Anti‐tumour efficacy on glioma models of PHA‐848125, a multi‐kinase inhibitor able to cross the blood–brain barrier

Abstract

BACKGROUND AND PURPOSEMalignant gliomas, the most common primary brain tumours, are highly invasive and neurologically destructive neoplasms with a very bad prognosis due to the difficulty in removing the mass completely by surgery and the limited activity of current therapeutic agents. PHA-848125 is a multi-kinase inhibitor with broad anti-tumour activity in pre-clinical studies and good tolerability in phase 1 studies, which could affect two main pathways involved in glioma pathogenesis, the G1-S phase progression control pathway through the inhibition of cyclin-dependent kinases and the signalling pathways mediated by tyrosine kinase growth factor receptors, such as tropomyosin receptors. For this reason, we tested PHA-848125 in glioma models. EXPERIMENTAL APPROACHPHA-848125 was tested on a panel of glioma cell lines in vitro to evaluate inhibition of proliferation and mechanism of action. In vivo efficacy was evaluated on two glioma models both as single agent and in combination with standard therapy. KEY RESULTSWhen tested on a subset of representative glioma cell lines, PHA-848125 blocked cell proliferation, DNA synthesis and inhibited both cell cycle and signal transduction markers. Relevantly, PHA-848125 was also able to induce cell death through autophagy in all cell lines. Good anti-tumour efficacy was observed by oral route in different glioma models both with s.c. and intracranial implantation. Indeed, we demonstrate that the drug is able to cross the blood-brain barrier. Moreover, the combination of PHA-848125 with temozolomide resulted in a synergistic effect, and a clear therapeutic gain was also observed with a triple treatment adding PHA-848125 to radiotherapy and temozolomide. CONCLUSIONS AND IMPLICATIONSAll the pre-clinical data obtained so far suggest that PHA-848125 may become a useful agent in chemotherapy regimens for glioma patients and support its evaluation in phase 2 trials for this indication.

Combined BET bromodomain and CDK2 inhibition in MYC-driven medulloblastoma

“…As expected, inhibition of CDK2 with Milciclib alone or in combination with JQ1 selectively reduced Cyclin A levels in GTML2 compared to control (Fig. 2c ), in line with results from Milciclib treatment in GBM cells [ 31 ]. To summarize, cell death and cell cycle arrest was most prominently affected and inhibited by Milciclib alone or in combination with JQ1.…”

“…Our results suggest a combined treatment approach in order to efficiently target MYC-dependent pathways preferably in MYC- or MYCN-driven Group 3 and Group 4 MB where these pathways are active. Both JQ1 and Milciclib passed the BBB (as previously reported [ 10 , 31 ]), were well tolerated, reduced tumor cell growth, and significantly prolonged survival in animals. BET inhibitors similar to JQ1 such as RG6146 (aka.…”

“…As both JQ1 and Milciclib were able to penetrate the blood–brain barrier (BBB) [ 10 , 31 ], we were further interested to see whether the drugs were able to show efficacy on MYCN- or MYC-driven tumors growing in the brain. Mice were orthotopically injected into the cerebellum with 100,000 luciferase- and MYCN-positive, stable GTML2 tumor cells or human MYC-amplified MB002 cells as previously described [ 13 , 14 ].…”

Tumor suppression by MEG3 lncRNA in a human pituitary tumor derived cell line

“…In contrast, cancer cell lines usually contain mutations in at least one of these tumor suppressor genes. For example, genetic mutations or epigenetic silencing of the p16 Ink4a gene are found in A549, AGS, MGC-803, SCC-15 and U251 cells (Albanese et al, 2013; Cody et al, 1999; Mack et al, 1999; Meng et al, 2007; Qin et al, 2014). P53 mutations are found in CAL-27, PRC/PRF/5, SSC-15 and U251 cells (Brazdova et al, 2009; Kaino, 1997; Kraljevic Pavelic et al, 2009; Min et al, 1994).…”

Cell cycle proteins as promising targets in cancer therapy

“…Inhibited tumour growth of ovarian cancer 287 and glioma xenografts 288 , KRAS G12D -induced lung cancer 289 and DMBA-induced mammary cancer 290 ; extended survival of mice bearing leukaemia 290 and intracranial glioma xenografts 288 …”