Targeting the ECM to Enhance Drug Delivery in Nf1-Associated Nerve Sheath Tumors
Technical Report,15 Sep 2015,14 Sep 2016
Regents of the University of Minnesota Minneapolis United States
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The focus of the proposal is to determine what factors limit delivery of drugs to tumors of the peripheral nerves, namely neurofibromas NFs and their derivative, the malignant peripheral nerve sheath tumor MPNST. The drugs in question include small molecule inhibitors of mTOR and MEK kinases, as well as a traditional chemotherapeutic agent, doxorubicin also called by its trade name Adriamycin. The major factor under study for limiting drug delivery is the extracellular matrix component hyaluronic acid HA. During the last research period we expanded two colonies of genetically engineered mice that develop NFs and MPNSTs for study. We also tested 2 drugs RAD001 and PD-0325901 in these models for efficacy and found both had moderate activity. We tested a drug called PEGPH20 for its ability to degrade HA in NFs and MPNST-like tumors in these mice when injected. PEGPH20 did reliably remove the HA from the NF and MPNST microenvironments and dramatically improve tumor blood vessel patency, and doxorubicin delivery to tumor cells in situ with no clear affect on tumor cell apoptosis or mitotic index. In the next year we will test PEGPH20 enhancement of doxorubicin, RAD001 and PD-0325901 delivery, therapeutic effect.
- Medicine and Medical Research