title: Preclinical therapeutic efficacy of a novel pharmacologic inducer of apoptosis in malignant peripheral nerve sheath tumors.
abstract: Neurofibromatosis type I (NF1) is an autosomal disorder that affects neural crest-derived tissues, leading to a wide spectrum of clinical presentations. Patients commonly present with plexiform neurofibromas, benign but debilitating growths that can transform into malignant peripheral nerve sheath tumors (MPNST), a main cause of mortality. Currently, surgery is the primary course of treatment for MPNST, but with the limitation that these tumors are highly invasive. Radiotherapy is another treatment option, but is undesirable because it can induce additional mutations. Patients with MPNST may also receive doxorubicin as therapy, but this DNA-intercalating agent has relatively low tumor specificity and limited efficacy. In this study, we exploited a robust genetically engineered mouse model of MPNST that recapitulates human NF1-associated MPNST to identify a novel small chemical compound that inhibits tumor cell growth. Compound 21 (Cpd21) inhibits growth of all available in vitro models of MPNST and human MPNST cell lines, while remaining nontoxic to normally dividing Schwann cells or mouse embryonic fibroblasts. We show that this compound delays the cell cycle and leads to cellular apoptosis. Moreover, Cpd21 can reduce MPNST burden in a mouse allograft model, underscoring the compound's potential as a novel chemotherapeutic agent.
authors.affiliation: Authors' Affiliations: Departments of Dermatology, Developmental Biology, and Biochemistry, and Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas.
authors.forename: Vincent
authors.initials: V
authors.lastname: Chau
authors.forename: S Kyun
authors.initials: SK
authors.lastname: Lim
authors.forename: Wei
authors.initials: W
authors.lastname: Mo
authors.forename: Chiachi
authors.initials: C
authors.lastname: Liu
authors.forename: Amish J
authors.initials: AJ
authors.lastname: Patel
authors.forename: Renée M
authors.initials: RM
authors.lastname: McKay
authors.forename: Shuguang
authors.initials: S
authors.lastname: Wei
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Posner
authors.forename: Jef K
authors.initials: JK
authors.lastname: De Brabander
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: Lu Q
authors.initials: LQ
authors.lastname: Le
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007364:Intercalating Agents / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D018317:Nerve Sheath Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D012583:Schwann Cells / Q000166:cytology / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007364:Intercalating Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA