pyrimidinones and Bone-Neoplasms

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Approximately 50% of metastatic melanoma patients harbor BRAF mutations. Several treatment options including the combination of BRAF and MEK inhibitors (BRAF/MEKi) and immunotherapy (mainly anti CTLA-4 and anti PD-1 antibodies), have been shown to improve survival in these patients. Although preclinical data support the synergistic effect of both modalities in combination, data confirming the activity and tolerability of these combinations are not yet available in the clinical setting. Herein, we report the case of a melanoma patient treated with sequential BRAF/MEKi (dabrafenib plus trametinib) followed by the anti CTLA-4 antibody ipilimumab who achieved a pathological complete response. Unfortunately, the patient died due to fatal gastrointestinal (GI) toxicity. Analysis of the BRAFV600E mutation in circulating tumoral DNA (ctDNA) from peripheral blood samples and serial tumor tissue biopsies throughout treatment demonstrated a good correlation with clinical evolution.

Topics: Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Bone Neoplasms; DNA, Neoplasm; Fatal Outcome; Gastrointestinal Tract; Humans; Imidazoles; Ipilimumab; Male; MAP Kinase Kinase Kinases; Melanoma; Middle Aged; Mutation; Neoplastic Cells, Circulating; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms; Treatment Outcome

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

Systemic therapy has improved osteosarcoma event-free and overall survival, but 30-50% of patients originally diagnosed will have progressive or recurrent disease, which is difficult to cure. Osteosarcoma has a complex karyotype, with loss of p53 in the vast majority of cases and an absence of recurrent, targetable pathways. In this study, we explored 54 agents that are clinically approved for other oncologic indications, agents in active clinical development, and others with promising preclinical data in osteosarcoma at clinically achievable concentrations in 5 osteosarcoma cell lines. We found significant single-agent activity of multiple agents and tested 10 drugs in all permutations of two-drug combinations to define synergistic combinations by Chou and Talalay analysis. We then evaluated order of addition to choose the combinations that may be best to translate to the clinic. We conclude that the repurposing of chemotherapeutics in osteosarcoma by using an in vitro system may define novel drug combinations with significant in vivo activity. In particular, combinations of proteasome inhibitors with histone deacetylase inhibitors and ixabepilone and MK1775 demonstrated excellent activity in our assays.

Topics: Animals; Apoptosis; Bone Neoplasms; Cell Survival; Drug Synergism; Drug Therapy, Combination; Epothilones; Female; Histone Deacetylase Inhibitors; Humans; Mice; Mice, Inbred C57BL; Mice, Nude; Middle Aged; Osteosarcoma; Proteasome Inhibitors; Pyrazoles; Pyrimidines; Pyrimidinones; Transplantation, Heterologous; Tumor Cells, Cultured

Combinations of targeted drugs have been employed to treat sarcomas, however, response rates have not improved notably, therefore emphasizing the need for novel treatments. In addition, imaging approaches to assess therapeutic response is lacking, as currently measurable indices, such as volume and/or diameter, do not accurately correlate with changes in tumor biology. In this study, quantitative and profound analyses of magnetic resonance imaging (MRI) were developed to evaluate these as imaging biomarkers for MK1775 and Gem in an osteosarcoma xenotransplant model at early time-points following treatment. Notably, we showed that Gem and Gem+MK1775 groups had significantly inhibited tumor growth by day 4, which was presaged by elevations in mean ADC by 24 hours post treatment. Significant differences were also observed at later time points for the Gem+MK1775 combination and MK1775 therapy. ADC distribution and entropy (randomness of ADC values) were also elevated by 24 hours following therapy. Immunohistochemistry demonstrated that these treatment-related increases in ADC correlated with apoptosis and observed cell condensations (dense- and exploded bodies). These findings underline the role of ADC as a quantitative imaging biomarker for therapy-induced response and show promising clinical relevance in the sarcoma patient population.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cell Cycle Checkpoints; Deoxycytidine; Diffusion Magnetic Resonance Imaging; Female; Gemcitabine; Humans; Mice; Mice, SCID; Middle Aged; Molecular Targeted Therapy; Osteosarcoma; Prognosis; Pyrazoles; Pyrimidines; Pyrimidinones; Treatment Outcome; Xenograft Model Antitumor Assays