RESUMO
Glioblastoma is the most frequent and the most lethal primary brain tumor among adults. Standard of care is the association of radiotherapy with concomitant or adjuvant temozolomide. However, to date, recurrence is inevitable. The CXCL12/CXCR4 pathway is upregulated in the glioblastoma tumor microenvironment regulating tumor cell proliferation, local invasion, angiogenesis, and the efficacy of radio-chemotherapy. In this study, we evaluated the effects of the novel CXCR4 antagonist, PRX177561, in preclinical models of glioblastoma. CXCR4 expression and PRX177561 effects were assessed on a panel of 12 human glioblastoma cells lines and 5 patient-derived glioblastoma stem cell cultures. Next, the effect of PRX177561 was tested in vivo, using subcutaneous injection of U87MG, U251, and T98G cells as well as orthotopic intrabrain inoculation of luciferase-transfected U87MG cells. Here we found that PRX177561 impairs the proliferation of human glioblastoma cell lines, increases apoptosis, and reduces CXCR4 expression and cell migration in response to stromal cell-derived factor 1alpha in vitro. PRX177561 reduced the expression of stem cell markers and increased that of E-cadherin and glial fibrillary acidic protein in U87MG cells consistent with a reduction in cancer stem cells. In vivo, PRX177561 reduced the weight and increased the time to progression of glioblastoma subcutaneous tumors while increasing disease-free survival and overall survival of mice bearing orthotopic tumors. Our findings suggest that targeting stromal cell-derived factor 1 alpha/CXCR4 axis by PRX177561 might represent a novel therapeutic approach against glioblastoma and support further investigation of this compound in more complex preclinical settings in order to determine its therapeutic potential.
Assuntos
Quimiocina CXCL12/genética , Glioblastoma/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Receptores CXCR4/genética , Adulto , Animais , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Intervalo Livre de Doença , Glioblastoma/genética , Humanos , Camundongos , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Receptores CXCR4/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacosRESUMO
OBJECTIVE: This study aimed to examine the long-term outcomes and health-related quality of life in patients with blunt thoracic injuries over 6 months from hospital discharge and develop models to predict long-term patient-reported outcomes. DESIGN: A prospective observational study using longitudinal survey design. SETTING: The study recruitment was undertaken at 12 UK hospitals which represented diverse geographical locations and covered urban, suburban and rural areas across England and Wales. PARTICIPANTS: 337 patients admitted to hospital with blunt thoracic injuries were recruited between June 2018-October 2020. METHODS: Participants completed a bank of two quality of life surveys (Short Form-12 (SF-12) and EuroQol 5-Dimensions 5-Levels) and two pain questionnaires (Brief Pain Inventory and painDETECT Questionnaire) at four time points over the first 6 months after discharge from hospital. A total of 211 (63%) participants completed the outcomes data at 6 months after hospital discharge. OUTCOMES MEASURES: Three outcomes were measured using pre-existing and validated patient-reported outcome measures. Outcomes included: Poor physical function (SF-12 Physical Component Score); chronic pain (Brief Pain Inventory Pain Severity Score); and neuropathic pain (painDETECT Questionnaire). RESULTS: Despite a trend towards improving physical functional and pain at 6 months, outcomes did not return to participants perceived baseline level of function. At 6 months after hospital discharge, 37% (n=77) of participants reported poor physical function; 36.5% (n=77) reported a chronic pain state; and 22% (n=47) reported pain with a neuropathic component. Predictive models were developed for each outcome highlighting important data collection requirements for predicting long-term outcomes in this population. Model diagnostics including calibration and discrimination statistics suggested good model fit in this development cohort. CONCLUSIONS: This study identified the recovery trajectories for patients with blunt thoracic injuries over the first 6 months after hospital discharge and present prognostic models for three important outcomes which after external validation could be used as clinical risk stratification scores.
Assuntos
Qualidade de Vida , Traumatismos Torácicos , Inglaterra/epidemiologia , Hospitais , Humanos , Alta do Paciente , Medidas de Resultados Relatados pelo Paciente , Inquéritos e Questionários , Traumatismos Torácicos/epidemiologia , Traumatismos Torácicos/terapia , País de Gales/epidemiologiaRESUMO
BACKGROUND: Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. It has been demonstrated that anti-VEGF/VEGFR therapies control the invasive phenotype and that relapse occurs through the increased activity of CXCR4. We therefore hypothesized that combining bevacizumab or sunitinib with the novel CXCR4 antagonist, PRX177561, would have superior antitumor activity. METHODS: The effects of bevacizumab, sunitinib, and PRX177561 were tested alone or in combination in subcutaneous xenografts of U87MG, U251, and T98G cells as well as on intracranial xenografts of luciferase tagged U87MG cells injected in CD1-nu/nu mice. Animals were randomized to receive vehicle, bevacizumab (4 mg/kg iv every 4 days), sunitinib (40 mg/kg po qd), or PRX177561 (50 mg/kg po qd). RESULTS: The in vivo experiments demonstrated that bevacizumab and sunitinib increase the in vivo expression of CXCR4, SDF-1α, and TGFß1. In addition, we demonstrate that the co-administration of the novel brain-penetrating CXCR4 antagonist, PRX177561, with bevacizumab or sunitinib inhibited tumor growth and reduced the inflammation. The combination of PRX177561 with bevacizumab resulted in a synergistic reduction of tumor growth with an increase of disease-free survival (DSF) and overall survival (OS), whereas the combination of PRX177561 with sunitinib showed a mild additive effect. CONCLUSIONS: The CXC4 antagonist PRX177561 may be a valid therapeutic complement to anti-angiogenic therapy, particularly when used in combination with VEGF/VEGFR inhibitors. Therefore, this compound deserves to be considered for future clinical evaluation.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Encéfalo/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Indóis/uso terapêutico , Pirróis/uso terapêutico , Receptores CXCR4/antagonistas & inibidores , Inibidores da Angiogênese , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Bevacizumab/farmacologia , Encéfalo/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Sinergismo Farmacológico , Xenoenxertos , Humanos , Indóis/farmacologia , Camundongos , Pirróis/farmacologia , SunitinibeRESUMO
Silylated methylenecyclopropyl hydrazones on treatment with BF3 x Et2O cyclise to give heterocyclic products involving a novel sequence of hydride and silyl shifts via a series of increasingly stable cationic intermediates.