Project Description Narrative:
Neurofibromatosis type 1 (NF1), an inherited or genetic disorder, is detected in approximately one out of 3,000 live births. Malignant Peripheral Nerve Sheath Tumors or MPNSTs are one of most severe malignancies associated with NF1, with over 67% of patients with metastatic disease and 40% recurrence rate after initial treatment. Conventional chemo/radiation and surgical resection therapies frequently fail to eliminate these large nerve-associated tumors, with five-year survival reported to be as low as 20%. There is no current targeted therapy for MPNSTs. A MEK-inhibitor Selumetinib has been tried; however, its clinical response is heterogeneous and systematic long-term adverse effects have been reported. Thus, there is a critical need for developing effective therapies for this disease which has an orphan disease status due to the low incidence, and the consequent lack of interest by pharmaceutical industry in developing targeted therapies. A distinguishing feature of MPNST tumors is the high percentage of immune cells known as macrophages which can comprise up to 40% of tumor mass. It is hypothesized that these macrophages enable tumors to survive rather than working to eliminate the tumor cells. Thus, novel therapies which target tumor cells but at the same time reprogram the macrophages to an inflammatory type for promoting tumor suppression can be very effective for achieving robust and long-term tumor remission.
In this project, the research team will develop light triggered and safe nanoparticles which can deliver multiple drugs to tumors and tumor associated macrophages and selectively release these drugs at the tumor site. These particles will then be tested in mouse models.
The researchers hypothesize that they can reprogram the immune environment in the tumor via light triggered multiple drug release from lipid nanoparticles, so that the tumor death achieved by light therapy is compounded by patients' own immune cells which flip from a tumor-promoting to tumor suppressing type and, thus, achieve long-term tumor control and avoid the emergence of therapy resistance.
Pre-clinical studies in this proposal will determine the feasibility of a dual-targeted chemotherapeutic/immunotherapy that would be inexpensive, easy to administer, adaptable to other cancers, and consequently lower the barriers to care that worsen health outcome disparities.