Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma

doi:10.3390/ijms18122732

Review

. 2017 Dec 16;18(12):2732.

doi: 10.3390/ijms18122732.

Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma

Ali S Arbab¹, Mohammad H Rashid², Kartik Angara³, Thaiz F Borin⁴, Ping-Chang Lin⁵, Meenu Jain⁶, Bhagelu R Achyut⁷

Affiliations

¹ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. aarbab@augusta.edu.
² Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. mrashid@augusta.edu.
³ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. kangara@augusta.edu.
⁴ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. tborin@augusta.edu.
⁵ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. plin@augusta.edu.
⁶ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. jainm25@hotmail.com.
⁷ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. bachyut@augusta.edu.

PMID: 29258180
PMCID: PMC5751333
DOI: 10.3390/ijms18122732

Review

Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma

Ali S Arbab et al. Int J Mol Sci. 2017.

. 2017 Dec 16;18(12):2732.

doi: 10.3390/ijms18122732.

Authors

Ali S Arbab¹, Mohammad H Rashid², Kartik Angara³, Thaiz F Borin⁴, Ping-Chang Lin⁵, Meenu Jain⁶, Bhagelu R Achyut⁷

Affiliations

¹ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. aarbab@augusta.edu.
² Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. mrashid@augusta.edu.
³ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. kangara@augusta.edu.
⁴ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. tborin@augusta.edu.
⁵ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. plin@augusta.edu.
⁶ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. jainm25@hotmail.com.
⁷ Tumor Angiogenesis laboratory, Georgia Cancer Center, Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA 30912, USA. bachyut@augusta.edu.

PMID: 29258180
PMCID: PMC5751333
DOI: 10.3390/ijms18122732

Abstract

Glioblastoma (GBM) is considered one of the most malignant, genetically heterogeneous, and therapy-resistant solid tumor. Therapeutic options are limited in GBM and involve surgical resection followed by chemotherapy and/or radiotherapy. Adjuvant therapies, including antiangiogenic treatments (AATs) targeting the VEGF-VEGFR pathway, have witnessed enhanced infiltration of bone marrow-derived myeloid cells, causing therapy resistance and tumor relapse in clinics and in preclinical models of GBM. This review article is focused on gathering previous clinical and preclinical reports featuring major challenges and lessons in GBM. Potential combination therapies targeting the tumor microenvironment (TME) to overcome the myeloid cell-mediated resistance problem in GBM are discussed. Future directions are focused on the use of TME-directed therapies in combination with standard therapy in clinical trials, and the exploration of novel therapies and GBM models for preclinical studies. We believe this review will guide the future of GBM research and therapy.

Keywords: Glioblastoma; antiangiogenic therapy; bone marrow-derived cells; myeloid cells; neovascularization; resistance; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Schematic representation of GBM tumor microenvironment. Bone marrow-derived cells (BMDCs) are recruited to the tumor during the GBM growth. Recent data suggest that BMDCs recruitment was enhanced following therapies, e.g., anti-tumor chemotherapy or antiangiogenic therapy. The tumor-promoting myeloid cells are the subpopulations of recruited BMDCs in the microenvironment. Here, we propose the combination of anti-CSF1R, anti-CYP4A, or immune therapy with standard therapies to overcome the myeloid cell-mediated resistance in GBM.

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References

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[1] Thakkar J.P., Dolecek T.A., Horbinski C., Ostrom Q.T., Lightner D.D., Barnholtz-Sloan J.S., Villano J.L. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol. Biomarkers Prev. 2014;23:1985–1996. doi: 10.1158/1055-9965.EPI-14-0275. - DOI - PMC - PubMed

[2] Thakkar J.P., Dolecek T.A., Horbinski C., Ostrom Q.T., Lightner D.D., Barnholtz-Sloan J.S., Villano J.L. Epidemiologic and molecular prognostic review of glioblastoma. Cancer Epidemiol. Biomarkers Prev. 2014;23:1985–1996. doi: 10.1158/1055-9965.EPI-14-0275. - DOI - PMC - PubMed

[3] Ostrom Q.T., Gittleman H., Liao P., Vecchione-Koval T., Wolinsky Y., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19(Suppl. 5):v1–v88. doi: 10.1093/neuonc/nox158. - DOI - PMC - PubMed

[4] Ostrom Q.T., Gittleman H., Liao P., Vecchione-Koval T., Wolinsky Y., Kruchko C., Barnholtz-Sloan J.S. CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19(Suppl. 5):v1–v88. doi: 10.1093/neuonc/nox158. - DOI - PMC - PubMed

[5] Oliver L., Olivier C., Marhuenda F.B., Campone M., Vallette F.M. Hypoxia and the malignant glioma microenvironment: Regulation and implications for therapy. Curr. Mol. Pharmacol. 2009;2:263–284. doi: 10.2174/1874467210902030263. - DOI - PubMed

[6] Oliver L., Olivier C., Marhuenda F.B., Campone M., Vallette F.M. Hypoxia and the malignant glioma microenvironment: Regulation and implications for therapy. Curr. Mol. Pharmacol. 2009;2:263–284. doi: 10.2174/1874467210902030263. - DOI - PubMed

[7] Brem S., Cotran R., Folkman J. Tumor angiogenesis: A quantitative method for histologic grading. J. Natl. Cancer Inst. 1972;48:347–356. - PubMed

[8] Brem S., Cotran R., Folkman J. Tumor angiogenesis: A quantitative method for histologic grading. J. Natl. Cancer Inst. 1972;48:347–356. - PubMed

[9] Wang N., Jain R.K., Batchelor T.T. New Directions in Anti-Angiogenic Therapy for Glioblastoma. Neurotherapeutics. 2017;14:321–332. doi: 10.1007/s13311-016-0510-y. - DOI - PMC - PubMed

[10] Wang N., Jain R.K., Batchelor T.T. New Directions in Anti-Angiogenic Therapy for Glioblastoma. Neurotherapeutics. 2017;14:321–332. doi: 10.1007/s13311-016-0510-y. - DOI - PMC - PubMed

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Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma

Affiliations

Major Challenges and Potential Microenvironment-Targeted Therapies in Glioblastoma

Authors

Affiliations

Abstract

Conflict of interest statement

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