Identification of Highly Active Drug Combinations for the Therapy of NF1-Associated Malignant Peripheral Nerve Sheath Tumors Using the Zebrafish Model
Abstract
Rationale and Objective: Malignant peripheral nerve sheath tumors (MPNSTs) are very aggressive and often metastatic soft tissue sarcomas. The prognosis is very poor, and the recurrence rate is relatively high. MPNSTs are frequently found in patients who have neurofibromatosis type 1 (NF1) disease. This disease is caused by mutation of the NF1 gene, which is among the most prevalent inherited tumor suppressor genes in humans. Currently, surgical excision is the only way to cure MPNSTs, although surgery is frequently not adequate because MPNSTs can metastasize and invade surrounding normal tissues and vital organs. Current chemotherapy regimens are often ineffective, and associated with significant toxicity that can severely reduce quality of life. Therefore, it is very important to identify promising drugs that can be rapidly moved into clinical trials to improve the therapy of patients with MPNSTs. Ultimate Applicability of the Research: We have developed a faithful zebrafish model of MPNSTs by breeding together zebrafish that harbor genetically engineered inactivation of both of the duplicated zebrafish nf1 genes and p53. To identify new drugs that inhibit pathways essential for MPNST cell growth and survival, we will transplant MPNST cells from primary zebrafish tumors into very small zebrafish embryos and array these embryos into 96 well plates for incubation with the drugs. The small size of the embryos and small volume of water allow us to analyze many different drugs in a relatively short amount of time. We plan to test drugs that are currently in clinical trials for other types of cancer. We also plan to test a collection of about 1200 drugs that are Food and Drug Administration (FDA)-approved for human use for all types of diseases. In each case, we will be analyzing the drugs for their ability to reduce the numbers of MPNST tumor cells in our model. To increase the likelihood of the success of our work, we will test each of these drugs alone and also in combination with two of the most potent available targeted inhibitors. We are likely to identify drugs that are not currently being used for MPNST but that can rapidly be repurposed for testing in human patients. This is because the very expensive and time-consuming toxicology studies and clinical evaluations to prove human tolerance have already been completed for these drugs. The drugs will still need to be tested in clinical trials to prove their efficacy in human patients with MPNSTs, but hopefully these trials can begin much sooner because the drugs are already in human use to treat another type of human disease or condition. Advancement of NF research and Patient Care: We predict that we will be likely to identify one or more FDA-approved drugs or drugs in current clinical trials that will show activity against MPNSTs. These tumors are a major problem for a subset of NF1 patients. The zebrafish model is ideal for the initial screen of these compounds because the embryos are small and can be treated in 96-well plates. Promising combinations can then be tested in mouse models of NF1-associated MPNST and human MPNST cell lines and then will be available for testing in clinical trials. The strategy we are using is called "repurposing" because we are hoping to identify an approved drug that was developed for a different disease that can be "repurposed" to improve the treatment of MPNSTs in NF1 patients. Our project is designed to make discoveries using the zebrafish model system that can be relatively quickly translated to improve the treatment of these malignant tumors that develop in patients with Neurofibromatosis type 1.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610093
Entities
People
- A. Thomas Look
Organizations
- Dana–Farber Cancer Institute
- United States Army