buparlisib and Medulloblastoma

Medulloblastoma (MB) is the most common malignant brain tumor in children. Current treatment for MB includes surgical resection, radiotherapy and chemotherapy. Despite significant progress in its management, a portion of children relapse and tumor recurrence carries a poor prognosis. Based on their molecular and clinical characteristics, MB patients are clinically classified into four groups: Wnt, Hh, Group 3, and Group 4. With our increased understanding of relevant molecular pathways disrupted in MB, the development of targeted therapies for MB has also increased. Targeted drugs have shown unique privileges over traditional cytotoxic therapies in balancing efficacy and toxicity, with many of them approved and widely used clinically. The aim of this review is to present the recent progress on targeted chemotherapies for the treatment of all classes of MB.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cerebellar Neoplasms; Humans; Medulloblastoma; Protein Kinase Inhibitors

Medulloblastoma (MB) is the most common malignant brain tumor in children, accounting for nearly 20 percent of all childhood brain tumors. New treatment strategies are needed to improve patient survival outcomes and to reduce adverse effects of current therapy. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway plays a key role in cellular metabolism, proliferation, survival and angiogenesis, and is often constitutively activated in human cancers, providing unique opportunities for anticancer therapeutic intervention. The aim of this study was to evaluate the pre-clinical activity of BKM120, a selective pan-class I PI3K inhibitor, on MB cell lines and primary samples. IC50 values of BKM120 in the twelve MB cell lines tested ranged from 0.279 to 4.38 μM as determined by cell viability assay. IncuCyte ZOOM Live-Cell Imaging system was used for kinetic monitoring of cytotoxicity of BKM120 and apoptosis in MB cells. BKM120 exhibited cytotoxicity in MB cells in a dose and time-dependent manner by inhibiting activation of downstream signaling molecules AKT and mTOR, and activating caspase-mediated apoptotic pathways. Furthermore, BKM120 decreased cellular glycolytic metabolic activity in MB cell lines in a dose-dependent manner demonstrated by ATP level per cell. In MB xenograft mouse study, DAOY cells were implanted in the flank of nude mice and treated with vehicle, BKM120 at 30 mg/kg and 60 mg/kg via oral gavage daily. BKM120 significantly suppressed tumor growth and prolonged mouse survival. These findings help to establish a basis for clinical trials of BKM120, which could be a novel therapy for the treatment of medulloblastoma patients.

Topics: Aminopyridines; Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Humans; Medulloblastoma; Mice; Morpholines; Phosphatidylinositol 3-Kinase; Phosphoinositide-3 Kinase Inhibitors; RNA, Neoplasm; Survival Analysis; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Sonic hedgehog (SHH) medulloblastoma (MB) subtype is driven by a proliferative CD15+ tumor propagating cell (TPC), also considered in the literature as a putative cancer stem cell (CSC). Despite considerable research, much of the biology of this TPC remains unknown. We report evidence that phosphatase and tensin homolog (PTEN) and phosphoinositide 3-kinase (PI-3K) play a crucial role in the propagation, survival and potential response to therapy in this CD15+ CSC/TPC-driven malignant disease. Using the ND2-SmoA1 transgenic mouse model for MB, mouse genetics and patient-derived xenografts (PDXs), we demonstrate that the CD15+TPCs are 1) obligately required for SmoA1Tg-driven tumorigenicity 2) regulated by PTEN and PI-3K signaling 3) selectively sensitive to the cytotoxic effects of pan PI-3K inhibitors in vitro and in vivo but resistant to chemotherapy 4) in the SmoA1Tg mouse model are genomically similar to the SHH human MB subgroup. The results provide the first evidence that PTEN plays a role in MB TPC signaling and biology and that PI-3K inhibitors target and suppress the survival and proliferation of cells within the mouse and human CD15+ cancer stem cell compartment. In contrast, CD15+ TPCs are resistant to cisplatinum, temozolomide and the SHH inhibitor, NVP-LDE-225, agents currently used in treatment of medulloblastoma. These studies validate the therapeutic efficacy of pan PI-3K inhibitors in the treatment of CD15+ TPC dependent medulloblastoma and suggest a sequential combination of PI-3K inhibitors and chemotherapy will have augmented efficacy in the treatment of this disease.

Topics: Aminopyridines; Animals; Antineoplastic Agents; Cell Line, Tumor; Cerebellar Neoplasms; Drug Resistance, Neoplasm; Fucosyltransferases; Gene Expression Regulation, Neoplastic; Hedgehog Proteins; Humans; Medulloblastoma; Mice; Mice, Transgenic; Microarray Analysis; Molecular Targeted Therapy; Morpholines; NADH Dehydrogenase; Neoplasm Transplantation; Neoplastic Stem Cells; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; PTEN Phosphohydrolase; Signal Transduction; Stereotaxic Techniques; Xenograft Model Antitumor Assays

Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit overexpression or amplification of the MYC oncogene (c-MYC) usually have an extremely poor prognosis, but there are no animal models of this subtype of the disease. Here, we show that cerebellar stem cells expressing Myc and mutant Trp53 (p53) generate aggressive tumors following orthotopic transplantation. These tumors consist of large, pleiomorphic cells and resemble human MYC-driven MB at a molecular level. Notably, antagonists of PI3K/mTOR signaling, but not Hedgehog signaling, inhibit growth of tumor cells. These findings suggest that cerebellar stem cells can give rise to MYC-driven MB and identify a novel model that can be used to test therapies for this devastating disease.

Topics: Aminopyridines; Animals; Cell Proliferation; Cell Transformation, Neoplastic; Cerebellar Neoplasms; Cerebellum; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Genes, p53; Imidazoles; Medulloblastoma; Mice; Morpholines; Neural Stem Cells; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-myc; Quinolines; TOR Serine-Threonine Kinases

The malignant brain cancer medulloblastoma is characterized by mutations in Hedgehog (Hh) signaling pathway genes, which lead to constitutive activation of the G protein (heterotrimeric guanosine triphosphate-binding protein)-coupled receptor Smoothened (Smo). The Smo antagonist NVP-LDE225 inhibits Hh signaling and induces tumor regression in animal models of medulloblastoma. However, evidence of resistance was observed during the course of treatment. Molecular analysis of resistant tumors revealed several resistance mechanisms. We noted chromosomal amplification of Gli2, a downstream effector of Hh signaling, and, more rarely, point mutations in Smo that led to reactivated Hh signaling and restored tumor growth. Analysis of pathway gene expression signatures also, unexpectedly, identified up-regulation of phosphatidylinositol 3-kinase (PI3K) signaling in resistant tumors as another potential mechanism of resistance. Probing the relevance of increased PI3K signaling, we demonstrated that addition of the PI3K inhibitor NVP-BKM120 or the dual PI3K-mTOR (mammalian target of rapamycin) inhibitor NVP-BEZ235 to the initial treatment with the Smo antagonist markedly delayed the development of resistance. Our findings may be useful in informing treatment strategies for medulloblastoma.

Topics: Aminopyridines; Animals; Cell Proliferation; Drug Resistance, Neoplasm; Gene Amplification; Hedgehog Proteins; Insulin-Like Growth Factor I; Kruppel-Like Transcription Factors; Medulloblastoma; Mice; Morpholines; Mutation; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Receptors, G-Protein-Coupled; Signal Transduction; Smoothened Receptor; Tumor Suppressor Protein p53; Up-Regulation; Zinc Finger Protein Gli2