazine inhibit the proliferation and survival of human neurofibroma and malignant peripheral nerve sheath tumor (MPNST) cells. When we grafted human MPNST cells into the nerves of mice and began treatment with tamoxifen and trifluoperazine 3 days later, we found that we could inhibit graft growth by up to 50%. Excitingly, however, combined therapy with tamoxifen and trifluoperazine was even more effective, reducing graft growth by nearly 90%. Although these results are very promising, there are several key questions that we still need to answer if we are to bring these drugs to human clinical trials. First, I would point out that our graft experiments tested these drugs under conditions that gave them the best chance of succeeding. We now need to test these drugs under the conditions that we encounter in the real world when treating NF1 patients. By this, I mean we need to find out whether combinatorial therapy with tamoxifen and trifluoperazine is effective against large established MPNSTs. Also, we do not yet know whether tamoxifen and trifluoperazine are effective against large established plexiform neurofibromas; answering this question is critically important as Dr. Alyssa Reddy and I have presented a proposal to the NF Clinical Consortium outlining a trial with tamoxifen in children with plexiform neurofibromas and were told that they will not move forward with a trial until we have preclinical therapeutic trial data in animal models of neurofibromas. As noted above, trifluoperazine and tamoxifen have excellent safety profiles and are given to patients long term for other chronic conditions. As NF1 patients are at high risk for developing plexiform neurofibromas and MPNSTs, this raises the question of whether these drugs could be given prophylactically to NF1 patients to keep them from developing plexiform neurofibromas and MPNSTs in the first place. If so, this would be the ideal approach to treatment -- it s always better to keep tumors from developing in the first place than to deal with them after they have developed. Consequently, we hypothesize that a combination of tamoxifen and trifluoperazine will effectively treat established neurofibromas and MPNSTs and prolong the survival of tumor-bearing mice. We also hypothesize that prophylactic treatment with these drugs will prevent neurofibroma and MPNST pathogenesis. To test these hypotheses, we will perform preclinical trials with robust mouse models that develop neurofibromas and MPNSTs. In Aim 1, mice with established neurofibromas or MPNSTs will be challenged with vehicle, tamoxifen, trifluoperazine, or combined tamoxifen-trifluoperazine therapy. We will then determine which of these treatme
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510193
Entities
People
- Steven Carroll
Organizations
- Medical University of South Carolina
- United States Army