Browsing by Subject "Nerve Sheath Neoplasms"
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Item Mechanistic and Therapeutic Insights for Epigenetic Regulation in Cancer Development(2014-10-03) Patel, Amish Jayantibhai; Galindo, Rene; Martinez, Elisabeth; Brekken, Rolf A.; Le, Lu Q.Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in patients with Neurofibromatosis type 1 (NF1). Effective treatment options are lacking, and MPNSTs are typically fatal. To gain insights into MPNST pathogenesis, we utilized a novel MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, we found that progression to MPNST and loss of MPNST relevant tumor suppressors is associated with increased levels of chromatin regulator/BET bromodomain protein BRD4, and paradoxically, sensitivity and resistance to BET bromodomain inhibition with small molecule inhibitor JQ1. Indeed, genetic and pharmacological inhibition of BRD4 profoundly suppresses both growth and tumorigenesis of MPNSTs. Mechanistically, we uncovered that BET bromodomain inhibition leads to engagement of the ER stress/UPR pathway, and apoptosis through induction of pro-apoptotic effector molecule BIM and suppression of anti-apoptotic BCL-2 in MPNSTs. Moreover, we find that suppressed transcription of Cyclin D1 oncogene upon BRD4 inhibition correlates with reduced proliferation of MPNSTs. All together, this dual restraint on proliferation (via Cyclin D1 downregulation) and survival (via BIM induction) may indicate how BRD4 inhibition is exquisitely effective against MPNSTs and may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate an epigenetic mechanism underlying the balance of anti-/pro-apoptotic molecules, which suggests that BET bromodomain inhibition can shift this balance in favor of cancer cell death. Collectively, these studies provide new insights for developing strategies to overcome resistance to BET bromodomain inhibitor therapy for subverting cancer cell survival.Item Novel Small Molecule Induces Apoptosis in Malignant Peripheral Nerve Sheath Tumors of Neurofibromatosis Type I(2013-07-24) Chau, Vincent; White, Michael A.; Johnson, Jane E.; Parada, Luis F.; Le, Lu Q.Neurofibromatosis Type 1 (NF1) is an autosomal disease 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 (MPNSTs), 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. MPNST patients 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 non-toxic 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.