IMPORTANCE: Medulloblastoma recurrence in patients who have previously received irradiation has a dismal prognosis and lacks a standard salvage regimen. OBJECTIVE: To evaluate the response rate of pediatric patients with medulloblastoma recurrence using an antiangiogenic metronomic combinatorial approach (Medulloblastoma European Multitarget Metronomic Anti-Angiogenic Trial [MEMMAT]). DESIGN, SETTING, AND PARTICIPANTS: This phase 2, investigator-initiated, multicenter nonrandomized controlled trial assessed 40 patients with relapsed or refractory medulloblastoma without a ventriculoperitoneal shunt who were younger than 20 years at original diagnosis. Patients were enrolled between April 1, 2014, and March 31, 2021. INTERVENTIONS: Treatment consisted of daily oral thalidomide, fenofibrate, celecoxib, and alternating 21-day cycles of low-dose (metronomic) oral etoposide and cyclophosphamide, supplemented by intravenous bevacizumab and intraventricular therapy consisting of alternating etoposide and cytarabine. MAIN OUTCOMES AND MEASURES: The primary end point was response after 6 months of antiangiogenic metronomic therapy. Secondary end points included progression-free survival (PFS), overall survival (OS), and quality of life. Adverse events were monitored to assess safety. RESULTS: Of the 40 patients (median [range] age at treatment start, 10 [4-17] years; 25 [62.5%] male) prospectively enrolled, 23 (57.5%) achieved disease control after 6 months of treatment, with a response detected in 18 patients (45.0%). Median OS was 25.5 months (range, 10.9-40.0 months), and median PFS was 8.5 months (range, 1.7-15.4 months). Mean (SD) PFS at both 3 and 5 years was 24.6% (7.9%), while mean (SD) OS at 3 and 5 years was 43.6% (8.5%) and 22.6% (8.8%), respectively. No significant differences in PFS or OS were evident based on molecular subgroup analysis or the number of prior recurrences. In patients demonstrating a response, mean (SD) overall 5-year PFS was 49.7% (14.3%), and for patients who remained progression free for the first 12 months of treatment, mean (SD) 5-year PFS was 66.7% (16.1%). Treatment was generally well tolerated. Grade 3 to 4 treatment-related adverse events included myelosuppression, infections, seizures, and headaches. One heavily pretreated patient with a third recurrence died of secondary acute myeloid leukemia. CONCLUSIONS AND RELEVANCE: This feasible and well-tolerated MEMMAT combination regimen demonstrated promising activity in patients with previously irradiated recurrent medulloblastoma. Given these results, this predominantly oral, well-tolerated, and outpatient treatment warrants further evaluation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01356290.

• MeSH
• Child MeSH
• Etoposide MeSH
• Quality of Life MeSH
• Humans MeSH
• Medulloblastoma * drug therapy   etiology   MeSH
• Administration, Metronomic MeSH
• Adolescent MeSH
• Cerebellar Neoplasms * drug therapy   etiology   MeSH
• Brain Neoplasms * drug therapy   MeSH
• Child, Preschool MeSH
• Antineoplastic Combined Chemotherapy Protocols adverse effects   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Controlled Clinical Trial MeSH
• Multicenter Study MeSH
• Names of Substances
• Etoposide MeSH

Combining low-dose chemotherapies is a strategy for designing less toxic and more potent childhood cancer treatments. We examined the effects of combining the novel thiosemicarbazones, di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC), or its analog, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), with the standard chemotherapies, celecoxib (CX), etoposide (ETO), or temozolomide (TMZ). These combinations were analyzed for synergism to inhibit proliferation of three pediatric tumor cell-types, namely osteosarcoma (Saos-2), medulloblastoma (Daoy) and neuroblastoma (SH-SY5Y). In terms of mechanistic dissection, this study discovered novel thiosemicarbazone targets not previously identified and which are important for considering possible drug combinations. In this case, DpC and Dp44mT caused: (1) up-regulation of a major protein target of CX, namely cyclooxygenase-2 (COX-2); (2) down-regulation of the DNA repair protein, O6-methylguanine DNA methyltransferase (MGMT), which is known to affect TMZ resistance; (3) down-regulation of mismatch repair (MMR) proteins, MSH2 and MSH6, in Daoy and SH-SY5Y cells; and (4) down-regulation in all three cell-types of the MMR repair protein, MLH1, and also topoisomerase 2α (Topo2α), the latter of which is an ETO target. While thiosemicarbazones up-regulate the metastasis suppressor, NDRG1, in adult cancers, it is demonstrated herein for the first time that they induce NDRG1 in all three pediatric tumor cell-types, validating its role as a potential target. In fact, siRNA studies indicated that NDRG1 was responsible for MGMT down-regulation that may prevent TMZ resistance. Examining the effects of combining thiosemicarbazones with CX, ETO, or TMZ, the most promising synergism was obtained using CX. Of interest, a positive relationship was observed between NDRG1 expression of the cell-type and the synergistic activity observed in the combination of thiosemicarbazones and CX. These studies identify novel thiosemicarbazone targets relevant to childhood cancer combination chemotherapy.

• Keywords
• Dp44mT, DpC, celecoxib, combined anti-cancer treatment, etoposide, medulloblastoma, neuroblastoma, osteosarcoma, temozolomide, thiosemicarbazones,
• Publication type
• Journal Article MeSH

Research has exposed cancer to be a heterogeneous disease with a high degree of inter-tumoral and intra-tumoral variability. Individual tumors have unique profiles, and these molecular signatures make the use of traditional histology-based treatments problematic. The conventional diagnostic categories, while necessary for care, thwart the use of molecular information for treatment as molecular characteristics cross tissue types.This is compounded by the struggle to keep abreast the scientific advances made in all fields of science, and by the enormous challenge to organize, cross-reference, and apply molecular data for patient benefit. In order to supplement the site-specific, histology-driven diagnosis with genomic, proteomic and metabolomics information, a paradigm shift in diagnosis and treatment of patients is required.While most physicians are open and keen to use the emerging data for therapy, even those versed in molecular therapeutics are overwhelmed with the amount of available data. It is not surprising that even though The Human Genome Project was completed thirteen years ago, our patients have not benefited from the information. Physicians cannot, and should not be asked to process the gigabytes of genomic and proteomic information on their own in order to provide patients with safe therapies. The following consensus summary identifies the needed for practice changes, proposes potential solutions to the present crisis of informational overload, suggests ways of providing physicians with the tools necessary for interpreting patient specific molecular profiles, and facilitates the implementation of quantitative precision medicine. It also provides two case studies where this approach has been used.

• Keywords
• genomics, metronomic chemotherapy, precision medicine, targeted therapy,
• MeSH
• Child MeSH
• Precision Medicine * MeSH
• Clinical Trials as Topic MeSH
• Medical Oncology * MeSH
• Humans MeSH
• Neoplasms drug therapy   genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Research Design MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Review MeSH

BACKGROUND: Children with high-grade glioma still have a poor prognosis despite the use of multimodal therapy including surgery, radiotherapy, and chemotherapy. New therapeutic strategies and methods evaluating such therapies are needed. OBSERVATION: Here we describe a child with anaplastic oligodendroglioma of the spinal cord who was unable to tolerate standard chemoradiotherapy and who had still-vital residual tumour during therapy. A good response was obtained with low-dose metronomic treatment containing vinblastine. The treatment was guided according to gradual response assessed using various positron-emission tomography tracers. CONCLUSIONS: Metronomic treatment guided by positron-emission tomography could be a reasonable option in some high-risk pediatric tumours.

• Keywords
• Metronomic chemotherapy, biomarkers, pediatric glioma, pet imaging, vinblastine,
• Publication type
• Journal Article MeSH

The Fourth Metronomic and Anti-angiogenic Therapy Meeting was held in Milan 24-25 June 2014. The meeting was a true translational meeting where researchers and clinicians shared their results, experiences, and insights in order to continue gathering useful evidence on metronomic approaches. Several speakers emphasised that exact mechanisms of action, best timing, and optimal dosage are still not well understood and that the field would learn a lot from ancillary studies performed during the clinical trials of metronomic chemotherapies. From the pre-clinical side, new research findings indicate additional possible mechanisms of actions of metronomic schedule on the immune and blood vessel compartments of the tumour micro-environment. New clinical results of metronomic chemotherapy were presented in particular in paediatric cancers [especially neuroblastoma and central nervous system (CNS) tumours], in angiosarcoma (together with beta-blockers), in hepatocellular carcinoma, in prostate cancer, and in breast cancer. The use of repurposed drugs such as metformin, celecoxib, or valproic acid in the metronomic regimen was reported and highlighted the potential of other candidate drugs to be repurposed. The clinical experiences from low- and middle-income countries with affordable regimens gave very encouraging results which will allow more patients to be effectively treated in economies where new drugs are not accessible. Looking at the impact of metronomic approaches that have been shown to be effective, it was admitted that those approaches were rarely used in clinical practice, in part because of the absence of commercial interest for companies. However, performing well-designed clinical trials of metronomic and repurposing approaches demonstrating substantial improvement, especially in populations with the greatest unmet needs, may be an easier solution than addressing the financial issue. Metronomics should always be seen as a chance to come up with new innovative affordable approaches and not as a cheap rescue strategy.

• Keywords
• adult, anti-angiogenesis, cancer, child, drug repurposing, metronomic chemotherapy, pharmacoeconomics,
• Publication type
• Journal Article MeSH

The induced differentiation of tumor cells into mature phenotypes is a promising strategy in cancer therapy. In this study, the effects of combined treatment with all-trans retinoic acid (ATRA) and lipoxygenase/cyclooxygenase inhibitors were examined in two osteosarcoma cell lines, Saos-2 and OSA-01. Caffeic acid and celecoxib were used as inhibitors of 5-lipoxygenase and of cyclooxygenase-2, respectively. Changes in the cell proliferation, matrix mineralization, and occurrence of differentiation markers were evaluated in treated cell populations at intervals. The results confirmed the capability of caffeic acid to enhance the antiproliferative effect of ATRA in both cell lines. In contrast, celecoxib showed the same effect in Saos-2 cells only. Furthermore, the extension of matrix mineralization was observed after combined treatment with ATRA and celecoxib or caffeic acid. The increased expression of osteogenic differentiation markers was observed in both cell lines after the combined application of ATRA and inhibitors. The obtained results clearly demonstrate the capability of lipoxygenase/cyclooxygenase inhibitors to enhance the antiproliferative and differentiating effect of ATRA in osteosarcoma cells, although some of these effects are specific and depend on the biological features of the respective tumor or cell line.

• MeSH
• Antineoplastic Agents pharmacology   MeSH
• Cell Differentiation drug effects   MeSH
• Celecoxib MeSH
• Cyclooxygenase Inhibitors pharmacology   MeSH
• Lipoxygenase Inhibitors pharmacology   MeSH
• Caffeic Acids pharmacology   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Bone Neoplasms drug therapy   pathology   MeSH
• Osteosarcoma drug therapy   pathology   MeSH
• Cell Proliferation drug effects   MeSH
• Pyrazoles pharmacology   MeSH
• Sulfonamides pharmacology   MeSH
• Tretinoin pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Antineoplastic Agents MeSH
• caffeic acid MeSH Browser
• Celecoxib MeSH
• Cyclooxygenase Inhibitors MeSH
• Lipoxygenase Inhibitors MeSH
• Caffeic Acids MeSH
• Pyrazoles MeSH
• Sulfonamides MeSH
• Tretinoin MeSH

BACKGROUND: A detailed analysis of the expression of 440 cancer-related genes was performed after the combined treatment of medulloblastoma cells with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). The combinations of retinoids and celecoxib as a COX-2 inhibitor were reported to be effective in some regimens of metronomic therapy of relapsed solid tumors with poor prognosis. Our previous findings on neuroblastoma cells using expression profiling showed that LOX/COX inhibitors have the capability of enhancing the differentiating action of ATRA. Presented study focused on the continuation of our previous work to confirm the possibility of enhancing ATRA-induced cell differentiation in these cell lines via the application of LOX/COX inhibitors. This study provides more detailed information concerning the mechanisms of the enhancement of the ATRA-induced differentiation of medulloblastoma cells. METHODS: The Daoy and D283 Med medulloblastoma cell lines were chosen for this study. Caffeic acid (an inhibitor of 5-LOX) and celecoxib (an inhibitor on COX-2) were used in combined treatment with ATRA. The expression profiling was performed using Human Cancer Oligo GEArray membranes, and the most promising results were verified using RT-PCR. RESULTS: The expression profiling of the selected cancer-related genes clearly confirmed that the differentiating effects of ATRA should be enhanced via its combined administration with caffeic acid or celecoxib. This effect was detected in both cell lines. An increased expression of the genes that encoded the proteins participating in induced differentiation and cytoskeleton remodeling was detected in both cell lines in a concentration-dependent manner. This effect was also observed for the CDKN1A gene encoding the p21 protein, which is an important regulator of the cell cycle, and for the genes encoding proteins that are associated with proteasome activity. Furthermore, our results showed that D283 Med cells are significantly more sensitive to treatment with ATRA alone than Daoy cells. CONCLUSIONS: The obtained results on medulloblastoma cell lines are in accordance with our previous findings on neuroblastoma cells and confirm our hypothesis concerning the common mechanism of the enhancement of ATRA-induced cell differentiation in various types of pediatric solid tumors.

• Keywords
• All-trans retinoic acid, Caffeic acid, Celecoxib, LOX and COX inhibitors, Medullobastoma,
• Publication type
• Journal Article MeSH

BACKGROUND: We performed expression profiling of two neuroblastoma cell lines, SK-N-BE(2) and SH-SY5Y, after combined treatment with all-trans retinoic acid (ATRA) and inhibitors of lipoxygenases (LOX) and cyclooxygenases (COX). This study is a continuation of our previous work confirming the possibility of enhancing ATRA-induced cell differentiation in these cell lines by the application of LOX/COX inhibitors and brings more detailed information concerning the mechanisms of the enhancement of ATRA-induced differentiation of neuroblastoma cells. METHODS: Caffeic acid, as an inhibitor of 5-lipoxygenase, and celecoxib, as an inhibitor on cyclooxygenase-2, were used in this study. Expression profiling was performed using Human Cancer Oligo GEArray membranes that cover 440 cancer-related genes. RESULTS: Cluster analyses of the changes in gene expression showed the concentration-dependent increase in genes known to be involved in the process of retinoid-induced neuronal differentiation, especially in cytoskeleton remodeling. These changes were detected in both cell lines, and they were independent of the type of specific inhibitors, suggesting a common mechanism of ATRA-induced differentiation enhancement. Furthermore, we also found overexpression of some genes in the same cell line (SK-N-BE(2) or SH-SY5Y) after combined treatment with both ATRA and CA, or ATRA and CX. Finally, we also detected that gene expression was changed after treatment with the same inhibitor (CA or CX) in combination with ATRA in both cell lines. CONCLUSIONS: Obtained results confirmed our initial hypothesis of the common mechanism of enhancement in ATRA-induced cell differentiation via inhibition of arachidonic acid metabolic pathway.

• MeSH
• Cell Differentiation drug effects   MeSH
• Celecoxib MeSH
• Cyclooxygenase Inhibitors pharmacology   MeSH
• Enzyme Inhibitors pharmacology   MeSH
• Lipoxygenase Inhibitors pharmacology   MeSH
• Caffeic Acids pharmacology   MeSH
• Humans MeSH
• Multigene Family MeSH
• Brain Neoplasms drug therapy   pathology   MeSH
• Neuroblastoma drug therapy   pathology   MeSH
• Oxidative Stress MeSH
• Pyrazoles pharmacology   MeSH
• Gene Expression Regulation, Neoplastic * MeSH
• Gene Expression Profiling MeSH
• Sulfonamides pharmacology   MeSH
• Tretinoin metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• caffeic acid MeSH Browser
• Celecoxib MeSH
• Cyclooxygenase Inhibitors MeSH
• Enzyme Inhibitors MeSH
• Lipoxygenase Inhibitors MeSH
• Caffeic Acids MeSH
• Pyrazoles MeSH
• Sulfonamides MeSH
• Tretinoin MeSH