Seminar

Targetting EGFR in Glioblastomas: paradigm of molecularly-directed therapies in cancer

Pilar Sánchez-Gómez, PhD

Glioblastoma (GBM) has been categorized as a highly chemoresistant cancer. In the last decades, the only significant change was the approval of Temozolomide (TMZ) for newly diagnosed GBMs. However, the standard protocol of an aggressive surgery, followed by radiotherapy and concomitant TMZ treatment, has produced only a slight increase in the median survival of patients with such tumors. New therapies, oriented to counteract the principal molecular alterations of GBMs are being tested, especially for recurrent tumors. One of the most promising ones, given the prevalence of EGFR overexpression in GBMs, is the use of tyrosine kinase inhibitors (TKIs) against this receptor, although the results so far have been disappointing. In the lab they have tested two different alternative approaches. In the first one they have used an irreversible third generation TKI (dacomitinib, Pfizer) that not only inhibits EGFR phosphorilation but also the downstream signaling pathway in the tumors. Morevoer dacomitinib clearly impairs GBM growth in the mouse models and has produced a clinical benefit in a subset of patients. As a second approach they have targetted EGFR for degradation by inhibiting DYRK1A, a modulator of the receptor turnover. Dr. Sánchez- Gómez will present the preclinical data and discuss the possible benefits and pitfalls of DYRKIA inhibition in GBM cells.