? PROJECT 2 The primary goal of this project is to develop better therapy for children with neurofibromatosis and malignant peripheral nerve sheath tumor (MPNST), the major life-threatening complication of neurofibromatosis. Sadly, children (and adults) with this aggressive soft tissue sarcoma are rarely cured if the tumor is large or has spread throughout the body. Further, the application of intensive chemotherapy, ionizing radiation, and surgery has done little to improve this dismal outcome. By leveraging robust pre-clinical models of neurofibromatosis, we are poised to erase major problems associated with MPNST. Our key insights stem from genetically engineered mouse models that recapitulate many facets of the human conditions. Their use has revealed two key ?vulnerabilities? in MPNST: the cell surface receptor CXCR4, and Cyclin D1, which drives cell proliferation by activating Cyclin-dependent kinases 4 and 6 (CDK4/6). Our complementary molecular and genetic studies show that impeding CXCR4 or Cyclin D1-associated CDK4/6 blocks cell proliferation and tumor growth in both mouse and human MPNST. Fortunately, drugs that block CXCR4 and CDK4/6 are already available for use in children and adults. Plerixafor, a CXCR4 inhibitor originally developed to fight HIV, is available and has already been used in children. Palbociclib was developed as a CDK4/6 inhibitor for breast cancer and other malignancies that are linked to genetic amplification of Cyclin D1. It, too, has been utilized as an anti-cancer agent. Neither drug has been systematically applied to patients with neurofibromatosis and MPNST. To speed the translation from our pre-clinical models illuminating CXCR4 and CDK4/6 as therapeutic targets to the effective use of plerixafor and palbociclib in children with neurofibromatosis and MPNST, we must close several gaps. First, we must leverage our pre-clinical models to optimize dose/schedule for these agents. Second, we must develop robust pathological and imaging biomarkers to confirm that these agents can reach their therapeutic target in an individual patient. And third, we must carry out a ?Phase 0? clinical trial to confirm that the optimized dose/schedule and response biomarkers can be applied to neurofibromatosis patients with MPNST. Accomplishing this will pave the way toward definitive clinical trials of these new agents for children with this disease.

Public Health Relevance

? PROJECT 2 Our major goal is to develop new therapeutic agents that our previous laboratory studies reveal to be promising therapies for children with malignant peripheral nerve sheath tumor (MPNST), an aggressive soft tissue sarcoma commonly observed in patients with neurofibromatosis. We are focusing on inhibitors of CXCR4 and Cyclin D1-associated CDK4 and 6, based on findings from genetically engineered models of neurofibromatosis and studies of mouse and human MPNST specimens. Optimizing drug dosing/schedules, developing robust response biomarkers, and completing sequential Phase 0 pilot studies of CXCR4 and CDK4/6 inhibitors will leave us positioned to effectively carry this work forward in clinical trials of one or both agents in children with neurofibromatosis and MPNST.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZCA1-RPRB-0 (M1))
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Indiana University-Purdue University at Indianapolis
United States
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