Efficacy of EGFR plus TNF inhibition in a preclinical model of temozolomide-resistant glioblastoma
| Autor: | Bruce E. Mickey, Jann N. Sarkaria, Dawen Zhao, Nishah Panchani, Edward Pan, Sandeep Burma, Amyn A. Habib, Toral R. Patel, Ke Gong, Sabrina Bharia, Gao Guo, Kimmo J. Hatanpaa, Bipasha Mukherjee, Ziba Damanwalla, Vineshkumar Thidil Puliyappadamba, David E. Gerber |
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| Rok vydání: | 2019 |
| Předmět: |
Cancer Research
Methyltransferase Mice Nude Apoptosis Afatinib Mice Antineoplastic Combined Chemotherapy Protocols medicine Temozolomide Tumor Cells Cultured Animals Humans Epidermal growth factor receptor neoplasms Cell Proliferation biology business.industry Brain Neoplasms Tumor Necrosis Factor-alpha Egfr inhibition Editorials O-6-methylguanine-DNA methyltransferase medicine.disease Xenograft Model Antitumor Assays nervous system diseases Thalidomide Clinical trial ErbB Receptors Gene Expression Regulation Neoplastic Mice Inbred C57BL Oncology Drug Resistance Neoplasm Cancer research biology.protein Tumor necrosis factor alpha Female Neurology (clinical) business Glioblastoma medicine.drug |
| Zdroj: | Neuro Oncol |
| ISSN: | 1523-5866 |
| Popis: | Background Glioblastoma (GBM) is the most common primary malignant adult brain tumor. Temozolomide (TMZ) is the standard of care and is most effective in GBMs that lack the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT). Moreover, even initially responsive tumors develop a secondary resistance to TMZ and become untreatable. Since aberrant epidermal growth factor receptor (EGFR) signaling is widespread in GBM, EGFR inhibition has been tried in multiple clinical trials without success. We recently reported that inhibiting EGFR leads to increased secretion of tumor necrosis factor (TNF) and activation of a survival pathway in GBM. Here, we compare the efficacy of TMZ versus EGFR plus TNF inhibition in an orthotopic mouse model of GBM. Methods We use an orthotopic model to examine the efficacy of TMZ versus EGFR plus TNF inhibition in multiple subsets of GBMs, including MGMT methylated and unmethylated primary GBMs, recurrent GBMs, and GBMs rendered experimentally resistant to TMZ. Results The efficacy of the 2 treatments was similar in MGMT methylated GBMs. However, in MGMT unmethylated GBMs, a combination of EGFR plus TNF inhibition was more effective. We demonstrate that the 2 treatment approaches target distinct and non-overlapping pathways. Thus, importantly, EGFR plus TNF inhibition remains effective in TMZ-resistant recurrent GBMs and in GBMs rendered experimentally resistant to TMZ. Conclusion EGFR inhibition combined with a blunting of the accompanying TNF-driven adaptive response could be a viable therapeutic approach in MGMT unmethylated and recurrent EGFR-expressing GBMs. |
| Databáze: | OpenAIRE |
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