piperidines and Medulloblastoma

Medulloblastoma is the most common malignant brain tumor in children. Despite improvement in overall survival rate, it still lacks an effective targeted treatment strategy. The Janus family of cytoplasmic tyrosine kinases (JAKs) and Src kinases, upstream protein kinases of signal transducer and activator of transcription 3 (STAT3), play important roles in medulloblastoma pathogenesis and therefore represent potential therapeutic targets.. In this report, we examined the inhibitory efficacy of the JAK1/2 inhibitor, ruxolitinib, the JAK3 inhibitor, tofacitinib and two Src inhibitors, KX2-391 and dasatinib.. These small molecule drugs significantly reduce cell viability and inhibit cell migration and colony formation in human medulloblastoma cells in vitro. Src inhibitors have more potent efficacy than JAK inhibitors in inhibiting medulloblastoma cell migration ability. The Src inhibitors can inhibit both phosphorylation of STAT3 and Src while JAK inhibitors reduce JAK/STAT3 phosphorylation. We also investigated the combined effect of the Src inhibitor, dasatinib with cisplatin. The results show that dasatinib exerts synergistic effects with cisplatin in human medulloblastoma cells through the inhibition of STAT3 and Src.. Our results suggest that the small molecule inhibitors of STAT3 upstream kinases, ruxolitinib, tofacitinib, KX2-391, and dasatinib could be novel and attractive candidate drugs for the treatment of human medulloblastoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Movement; Cell Proliferation; Cerebellar Neoplasms; Cisplatin; Dasatinib; Drug Synergism; Humans; Medulloblastoma; Nitriles; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Pyrroles; src-Family Kinases; STAT3 Transcription Factor; Tumor Cells, Cultured

Medulloblastoma is comprised of at least four molecular subgroups with distinct clinical outcome (WHO classification 2016). SHH-TP53-mutated as well as MYC-amplified Non-WNT/Non-SHH medulloblastoma show the worst prognosis.Here we present evidence that single application of the multi-kinase inhibitor Vandetanib displays anti-neoplastic efficacy against cell lines derived from high-risk SHH-TP53-mutated and MYC-amplified Non-WNT/Non-SHH medulloblastoma. The narrow target spectrum of Vandetanib along with a favourable toxicity profile renders this drug ideal for multimodal treatment approaches. In this context our investigation documents that Vandetanib in combination with the clinically available PI3K inhibitor GDC-0941 leads to enhanced cytotoxicity against MYC-amplified and SHH-TP53-mutated medulloblastoma. In line with these findings we show for MYC-amplified medulloblastoma a profound reduction in activity of the oncogenes STAT3 and AKT. Furthermore, we document that Vandetanib and the standard chemotherapeutic Etoposide display additive anti-neoplastic efficacy in the investigated medulloblastoma cell lines that could be further enhanced by PI3K inhibition. Of note, the combination of Vandetanib, GDC-0941 and Etoposide results in MYC-amplified and SHH-TP53-mutated cell lines in complete loss of cell viability. Our findings therefore provide a rational to further evaluate Vandetanib in combination with PI3K inhibitors as well as standard chemotherapeutics in vivo for the treatment of most aggressive medulloblastoma variants.

Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cerebellar Neoplasms; Dose-Response Relationship, Drug; Drug Synergism; Etoposide; Humans; Indazoles; Medulloblastoma; Molecular Targeted Therapy; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; Sulfonamides

We previously showed the involvement of the tyrosine kinase receptor c-Met in medulloblastoma malignancy. The nonreceptor tyrosine kinases focal adhesion kinase (FAK) and Pyk2 are key players in the progression of different cancers. However, their role in medulloblastoma malignancy is not well understood. In this study, using a protein array approach, we found that c-Met induces FAK and Pyk2 phosphorylation in medulloblastoma cells. We therefore studied the interactions between c-Met and FAK/Pyk2 and their implications for medulloblastoma therapy. We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines. We also found that FAK and Pyk2 mediate the malignant effects of c-Met on medulloblastoma cell proliferation, migration, and invasion. On the basis of these findings, we hypothesized that combined c-Met and FAK inhibitions would have additive effects on the inhibition of medulloblastoma malignancy. To test this hypothesis, we assessed the effects on medulloblastoma malignancy parameters of single or combined treatments of medulloblastoma cells with c-Met and FAK small-molecule kinase inhibitors. We found a significant increase in the inhibitory effect of both inhibitors on medulloblastoma cell migration and cell invasion as compared with single inhibitions (P < 0.05). In addition, oral gavage treatment with c-Met inhibitor of mice bearing medulloblastoma xenografts significantly reduced in vivo tumor growth. Therefore, combining c-Met inhibitors with FAK inhibitors constitutes a new potential strategy for medulloblastoma therapy. Altogether, our study describes a role for FAK and Pyk2 in medulloblastoma malignancy, uncovers new interactions between c-Met and FAK/Pyk2, and proposes for the first time combining anti-c-Met and anti-FAK inhibitors as a new strategy for medulloblastoma therapy.

Topics: Administration, Oral; Animals; Cell Line, Tumor; Cell Movement; Cell Proliferation; Crizotinib; Drug Synergism; Enzyme Activation; Focal Adhesion Kinase 1; Focal Adhesion Kinase 2; Hepatocyte Growth Factor; Humans; Immunoblotting; Medulloblastoma; Mice; Mice, SCID; Molecular Structure; Phosphorylation; Piperidines; Protein Array Analysis; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Quinolones; RNA Interference; Sulfones; Time Factors; Xenograft Model Antitumor Assays

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has great potential for cancer treatment since it provokes cell death in most tumor cells while leaving most normal cells unscathed. Some cancers, however, show resistance to TRAIL, indicating that TRAIL alone may be insufficient for cancer therapy. Here we studied whether the apoptotic susceptibility of A549 non-small cell lung cancer cells could be modulated by inhibiting protein kinase C (PKC). We show that an inhibitor with preference for novel PKC isozymes, NPC 15437, significantly augmented TRAIL sensitivity of A549 cells, as judged by assessing cell death and mitochondrial membrane potential. Likewise, NPC 15437 also significantly potentiated the responsiveness of DAOY medulloblastoma cells to TRAIL. In contrast, an inhibitor with preference for conventional PKC isozymes, Gö6976, did not augment TRAIL sensitivity of A549 cells. To further specify the PKC isozyme responsible for TRAIL sensitization, we used a peptide inhibitor with selectivity for the novel PKC isozyme epsilon, myr-PKC-epsilon V1-2. The inhibition of PKC-epsilon resulted in a significant amplification of the cytotoxic activity of TRAIL in A549 cells. Altogether, our study provides evidence for a considerable role of PKC-epsilon in the apoptotic responsiveness of A549 lung cancer cells, and possibly other malignancies, to TRAIL.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cerebellar Neoplasms; Drug Synergism; Humans; Indoles; Lung Neoplasms; Medulloblastoma; Peptide Fragments; Piperidines; Protein Kinase C-epsilon; Protein Kinase Inhibitors; TNF-Related Apoptosis-Inducing Ligand; Tumor Necrosis Factor-alpha

A 6-year-old boy with a positive family history of malignant hyperthermia presented for posterior fossa craniectomy and excision of medulloblastoma. A nontriggering anaesthetic was therefore planned using infusions of propofol and remifentanil and a vapour free anaesthetic system delivering an oxygen/air mixture. The surgery was carried out with the child in the sitting position.

Topics: Anesthesia; Anesthesia, Intravenous; Anesthetics, Intravenous; Cerebellar Neoplasms; Child; Cranial Fossa, Posterior; Craniotomy; Genetic Predisposition to Disease; Humans; Infratentorial Neoplasms; Male; Malignant Hyperthermia; Medulloblastoma; Piperidines; Posture; Propofol; Remifentanil