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Cancer: Medulloblastoma

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Total 26 results found since Jan 2013.

Cancers, Vol. 12, Pages 3781: Novel Thiosemicarbazones Sensitize Pediatric Solid Tumor Cell-Types to Conventional Chemotherapeutics through Multiple Molecular Mechanisms
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 importa...
Source: Cancers - December 15, 2020 Category: Cancer & Oncology Authors: Silvia Paukovcekova Jan Skoda Jakub Neradil Erika Mikulenkova Petr Chlapek Jaroslav Sterba Des R. Richardson Renata Veselska Tags: Article Source Type: research

Cancers, Vol. 12, Pages 542: CITK Loss Inhibits Growth of Group 3 and Group 4 Medulloblastoma Cells and Sensitizes Them to DNA-Damaging Agents
llis Di C.o Medulloblastoma (MB) is the most common malignant brain tumor in children, and it is classified into four biological subgroups: WNT, Sonic Hedgehog (SHH), Group 3 and Group 4. The current treatment is surgery, followed by irradiation and chemotherapy. Unfortunately, these therapies are only partially effective. Citron kinase protein (CITK) has been proposed as a promising target for SHH MB, whose inactivation leads to DNA damage and apoptosis. D283 and D341 cell lines (Group 3/Group 4 MB) were silenced with established siRNA sequences against CITK, to assess the direct effects of its loss. Next, D283, D...
Source: Cancers - February 25, 2020 Category: Cancer & Oncology Authors: Pallavicini Iegiani Berto Calamia Trevisiol Veltri Allis Di Cunto Tags: Article Source Type: research

Hedgehog signaling negatively co-regulates BH3-only protein Noxa and TAp73 in TP53-mutated cells
In the present study, we show that pharmacological repression by the Hedgehog (Hh) pathway inhibitor (HPI) GANT61 induces expression of the proapoptotic protein Noxa in TP53-mutated embryonal pediatric tumor cells driven by Hh signaling (i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB)). Similarly, genetic silencing of Gli1 by siRNA causes increased Noxa mRNA and protein levels, while overexpression of Gli1 results in decreased Noxa expression. Furthermore, TAp73 mRNA and protein levels are increased upon Gli1 knockdown, while Gli1 overexpression reduces TAp73 mRNA and protein levels.
Source: Cancer Letters - April 24, 2018 Category: Cancer & Oncology Authors: Michael Torsten Meister, Cathinka Boedicker, Thomas Klingebiel, Simone Fulda Tags: Original Articles Source Type: research

PDTB-15. Bcl-XL AS A RADIOSENSITIZER IN THE TREATMENT OF GROUP 3 MEDULLOBLASTOMA
Medulloblastoma is the most common malignant pediatric brain tumor. Although significant progress has been made in the treatment of medulloblastoma patients over the past several decades, the five-year disease-free survival for high-risk patients, characterized by metastatic dissemination at presentation or significant post-operative residual tumor, remains relatively poor (25-40%). Group 3 medulloblastoma has by far the worst prognosis with a 5-year survival probability of approximately 30% regardless of stage. Current therapeutic modalities, in particular ionizing radiation (IR), have significant long-term side-effe...
Source: Neuro-Oncology - November 6, 2016 Category: Cancer & Oncology Authors: Ruggieri, M., Kelley, K., Powell, C., Navati, M., Chakraborty, S., Wright, A., Remke, M., Friedman, J., Symons, M. Tags: PEDIATRIC TUMORS - PRECLINICAL STUDIES (NON-IMMUNOLOGICAL) Source Type: research

P10.06 Oxamate attenuates aerobic glycolysis, motility, viability and proliferation of medulloblastoma but LDHA siRNA does not
Conclusions:It is possible that oxamate inhibits multiple LDH family members as the active site for LDH isoenzymes, comprised of LDHA and LDHB subunits are identical. The results of further investigations will be critical as LDHA may prove to be an inadequate target for MB and a broader LDH family inhibitor or lactate inhibitor may be more appropriate. However these studies, combined with extensive research into the literature, support the concept and provide proof of principle that targeting aerobic glycolysis and lactate production in medulloblastoma is worthwhile therapeutic avenue worth pursuing further.
Source: Neuro-Oncology - September 20, 2016 Category: Cancer & Oncology Authors: Valvona, C. J., Pilkington, G. J. Tags: P10 Pediatric brain tumours Source Type: research

Pharmacological Inhibition of the Protein Kinase MRK/ZAK Radiosensitizes Medulloblastoma
Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule in...
Source: Molecular Cancer Therapeutics - August 2, 2016 Category: Cancer & Oncology Authors: Markowitz, D., Powell, C., Tran, N. L., Berens, M. E., Ryken, T. C., Vanan, M., Rosen, L., He, M., Sun, S., Symons, M., Al-Abed, Y., Ruggieri, R. Tags: Small Molecule Therapeutics Source Type: research

Radiosensitization of Medulloblastoma by Inhibition of MRK
Medulloblastoma is a cerebellar tumor and the most common pediatric brain malignancy. Radiotherapy is part of the standard care for this tumor, but its effectiveness is accompanied by significant neurocognitive sequelae due to the deleterious effects of radiation on the developing brain. We have previously shown that the protein kinase MRK/ZAK protects tumor cells from radiation-induced cell death by regulating cell-cycle arrest after ionizing radiation. Here, we show that siRNA-mediated MRK depletion sensitizes medulloblastoma primary cells to radiation. We have, therefore, designed and tested a specific small molecule in...
Source: Molecular Cancer Therapeutics - August 2, 2016 Category: Cancer & Oncology Authors: Markowitz, D., Powell, C., Tran, N. L., Berens, M. E., Ryken, T. C., Vanan, M., Rosen, L., He, M., Sun, S., Symons, M., Al-Abed, Y., Ruggieri, R. Tags: Small Molecule Therapeutics Source Type: research

Cambogin exerts anti-proliferative and pro-apoptotic effects on breast adenocarcinoma through the induction of NADPH oxidase 1 and the alteration of mitochondrial morphology and dynamics.
Authors: Shen K, Lu F, Xie J, Wu M, Cai B, Liu Y, Zhang H, Tan H, Pan Y, Xu H Abstract Cambogin, a bioactive polycyclic polyprenylated acylphoroglucinol (PPAP) derived from the Garcinia genus, possesses proapoptotic effect in medulloblastoma and breast cancer cells. We have previously demonstrated that the proapoptotic effect of cambogin is driven by the production of reactive oxygen species (ROS). Here we have shown that the inhibitory effect of cambogin on cell proliferation is associated with the loss of mitochondrial transmembrane potential (ΔΨm) and mitochondrial fragmentation. Cambogin also promotes the mut...
Source: Oncotarget - July 17, 2016 Category: Cancer & Oncology Tags: Oncotarget Source Type: research

Abstract C25: Targeting cancer stem cells using ALDH-dependent 5-nitrofuran pro-drugs
We hypothesise that cancer stem cells with high aldehyde dehydrogenase (ALDHhigh) activity present a new therapeutic target and will be selectively sensitive to 5-nitrofuran pro-drugs.Cancers are heterogeneous and contain subpopulations of ALDHhigh cells with tumour initiating potential. ALDH enzymes metabolize toxic aldehydes, and are highly expressed in somatic and cancer stem cells (CSCs), although their function in stem cells is not fully understood. In a small molecule screen coupled with target ID, we recently discovered that clinically active 5-nitrofurans (5-NFNs) are substrates of ALDH2 (Zhou et al., 2012). 5-NFNs...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Crispin, R., Spockeli, N., Brunton, V., Carragher, N., Gourley, C., Houston, D., Unciti-Broceta, A., Patton, E. E. Tags: Cancer Stem Cells: Poster Presentations - Proffered Abstracts Source Type: research

Abstract C195: A Wee1 inhibitor analog of AZD1775 demonstrates synergy with cisplatin with reduced single-agent toxicity in medulloblastoma
Medulloblastoma is the most common primary brain tumor in children. Current treatment for medulloblastoma includes surgical resection, radiation and cytotoxic chemotherapy. Although this approach has improved survival rates, the high doses of chemotherapy required to circumvent drug resistance mechanisms and result in clinical efficacy often give rise to lasting neurocognitive defects, stunted growth, deafness, and even secondary tumors. Therefore, synergistic drug combinations that maintain clinical efficacy, but allow dose reductions of cytotoxic agents limiting their adverse effects would be an attractive approach for p...
Source: Molecular Cancer Therapeutics - January 7, 2016 Category: Cancer & Oncology Authors: Matheson, C. J., Venkataraman, S., Amani, V., Harris, P., Backos, D. S., Foreman, N. K., Vibhakar, R., Reigan, P. Tags: Therapeutic Agents: Small Molecule Kinase Inhibitors: Poster Presentations - Proffered Abstracts Source Type: research

OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways.
In this study on retinoblastoma, OTX2 was frequently amplified and/or overexpressed in primary tumors and cell lines. Knockdown of OTX2 expression by siRNA or pharmacologic inhibition by all-trans retinoic acid (ATRA) repressed OTX2 expression and cell proliferation and significantly decreased tumor growth in vivo. Loss of OTX2 expression also resulted in decreased expression of C-MYC and CRX, genes previously implicated in retinoblastoma tumorigenesis. Loss of OTX2 expression increased the phosphorylation of RB, a potential mechanism of modulating cell proliferation. Aberrant expression of OTX2 may contribute to the deve...
Source: International Journal of Oncology - September 23, 2015 Category: Cancer & Oncology Authors: Li J, Di C, Jing J, Di Q, Nakhla J, Adamson DC Tags: Int J Oncol Source Type: research

Abstract 487: Whole genome screen to identify genes targeting MYCN-driven embryonal tumors
MYCN is a driver of neuroblastoma (NB) tumorigenesis and is over-expressed in a number of tumors of embryonal origin, including rhabdomyosarcoma, medulloblastoma and diffuse intrinsic pontine gliomas. We sought to identify regulators of MYCN transcription by performing a whole genome screen (WGS) for regulators of MYCN promoter activity using a NB cell model. A plasmid containing the MYCN promoter (1.3kb upstream of MYCN TSS) fused to luciferase and stably integrated into the genome of NGP NB cells was the readout system. NGP-MYCNpluc, was selected based on MYCN luciferase activity inhibition by ATRA and HDAC inhibitors to...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Thiele, C. J., Liu, Z., Veschi, V., Buehler, E., Martin, S. Tags: Tumor Biology Source Type: research

Abstract 3338: Pharmacological inhibition of MRK/ZAK kinase for the treatment of medulloblastoma
In conclusion, we have developed a new small molecule inhibitor of MRK/ZAK that radio-sensitizes medulloblastoma cells. We hypothesize that combining radio-therapy with M443 will allow us to lower the radiation dose while maintaining therapeutic efficacy, thereby minimizing radiation-induced side effects.Citation Format: Rosamaria Ruggieri, Daniel Markowitz, Caitlin Powell, Nhan Tran, Magimairajanissai Vanan, Mingzu He, Yousef Al-Abed, Marc Symons. Pharmacological inhibition of MRK/ZAK kinase for the treatment of medulloblastoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Ruggieri, R., Markowitz, D., Powell, C., Tran, N., Vanan, M., He, M., Al-Abed, Y., Symons, M. Tags: Tumor Biology Source Type: research

Abstract 2090: GLI3 repressor levels determine Hedgehog pathway activity and predict response to Smoothened antagonist in acute myeloid leukemia
The Hedgehog (Hh) signaling pathway is activated in most hematological and solid cancers and is a promising target for therapeutic development. Deletions in the receptor Patched (PTCH) or activating mutations in the upstream positive regulator Smoothened (SMO) have been reported in a few cancers such as basal cell carcinoma and medulloblastoma, but are largely absent in most tumor types; therefore, the mechanism of pathway activation in most cancers remains unknown. In normal tissues, Hh pathway activation via PTCH/SMO causes an increase in the downstream activating transcription factor GLI1 and a decrease in the transcr...
Source: Cancer Research - August 2, 2015 Category: Cancer & Oncology Authors: Chaudhry, P., Singh, M., Triche, T., Jorapur, A., Gill, P. S., Merchant, A. Tags: Molecular and Cellular Biology Source Type: research