👤 Elisabeth Cohen-Jonathan Moyal

Glioblastoma (GBM) is an aggressive and highly heterogeneous tumor that frequently recurs despite surgery followed by radio-chemotherapy and, more recently, TTFields. This recurrence is largely driven by glioblastoma stem cells (GSCs), which are intrinsically resistant to standard therapies. Identifying molecular targets that underlie this resistance is therefore critical. Here, we investigated whether the inhibition of FGFR1, previously identified as a key mediator of GBM radioresistance, using pemigatinib, a selective FGFR1-3 inhibitor, could enhance GSC radiosensitivity in vitro and in vivo. Pemigatinib treatment inhibited FGFR1 signaling, promoted proteasome-dependent FGFR1 degradation, and reduced the viability, neurosphere formation, and sphere size in GSCs with unmethylated MGMT, a subgroup known for poor response to standard treatments. In MGMT-unmethylated differentiated GBM cell lines, pemigatinib combined with temozolomide further enhanced radiosensitivity. Transcriptomic analysis revealed that pemigatinib treatment led to the downregulation of Show less

Glioblastomas (GBM) are aggressive tumors, which systematically relapse despite standard treatment associating surgery, chemotherapy and radiation therapy. More recently, GBM therapy now includes another therapeutic modality option, Tumor Treating Fields (TTFields) given in combination with Temozolomide (TMZ) following standard treatment. However even with the adjunction of TTFields, GBM remains a lethal disease due to treatment resistance. One of the causes of resistance is the presence of cancer stem cells (GSC) known to be chemo and radioresistant and responsible for tumor regrowth. Studying mechanisms of resistance of GSC to TTFields is thus a major issue to address. Fibroblast Growth Factor Receptors (FGFR) play a major role in numerous processes essential for cancer development, and dysregulation of FGFR signaling has been observed in many cancer types, including GBM. We have previously shown that tyrosine kinase receptor Fibroblast Growth Factor Receptor 1 (FGFR1) controls GBM aggressiveness and GSC radioresistance and that its inhibition leads to radiosensitization through increasing mitotic cell death and microenvironment modulation. Because one of the main mechanisms of action of TTFields is mitotic disturbance and because TTFields act synergistically in vitro with irradiation (IR), we hypothesize that targeting FGFR could sensitize GSC to TTFields. Here we show that, like IR, TTFields significantly decrease GSC growth. Treatment of GSC with pemigatinib (Pem), a FGFR1-3 inhibitor, alters FGFR signalling pathway. We demonstrate that Pem, sensitizes GSC to TTFields by synergistically decreasing their survival and clonogenic ability. Finally, the adjunction of Pem to treatment combining IR and TTFields could sensitize GSC by inducing, in some GSC, a further decrease in the repair of IR-induced DNA damages. Altogether, these results highlight the potential benefits of inhibiting FGFR with the concomitant application of TTFields in the first-line standard GBM treatment to improve patient prognosis. Show less

Oncogenic FGFR-TACC fusions are present in 3-5% of high-grade gliomas (HGGs). Fexagratinib (AZD4547) is an oral FGFR1-3 inhibitor with preclinical activity in FGFR-TACC+ gliomas. We tested its safety and efficacy in patients with recurrent FGFR-TACC + HGGs. TARGET (NCT02824133) is a phase I/II open-label multicenter study that included adult patients with FGFR-TACC + HGGs relapsing after ≥1 line of standard chemoradiation. Patients received fexagratinib 80 mg bd on a continuous schedule until disease progression or unacceptable toxicity. The primary endpoint was the 6-month progression-free survival rate (PFS6). Twelve patients with recurrent IDH wildtype FGFR-TACC + HGGs (all FGFR3-TACC3+) were included in the efficacy cohort (male/female ratio = 1.4, median age = 61.5 years). Most patients (67%) were included at the first relapse. The PFS6 was 25% (95% confidence interval 5-57%), with a median PFS of 1.4 months. All patients without progression at 6 months ( Fexagratinib exhibited acceptable toxicity but limited efficacy in recurrent FGFR3-TACC3 + HGGs. Patients treated at first recurrence appeared more likely to benefit, yet additional evidence is required. Show less