pci-32765 and Glioblastoma

Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood-brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting pericytes, improving blood-brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte's role in the glioblastoma microenvironment.

Topics: Adenine; Animals; Blood-Brain Barrier; Brain Neoplasms; Drug Delivery Systems; Glioblastoma; Mice; Pericytes; Piperidines; Pyrazoles; Pyrimidines; Tumor Microenvironment; Xenograft Model Antitumor Assays

Monotherapy clinical trials with mutation-targeted kinase inhibitors, despite some success in other cancers, have yet to impact glioblastoma (GBM). Besides insufficient blood-brain barrier penetration, combinations are key to overcoming obstacles such as intratumoral heterogeneity, adaptive resistance, and the epistatic nature of tumor genomics that cause mutation-targeted therapies to fail. With now hundreds of potential drugs, exploring the combination space clinically and preclinically is daunting. We are building a simulation-based approach that integrates patient-specific data with a mechanistic computational model of pan-cancer driver pathways (receptor tyrosine kinases, RAS/RAF/ERK, PI3K/AKT/mTOR, cell cycle, apoptosis, and DNA damage) to prioritize drug combinations by their simulated effects on tumor cell proliferation and death. Here we illustrate a first step, tailoring the model to 14 GBM patients from The Cancer Genome Atlas defined by an mRNA-seq transcriptome, and then simulating responses to three promiscuous FDA-approved kinase inhibitors (bosutinib, ibrutinib, and cabozantinib) with evidence for blood-brain barrier penetration. The model captures binding of the drug to primary targets and off-targets based on published affinity data and simulates responses of 100 heterogeneous tumor cells within a patient. Single drugs are marginally effective or even counterproductive. Common copy number alterations (PTEN loss, EGFR amplification, and NF1 loss) have a negligible correlation with single-drug or combination efficacy, reinforcing the importance of postgenetic approaches that account for kinase inhibitor promiscuity to match drugs to patients. Drug combinations tend to be either cytostatic or cytotoxic, but seldom both, highlighting the need for considering targeted and nontargeted therapy. Although we focus on GBM, the approach is generally applicable.

Topics: Adenine; Anilides; Aniline Compounds; Antineoplastic Agents; Apoptosis; Blood-Brain Barrier; Cell Cycle; Cell Proliferation; Central Nervous System Neoplasms; Clinical Trials as Topic; Computer Simulation; Drug Discovery; Drug Therapy, Combination; Genomics; Glioblastoma; Humans; Models, Theoretical; Nitriles; Piperidines; Protein-Tyrosine Kinases; Pyrazoles; Pyridines; Pyrimidines; Quinolines; RNA, Messenger; Stochastic Processes; Transcriptome

Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM.. Cell proliferation was determined by using cell viability, colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assays. Cell cycle and cell apoptosis were analyzed by flow cytometry. Cell migratory ability was evaluated by wound healing assays and trans-well migration assays. ATG7 expression was knocked-down by transfection with Atg7-specific small interfering RNA. Overexpression of active Akt protein was achieved by transfecting the cells with a plasmid expressing constitutively active Akt (CA-Akt). Transmission electron microscopy was performed to examine the formation of autophagosomes in cells. Immunofluorescence and western blot analyses were used to analyze protein expression. Tumor xenografts in nude mice and immunohistochemistry were performed to evaluate the effect of ibrutinib on tumor growth in vivo.. Ibrutinib inhibited cellular proliferation and migration, and induced apoptosis and autophagy in LN229 and U87 cells. Overexpression of the active Akt protein decreased ibrutinib-induced autophagy, while inhibiting Akt by LY294002 treatment enhanced ibrutinib-induced autophagy. Specific inhibition of autophagy by 3-methyladenine (3MA) or Atg7 targeting with small interfering RNA (si-Atg7) enhanced the anti-GBM effect of ibrutinib in vitro and in vivo.. Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.

Topics: Adenine; Animals; Autophagy; Cell Line, Tumor; Cell Proliferation; Glioblastoma; Humans; Mice; Mice, Inbred BALB C; Mice, Nude; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines