? 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
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Brosseau, Jean-Philippe; Liao, Chung-Ping; Wang, Yong et al. (2018) NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation. Nat Commun 9:5014
Liao, Chung-Ping; Booker, Reid C; Brosseau, Jean-Philippe et al. (2018) Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis. J Clin Invest 128:2848-2861
Lu, Jia; Bera, Asim K; Gondi, Sudershan et al. (2018) KRAS Switch Mutants D33E and A59G Crystallize in the State 1 Conformation. Biochemistry 57:324-333
Dvorak, Christopher C; Satwani, Prakash; Stieglitz, Elliot et al. (2018) Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study. Pediatr Blood Cancer 65:e27034
Stieglitz, Elliot; Mazor, Tali; Olshen, Adam B et al. (2017) Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia. Nat Commun 8:2127
Sherborne, Amy L; Lavergne, Vincent; Yu, Katharine et al. (2017) Somatic and GermlineTP53Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors. Clin Cancer Res 23:1852-1861
Davidson, Philip R; Sherborne, Amy L; Taylor, Barry et al. (2017) A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies. Sci Rep 7:7645
Liao, Chung-Ping; Booker, Reid C; Morrison, Sean J et al. (2017) Identification of hair shaft progenitors that create a niche for hair pigmentation. Genes Dev 31:744-756
Yoshimi, Akihide; Balasis, Maria E; Vedder, Alexis et al. (2017) Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML. Blood 130:397-407
Strowd 3rd, Roy E; Blakeley, Jaishri O (2017) Common Histologically Benign Tumors of the Brain. Continuum (Minneap Minn) 23:1680-1708

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