Medical research funded by the Department of Veterans Affairs has led to therapeutic technology relative to treating glioblastoma, a fatal cancer in the brain.
Aberrant epidermal growth factor receptor (EGFR) signaling is widespread in cancer, making it an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma, but EGFR inhibition has not been effective in treating this tumor.
Dr. Amin Habib has found that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. Further, in glioma cells expressing either EGFR wild type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased TNF secretion that leads to activation of a TNF-JNK-Axl-ERK signaling axis. Inhibition of this adaptive axis, preferably at one or multiple nodes, renders glioma cells with primary resistance sensitive to EGFR inhibition, and thus vulnerable to therapeutic treatment. With this information, the multiple failures of anti-EGFR therapy in glioblastoma may be reversed and a new approach for the treatment of EGFR expressing glioblastoma is provided through a combination of EGFR and TNF-JNK-Axl-ERK signaling axis inhibition. A list of the inhibitors is detailed in the patent.
Temozolomide is the first line chemotherapy drug used in glioblastoma, and in combination with surgery and radiation, results in a modest increase in overall survival of patients. No targeted treatment has proven effective in glioblastoma.
The research data indicate that EGFR inhibition may be effective if combined with an inhibition of a component of the TNF-JNK-Axl-ERK signaling axis. Remarkably, the combined inhibition of EGFR and TNF -pathway is effective even in established glioblastoma cell lines that are otherwise completely resistant to EGFR inhibition.
- Rapid translation of this research to the clinic is possible, given the wealth of TNF inhibiting drugs and biologicals in clinical practice, including drugs such as thalidomide, pomalidomide, lenalidomide, and apremilast, that penetrate the blood brain barrier
- Approach is effective in EGFRwt as well as mutant EGFRvIII expressing tumors
- Animal model data available
- Businesses can access the technology for commercialization by licensing international patent application WO2018183762 from the VA
- License fees paid to the VA are negotiable
- Techlink navigates businesses through VA licensing at no charge