pyrimidinones and Sarcoma

Topics: Adult; Fatal Outcome; Female; Gene Fusion; Humans; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; RNA-Binding Proteins; Sarcoma; Spinal Cord Neoplasms; Treatment Outcome

Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5 cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow. Here we describe the development of a synergistic combination treatment strategy that may be applicable in both soft tissue sarcomas as well as sarcomas of bone that takes advantage of targeting the cell cycle. We show that Rb-positive cell lines treated with the CDK4/6 inhibitor palbociclib reversibly arrest in the G

Topics: Animals; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Disease Models, Animal; Drug Resistance, Neoplasm; Gene Knockdown Techniques; Humans; Male; Mice; Nuclear Proteins; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Pyrimidinones; Retinoblastoma Protein; Sarcoma; Xenograft Model Antitumor Assays

Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumors with more than 50 different subtypes. The Wnt signaling pathway is involved in the development and in the regulation, self-renewal, and differentiation of mesenchymal stem cells, and plays a role in sarcomagenesis. In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 produces

Topics: Antineoplastic Agents; Apoptosis; beta Catenin; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell Survival; Doxorubicin; Drug Synergism; Humans; Protein Binding; Pyrimidinones; Sarcoma; TCF Transcription Factors; Triazines; Wnt Signaling Pathway

Musculoskeletal sarcomas are aggressive malignancies of bone and soft tissues often affecting children and adolescents. Histone deacetylase inhibitors (HDACi) have been proposed to counteract cancer stem cells (CSCs) in solid neoplasms. When tested in human osteosarcoma, rhabdomyosarcoma, and Ewing's sarcoma stem cells, the new HDACi MC1742 (1) and MC2625 (2) increased acetyl-H3 and acetyl-tubulin levels and inhibited CSC growth by apoptosis induction. At nontoxic doses, 1 promoted osteogenic differentiation. Further investigation with 1 will be done in preclinical sarcoma models.

Topics: Aminopyridines; Apoptosis; Bone Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Neoplastic Stem Cells; Osteogenesis; Osteosarcoma; Pyrimidinones; Rhabdomyosarcoma; Sarcoma; Sarcoma, Ewing; Structure-Activity Relationship

Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy. Here, we investigated the in vitro activity of the pan-class I PI3K inhibitor buparlisib (BKM120) in pediatric bone and soft tissue sarcomas. Buparlisib inhibited activation of Akt and signaling molecules downstream of mTORC1 (mTOR complex 1) in Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines. Anti-proliferative effects were observed in both anchorage dependent and independent conditions and apoptosis was induced within 24 hours of drug treatment. Buparlisib demonstrated cytotoxicity as a single agent, but was found to be more effective when used in combination. Synergy was observed when buparlisib was combined with the IGF1R inhibitor NVP-AEW541 and the mTORC1 inhibitor rapamycin. The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone. Additionally, the combination of buparlisib with the MEK1/2 inhibitor trametinib resulted in synergy in sarcoma cell lines possessing MAPK pathway mutations. Taken together, these data indicate buparlisib could be a novel therapy for the treatment of pediatric bone and soft tissue sarcomas.

Topics: Aminopyridines; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cells, Cultured; Class I Phosphatidylinositol 3-Kinases; Drug Synergism; Extracellular Signal-Regulated MAP Kinases; Humans; Mechanistic Target of Rapamycin Complex 1; Morpholines; Multiprotein Complexes; Mutation; Osteosarcoma; Phosphorylation; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Pyridones; Pyrimidines; Pyrimidinones; Pyrroles; Sarcoma; Signal Transduction; TOR Serine-Threonine Kinases

Wee1 is a critical component of the G(2)-M cell-cycle checkpoint control and mediates cell-cycle arrest by regulating the phosphorylation of CDC2. Inhibition of Wee1 by a selective small molecule inhibitor MK1775 can abrogate G(2)-M checkpoint, resulting in premature mitotic entry and cell death. MK1775 has recently been tested in preclinical and clinical studies of human carcinoma to enhance the cytotoxic effect of DNA-damaging agents. However, its role in mesenchymal tumors, especially as a single agent, has not been explored. Here, we studied the cytotoxic effect of MK1775 in various sarcoma cell lines and patient-derived tumor explants ex vivo. Our data show that MK1775 treatment at clinically relevant concentrations leads to unscheduled entry into mitosis and initiation of apoptotic cell death in all sarcomas tested. In MK1775-treated cells, CDC2 activity was enhanced, as determined by decreased inhibitory phosphorylation of tyrosine-15 residue and increased expression of phosphorylated histone H3, a marker of mitotic entry. The cytotoxic effect of Wee1 inhibition on sarcoma cells seems to be independent of p53 status as all sarcoma cell lines with different p53 mutation were highly sensitive to MK1775 treatment. Finally, in patient-derived sarcoma samples, we showed that MK1775 as a single agent causes significant apoptotic cell death, suggesting that Wee1 inhibition may represent a novel approach in the treatment of sarcomas.

Topics: Antineoplastic Agents; Apoptosis; CDC2 Protein Kinase; Cell Cycle Checkpoints; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cyclin B; Cyclin-Dependent Kinases; Histones; Humans; Mitosis; Nuclear Proteins; Phosphorylation; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; Sarcoma; Tumor Suppressor Protein p53