Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma

Abstract

<jats:p>Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. We hypothesized that co-treatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. Methods: Dose response, synergism studies, P-gp inhibition and pharmacokinetic studies were performed on in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. Results: Dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with reduction in mTOR signaling that persists after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended survival of PPK tumor bearing mice. Pediatric patients (n=6) with glioma tolerated this combination without significant adverse events. Recurrent patients (n=4) demonstrated median overall survival of 8.5 months. Conclusion: Efficacy of dasatinib treatment of PDGFRα-driven HGG is improved with everolimus and suggests a promising route for improving targeted therapy for this patient population. Clinical Trial Registration ID #<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="clintrialgov" xlink:href="NCT03352427">NCT03352427</jats:ext-link>.</jats:p>

Therapeutic targeting of differentiation state-dependent metabolic vulnerabilities in DIPG

“…In contrast, their differential response to statins ranged from modest (DIPG-XIII) to substantial (DIPG-XIII-P*) ( Supplementary Figures 6E-H ). Notably, the murine cell line of P 53 P DGFRA H3 K 27M DIPG (PPK cells), which has been demonstrated to replicate the H3K27M DIPG biology 38 and was similarly established in culture as either GS or DGC, also displayed differential sensitivity to Phenformin and Pitavastatin ( Supplementary Figures 6J-K ).…”

“…IUE was performed using sterile technique on isoflurane/oxygen-anesthetized pregnant C57BL/6 or CD1 females at E13.5. Tumors were generated with lateral ventricle (forebrain) introduction of plasmids: (1) PB-CAG-DNp53-Ires-Luciferase (dominant negative T P 53), (2) PB-CAG-PdgfraD824V-Ires-eGFP ( P DGFRA D842V), and (3) PB-CAG-H3.3 K 27M-Ires-eGFP (H3K27M), and therefore referred to as “PPK” model 38 . PPK gliomaspheres were cultured in base media containing Neurobasal-A medium (1X), MEM sodium pyruvate solution (1mM), MEM Non-Essential Amino Acids (1X), L-glutamine (2 mM), Antibiotic-Antimycotic (1X), and supplemented with fresh B27, N2, heparin (2 μg/mL), EGF (20 ng/mL), FGF (20 ng/mL).…”

Repurposing Vandetanib plus Everolimus for the Treatment ofACVR1-Mutant Diffuse Intrinsic Pontine Glioma

“…The experience of everolimus in this age group may be of particular importance given the reservations expressed about the ability to provide clinical doses of the drug at sufficient concentrations to elicit significant inhibition of Pg-P (52). Notably, another recent study reported the use of everolimus to improve the CNS penetration of dasatinib in PDGFRA-driven high grade gliomas in children (53). Here, the authors found an increase in both plasma (11.2 ng/mL to 31.5 ng/mL) and CSF (0.44 ng/mL to 0.91 mg/mL) dasatinib levels in two patients after one week of dasatinib monotherapy and then after two cycles of dual therapy with dasatinib and everolimus (53), and pointed to adult phase I studies of higher doses of everolimus (up to 70 mg weekly) that were well-tolerated and resulted in mean peak levels of everolimus 10-fold higher than standard regimens (54).…”

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

“…Growth factor signaling inhibitors: Growth factor signaling inhibitors have typically been explored in combination with additional treatments given concerns regarding the subclonal nature of relevant mutations as well as redundancy in the downstream signaling networks. PDGFRA signaling inhibition with dasatinib prolonged survival in an IUE-based H3.3K27M pHGG model, and combination with the mTOR inhibitor everolimus demonstrated synergy [ 33 ].…”