osimertinib and Glioblastoma

Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib's growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility.. All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Animals; Azithromycin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chemotherapy, Adjuvant; Cyproheptadine; Drug Repositioning; Drug Resistance, Neoplasm; ErbB Receptors; Glioblastoma; Humans; Loratadine; Lung Neoplasms; Mice; Neoplasm Metastasis; Pyrimethamine; Spironolactone

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and carries a dismal prognosis. The

Topics: Acrylamides; Adult; Aniline Compounds; Brain Neoplasms; ErbB Receptors; Female; Glioblastoma; Humans; Mutation; Prognosis; Protein Kinase Inhibitors

Glioblastoma (GBM) is a deadly brain cancer, and all attempts to control it have failed so far. However, the future looks bright, as we now know the molecular landscape of GBM through the work of The Cancer Genome Atlas (TCGA) program. GBMs exhibit significant inter- and intratumoral heterogeneity, and to control this type of tumor, a personalized approach is required. One target, whose gene is amplified and mutated in a large number of GBMs, is the epidermal growth factor receptor (EGFR). But all attempts to target it have been unsuccessful. We attribute the reason for this failure to the molecular heterogeneity of EGFR in GBM, as well as to the poor brain penetration of previously tested EGFR-Tyrosine Kinase Inhibitors (EGFR-TKIs). In this review, we discuss the molecular heterogeneity of EGFR and provide rational preclinical and clinical guidelines for testing AZD9291, a third generation, irreversible EGFR-TKI with both a high affinity for EGFRvIII and excellent brain penetration.

Topics: Acrylamides; Aniline Compounds; Antineoplastic Agents; Brain Neoplasms; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Screening Assays, Antitumor; ErbB Receptors; Glioblastoma; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors

Glioblastoma (GBM) is a high-grade adult-type IDH-wildtype diffuse glioma, commonly harboring epidermal growth factor receptor (EGFR) amplification. Here, we describe a case of a 49-year-old man with a GBM harboring a TERT promoter mutation. Despite surgical and chemoradiation therapy, the tumor recurred. At that time, comprehensive genomic profiling by next-generation sequencing identified two rare mutations in EGFR: T790M and an exon 20 insertion. Based on these findings, the patient elected to undergo off-label therapy with osimertinib, a third-generation EGFR tyrosine kinase inhibitor that has shown promising results in non-small cell lung carcinoma, including metastatic to brain, with exactly the same EGFR mutations. Moreover, the drug has excellent central nervous system penetration. Even so, no clinical response was observed, and the patient succumbed to the disease. The lack of response may be related to the specific nature of the EGFR mutations, and/or other unfavorable tumor biology overriding any benefit from osimertinib.

Topics: Adult; ErbB Receptors; Glioblastoma; Glioma; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors

Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer.. We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial next-generation sequencing panel in liquid biopsy.. There were ten males (66.7%), and the median patient's age was 56 years (range 38-70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6-12). The median follow-up after recurrence was 17.1 months (95% CI 12.3-22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8-7.3) and overall survival of 9.0 months (95% CI 3.9-14.0). The PFS6 was 46.7%, and the overall response rate was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR.. While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

Topics: Acrylamides; Adult; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Glioblastoma; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Retrospective Studies

Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3 μM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC

Topics: Acrylamides; Adolescent; Adult; Aged; Aniline Compounds; Animals; Antineoplastic Agents; Cell Proliferation; Cells, Cultured; Child; ErbB Receptors; Eukaryotic Initiation Factor-4E; Female; Glioblastoma; Humans; Intracellular Signaling Peptides and Proteins; Male; MAP Kinase Signaling System; Mice; Middle Aged; Phosphorylation; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Xenograft Model Antitumor Assays; Young Adult

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Biomarkers, Tumor; Brain Neoplasms; Cell Proliferation; ErbB Receptors; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Mice; Mice, Inbred NOD; Mice, SCID; STAT3 Transcription Factor; Transcriptional Coactivator with PDZ-Binding Motif Proteins; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients. SIGNIFICANCE: These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Autophagy; Brain Neoplasms; Cell Line, Tumor; ErbB Receptors; Erlotinib Hydrochloride; Female; Glioblastoma; Humans; Indoles; Janus Kinase 2; Mice; Morpholines; Protein Kinase C-alpha; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Signal Transduction; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Glioblastoma (GBM) is a fatal brain tumor, lacking effective treatment. Epidermal growth factor receptor (EGFR) is recognized as an attractive target for GBM treatment. However, GBMs have very poor responses to the first- and second-generation EGFR inhibitors. The third-generation EGFR-targeted drug, AZD9291, is a novel and irreversible inhibitor. It is noteworthy that AZD9291 shows excellent blood-brain barrier penetration and has potential for the treatment of brain tumors.. In this study, we evaluated the anti-tumor activity and effectiveness of AZD9291 in a preclinical GBM model.. AZD9291 showed dose-responsive growth inhibitory activity against six GBM cell lines. Importantly, AZD9291 inhibited GBM cell proliferation > 10 times more efficiently than the first-generation EGFR inhibitors. AZD9291 induced GBM cell cycle arrest and significantly inhibited colony formation, migration, and invasion of GBM cells. In an orthotopic GBM model, AZD9291 treatment significantly inhibited tumor survival and prolonged animal survival. The underlying anti-GBM mechanism of AZD9291 was shown to be different from that of the first-generation EGFR inhibitors. In contrast to erlotinib, AZD9291 continuously and efficiently inhibited the EGFR/ERK signaling in GBM cells.. AZD9291 demonstrated an efficient preclinical activity in GBM in vitro and in vivo models. AZD9291 has been approved for the treatment of lung cancer with good safety and tolerability. Our results support the possibility of conducting clinical trials of anti-GBM therapy using AZD9291.

Topics: Acrylamides; Aniline Compounds; Animals; Brain Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; ErbB Receptors; Glioblastoma; Humans; Male; MAP Kinase Signaling System; Mice; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays