Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance

doi:10.3390/ijms19061765

Review

. 2018 Jun 14;19(6):1765.

doi: 10.3390/ijms19061765.

Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance

Ha S Nguyen^{1

2}, Saman Shabani³, Ahmed J Awad^{4

5}, Mayank Kaushal⁶, Ninh Doan^{7

8}

Affiliations

¹ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. hsnguyen@mcw.edu.
² Faculty of Neurosurgery, California Institute of Neuroscience, Thousand Oaks, CA 91360, USA. hsnguyen@mcw.edu.
³ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. sshabani@mcw.edu.
⁴ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. aawad@mcw.edu.
⁵ Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 11941, Palestine. aawad@mcw.edu.
⁶ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. mkaushal@mcw.edu.
⁷ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. ndoan@mcw.edu.
⁸ Department of Neurosurgery, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36688, USA. ndoan@mcw.edu.

PMID: 29899215
PMCID: PMC6032212
DOI: 10.3390/ijms19061765

Review

Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance

Ha S Nguyen et al. Int J Mol Sci. 2018.

. 2018 Jun 14;19(6):1765.

doi: 10.3390/ijms19061765.

Authors

Ha S Nguyen^{1

2}, Saman Shabani³, Ahmed J Awad^{4

5}, Mayank Kaushal⁶, Ninh Doan^{7

8}

Affiliations

¹ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. hsnguyen@mcw.edu.
² Faculty of Neurosurgery, California Institute of Neuroscience, Thousand Oaks, CA 91360, USA. hsnguyen@mcw.edu.
³ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. sshabani@mcw.edu.
⁴ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. aawad@mcw.edu.
⁵ Faculty of Medicine and Health Sciences, An-Najah National University, Nablus 11941, Palestine. aawad@mcw.edu.
⁶ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. mkaushal@mcw.edu.
⁷ Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. ndoan@mcw.edu.
⁸ Department of Neurosurgery, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36688, USA. ndoan@mcw.edu.

PMID: 29899215
PMCID: PMC6032212
DOI: 10.3390/ijms19061765

Abstract

Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system. With its overall dismal prognosis (the median survival is 14 months), GBMs demonstrate a resounding resilience against all current treatment modalities. The absence of a major progress in the treatment of GBM maybe a result of our poor understanding of both GBM tumor biology and the mechanisms underlying the acquirement of treatment resistance in recurrent GBMs. A comprehensive understanding of these markers is mandatory for the development of treatments against therapy-resistant GBMs. This review also provides an overview of a novel marker called acid ceramidase and its implication in the development of radioresistant GBMs. Multiple signaling pathways were found altered in radioresistant GBMs. Given these global alterations of multiple signaling pathways found in radioresistant GBMs, an effective treatment for radioresistant GBMs may require a cocktail containing multiple agents targeting multiple cancer-inducing pathways in order to have a chance to make a substantial impact on improving the overall GBM survival.

Keywords: S1P; acid ceramidase; acid ceramidase inhibitors; carmofur; glioblastoma; radiation; radioresistance; sphingosine; sphingosine-1-phosphate.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

**Figure 1**
A cartoon showing temozolomide (TMZ) alkylating DNA at the O-6 position of guanine residues and the removal of this alkyl group by O6-methylguanine methyltransferase (MGMT) through a DNA repair process.

**Figure 2**
A schematic diagram of the sphingolipid signaling pathway, demonstrating the conversion of ceramides into sphingosine by acid ceramidase (*ASAH1*) and the subsequent transformation of sphingosine into sphingosine-1-phosphate by sphingosine kinase 1 or 2 (*SPHK1*, *SPHK2*).

**Figure 3**
Schematic diagram is shown describing the molecular changes occurring in a glioblastoma (GBM) cell following radiation: increased secretion of *ASAH1*, increased intracellular levels of ASAH1 and S1P and decreased level of ceramides. ↑: Upregulation, ↓: Downregulation

See this image and copyright information in PMC

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References

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[1] Ostrom Q.T., Gittleman H., Farah P., Ondracek A., Chen Y., Wolinsky Y., Stroup N.E., Kruchko C., Barnholtz-Sloan J.S. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 2013;15:ii1–ii56. doi: 10.1093/neuonc/not151. - DOI - PMC - PubMed

[2] Ostrom Q.T., Gittleman H., Farah P., Ondracek A., Chen Y., Wolinsky Y., Stroup N.E., Kruchko C., Barnholtz-Sloan J.S. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro Oncol. 2013;15:ii1–ii56. doi: 10.1093/neuonc/not151. - DOI - PMC - PubMed

[3] Ostrom Q.T., Gittleman H., Fulop J., Liu M., Blanda R., Kromer C., Wolinsky Y., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol. 2015;17:iv1–iv62. doi: 10.1093/neuonc/nov189. - DOI - PMC - PubMed

[4] Ostrom Q.T., Gittleman H., Fulop J., Liu M., Blanda R., Kromer C., Wolinsky Y., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol. 2015;17:iv1–iv62. doi: 10.1093/neuonc/nov189. - DOI - PMC - PubMed

[5] Ostrom Q.T., Gittleman H., Liao P., Rouse C., Chen Y., Dowling J., Wolinsky Y., Kruchko C., Barnholtz-Sloan J. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011. Neuro Oncol. 2014;16:1–63. doi: 10.1093/neuonc/nou223. - DOI - PMC - PubMed

[6] Ostrom Q.T., Gittleman H., Liao P., Rouse C., Chen Y., Dowling J., Wolinsky Y., Kruchko C., Barnholtz-Sloan J. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007–2011. Neuro Oncol. 2014;16:1–63. doi: 10.1093/neuonc/nou223. - DOI - PMC - PubMed

[7] Fisher J.L., Schwartzbaum J.A., Wrensch M., Wiemels J.L. Epidemiology of brain tumors. Neurol. Clin. 2007;25:867–890. doi: 10.1016/j.ncl.2007.07.002. - DOI - PubMed

[8] Fisher J.L., Schwartzbaum J.A., Wrensch M., Wiemels J.L. Epidemiology of brain tumors. Neurol. Clin. 2007;25:867–890. doi: 10.1016/j.ncl.2007.07.002. - DOI - PubMed

[9] Goodenberger M.L., Jenkins R.B. Genetics of adult glioma. Cancer Genet. 2012;205:613–621. doi: 10.1016/j.cancergen.2012.10.009. - DOI - PubMed

[10] Goodenberger M.L., Jenkins R.B. Genetics of adult glioma. Cancer Genet. 2012;205:613–621. doi: 10.1016/j.cancergen.2012.10.009. - DOI - PubMed

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Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance

Affiliations

Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance

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