Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors
Abstract
The aim of this project is to allow drug delivery to nerve tumors that plague patents with Neurofibromatosis Type 1 (NF1) syndrome. These tumors include troublesome, painful, and dangerous plexiform neurofibromas and their cancerous counterpart, the malignant peripheral nerve sheath tumors (MPNSTs). We have discovered that the composition of these tumors (that is, the material around and between the cancer cells called the extracellular matrix) prevents drugs from getting to the cancer cells in their interiors. A similar situation exists for pancreatic cancer. Therefore, almost all current drug testing done for plexiform neurofibromas and MPNSTs are doomed to fail! We have a solution, however. We are collaborating with a company called Halozyme Therapeutics to determine if their long-acting formulation of an enzyme that will destroy the special extracellular matrix, composed of high quantities of hyaluronic acid, around plexiform neurfibromas and MPNSTs will allow drugs to reach the tumor cells and kill them -- thus vastly improving the response to all drug therapies. Their enzyme formulation, called PEGPH20, is a pegylated form of human hyaluronidase. We will test our ideas using several mouse models of plexiform neurofibroma and MPNST that we and others have developed, as well as engrafted human tissues in mice. We will test the enzyme treatment with various drugs that could be useful for treating these tumors including standard chemotherapy and a next-generation targeted therapies (a MEK inhibitor). We expect the mouse testing to take 2 to 3 years. One member of our team is Dr. Christopher Moertel, M.D., who runs a large NF clinic at the University of Minnesota. He will initiate Phase I clinical studies in NF1 patients by the end of year 3 in a parallel effort, if the preclinical results we ve obtained via this grant are promising. PEGPH20 is currently being tested in Phase I clinical trials in human pancreatic cancer patients. We expect that combining the use of Halozyme Therapeutic s PEGPH20 with other drugs will benefit patients by causing much greater reductions in tumor size, perhaps even allowing tumors to completely disappear. This work will benefit children and adult NF1 patients with plexiform neurofibromas causing significant health problems and patients who have developed an MPNST. Risks of the use of PEGPH20 could include damage to joints, changes to the growth of children, and could change the response of patients to drugs that are given concurrently.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510114
Entities
People
- David A. Largaespada
Organizations
- United States Army
- University of Minnesota