Efficacy Of Kinase Inhibitors Research Articles

Factors associated with efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.

The finding of epidermal growth factor receptor tyrosine kinase inhibitors, which reflects a classical process of translational research, is a critical milestone for non-small-cell lung cancer treatment. Currently, epidermal growth factor receptor tyrosine kinase inhibitors are recommended as first-line therapy for non-small-cell lung cancer patients harboring epidermal growth factor receptor-sensitive mutations. The status of epidermal growth factor receptor mutation is widely acknowledged as superior to other clinical factors, such as smoking, gender, and histological types for predicting the response to epidermal growth factor receptor tyrosine kinase inhibitors. However, recent studies have shown that the efficacy might differ in patients with the same epidermal growth factor receptor-sensitive mutations, highlighting the need to investigate the putative factors related to the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors. This article reviews the factors associated with clinical efficacy of first-generation epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib and erlotinib, and analyzes their potential implications with respect to clinical application. In addition, new findings related to clinical practice with respect to epidermal growth factor receptor tyrosine kinase inhibitors efficacy were summarized in this article.

MET overexpression coexisting with epidermal growth factor receptor mutation influence clinical efficacy of EGFR-tyrosine kinase inhibitors in lung adenocarcinoma patients

Background: MET overexpression in non-small cell lung cancer (NSCLC) is known to be associated with unfavorable survival. We investigated the MET overexpression in epidermal growth factor receptor (EGFR)-mutated NSCLC and further to observe its value to the efficacy of patients treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Methods: Consecutive lung adenocarcinoma patients were screened by immunohistochemistry (IHC) for the presence of MET overexpression with concurrent EGFR mutation from January 2013 to July 2015. MET positivity was defined as strong staining intensity (grade 3+) in >50% tumor cells with moderate staining (2+). EGFR mutations were confirmed by amplification refractory mutation system (ARMS). Progression-free survival (PFS) and overall survival (OS) were evaluated by Kaplan-Meier method and compared with log-rank tests. Results: Among 167 EGFR-TKIs-treated patients, the frequency of MET overexpression was 34.1% (57/167). No difference in MET overexpression was observed among EGFR mutation type, age, gender or smoking status. The median PFS of all patients was 10.8 months and the objective response was 68.9%. Significant difference in response rate existed between MET positive and negative patients (73.6% vs. 59.6%, P=0.06). And a shorter PFS was observed for EGFR-TKIs treatment in MET-positive group than MET-negative group (10.9 vs. 10.6 months, P=0.027). Conclusions: Concurrent MET overexpression occurred in approximately 30% EGFR -mutant patients. MET overexpression was associated with an inferior efficacy of EGFR-TKI.

The effectiveness of EGFR-TKIs against brain metastases in EGFR mutation-positive non-small-cell lung cancer.

Brain metastases are usual in non-small-cell lung cancer (NSCLC) with poor prognosis and few available therapeutic options. This retrospective study aims to evaluate the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) against brain metastases from NSCLC harboring activating EGFR mutation. A total of 148 patients with brain metastases from EGFR mutation-positive NSCLC were analyzed retrospectively. The patients were orally given gefitinib (250 mg) or erlotinib (150 mg) once a day until intracranial disease progression, death, or intolerable side effects. A survival analysis was done using the Kaplan–Meier analysis and log-rank test. Objective response rate and disease control rate within brain lesions were 36.5% and 87.2%, respectively, with a median progression-free survival (PFS) and overall survival (OS) of 11.2 months (95% confidence interval [CI], 10.1–12.3) and 13.6 months (95% CI, 12.3–14.9), respectively. The patients’ characteristics were not statistically associated with PFS and OS. EGFR-TKIs showed promising antitumor activity against brain metastases in NSCLC patients with activating EGFR mutation and might be the treatment choice in this clinical setting.

MET overexpression coexisting with epidermal growth factor receptor mutation influence clinical efficacy of EGFR-tyrosine kinase inhibitors in lung adenocarcinoma patients

MET overexpression coexisting with epidermal growth factor receptor mutation influence clinical efficacy of EGFR-tyrosine kinase inhibitors in lung adenocarcinoma patients

Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer.

The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200-11. ©2017 AACR.

Progress of Researches on Prediction of Tyrosine Kinase Inhibitor Efficacy for Treatment of Chronic Myelocid Leukemia -Review

Tyrosine kinase inhibitors (TKI) have made a dramatic improvement in the clinical efficacy of chronic myelogenous leukemia, but the occurrence of TKL resistance and intolerance does not enable some patients to acquire the satisfactory efficacy. Screening the proper TKL for patients with high risk before the treatment and conversing drug timely based on early detection of TKL resistance are helpful to accurately use TKI and enhance therapeutic efficacy. In this article, the function of some indicators, such as baseline clinical, biochemical and molecular biological characteristics and influence of early treatment response law of imatinib on long-term prognosis of newly diagnosed patients are summarized.

Alopecia universalis unresponsive to treatment with tofacinitib: report of a case with a brief review of the literature

Janus kinase inhibitors are emerging treatment alternatives in various immune-mediated diseases including alopecia universalis. Herein, we report a patient with psoriasis and alopecia universalis in whom treatment with tofacitinib led to remission of psoriasis without improvement in alopecia universalis. Despite the promising potential in alopecia areata treatment, research evaluating the efficacy of different Janus kinase inhibitors and possible prognostic factors related with a more favorable response are warranted.

Drug-drug interactions in patients receiving tyrosine kinase inhibitors.

Rationale Tyrosine kinase inhibitors are increasingly used in the treatment of cancer. Drug interactions involving tyrosine kinase inhibitors are commonly encountered in clinical practice. The objective of this study was to describe the frequency of tyrosine kinase inhibitor-associated drug interactions among a cohort of oncology patients. Methods Adult patients were included who presented to either of two outpatient oncology practices and were prescribed a tyrosine kinase inhibitor during 2 January 2013 to 1 January 2015. Demographic and medication data were abstracted from electronic medical records. Lexicomp®, Micromedex Solutions®, and medication labeling were utilized to identify potential interactions between tyrosine kinase inhibitors and concomitant medications. Interactions were then assessed by the investigators for clinical significance. The primary outcome was the frequency of significant drug interactions involving tyrosine kinase inhibitors and concomitant medications. Secondary outcomes included describing the nature and clinical impact of interactions, and describing interactions by medication class. Results A total of 356 patients were identified for analysis, in whom 244 potential interactions were identified, and 109 (44.7%) of which were considered severe. Decreased tyrosine kinase inhibitor absorption due to acid suppressive therapy and CYP3A4 interactions were the most frequent mechanisms of potential subtherapeutic and supratherapeutic concentrations, respectively. Potential clinical consequences included QTc prolongation ( n = 53, 48.6%), decreased tyrosine kinase inhibitor concentration ( n = 53, 48.6%), and increased tyrosine kinase inhibitor concentration ( n = 3, 2.8%). Conclusions Safer alternative therapy and/or more frequent clinical monitoring should be considered if an interaction poses a significant risk of increased tyrosine kinase inhibitor toxicity or decreased tyrosine kinase inhibitor efficacy. Oncology pharmacists can play a role in screening for tyrosine kinase inhibitor-associated interactions, recommending alternative therapies or dosing strategies, and monitoring tyrosine kinase inhibitor efficacy and toxicity.

The association between clinical prognostic factors and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer patients: a retrospective assessment of 94 cases with EGFR mutations.

ObjectiveThis study aimed to examine the association of clinical prognostic factors with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer (NSCLC) patients.MethodsThe demographic and clinical characteristics of 94 patients with stage IV NSCLC were retrospectively reviewed, and the association between clinical factors and EGFR-TKIs efficacy was evaluated.ResultsOf the 94 stage IV NSCLC patients enrolled in this study, a 74.5% objective response rate (ORR) and 97.9% disease control rate (DCR) were observed for EGFR-TKIs treatment, and a higher ORR was seen in patients with 0 and 1 ECOG scores than those with 2 or greater scores (P = 0.049). The subjects had a median PFS of 11 months and a median OS of 31 months after EGFR-TKIs treatment. ECOG score and timing of targeted therapy were factors affecting PFS, and ECOG score, smoking status and brain metastasis were factors affecting OS. In addition, ECOG score was an independent prognostic factor for PFS in stage IV NSCLC patients, and the patients with EGFR 19del mutation had a longer PFS than those with exon 21 L855R mutation (P = 0.003), while ECOG score and brain metastasis were independent prognostic factors for OS.ConclusionsThe results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy. ECOG score is an independent prognostic factor for PFS, and ECOG score and brain metastasis are independent prognostic factors for OS in advanced NSCLC patients.

Correlation between epidermal growth factor receptor tyrosine kinase inhibitor efficacy and circulating tumor cell levels in patients with advanced non-small cell lung cancer.

ObjectiveThe aim of this study was to investigate the correlation between the efficacy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and circulating tumor cell (CTC) levels in patients with advanced non-small cell lung cancer (NSCLC). The efficacy of EGFR-TKIs in reducing CTC counts in patients with advanced NSCLC was studied.Patients and methodsA total of 66 patients with advanced NSCLC were enrolled and divided into two groups (those with high CTC counts and those with low CTC counts) based on the patients’ median CTC counts. All the patients were treated with an EGFR-TKI, and the treatment efficacy and prognoses were compared.ResultsThe treatment efficacies were 53.3% (16/30) and 27.8% (10/36) for the low CTC group and high CTC group, respectively, and this difference was statistically significant (P<0.05). The median overall survival was 22.8 months (95% confidence interval [CI]: 18.9–26.8 months) for the low CTC group and 18.3 months (95% CI: 2.9–8.2 months) for the high CTC group. The median progression-free survival was 11.5 months (95% CI: 8.1–15 months) and 5.6 months (95% CI: 2.9–8.2 months) for the low and high CTC groups, respectively, and the difference was statistically significant (P<0.05).ConclusionThe CTC count can be used as an index for predicting the EGFR-TKI effect on patients with advanced NSCLC. Efficacy and prognosis of EGFR-TKI treatment and CTC count were considered important, and the CTC count could be used to predict the efficacy of EGFR-TKI treatment and prognosis of advanced NSCLC. The change in CTC expression levels can be used as an index for evaluating the prognosis of patients with advanced NSCLC.

Efficacy and safety of tyrosine kinase inhibitor in treating elderly patients with chronic myeloid leukemia during chronic phrase

Objective To evaluate the efficacy and safety of tyrosine kinase inhibitors (TKI) in treating the elderly patients with chronic myeloid leukemia (CML) during chronic phrase. Methods From January 2015 to January 2016, a total of 52 cases of chronic phrase CML patients who received TKI treatment, over 60-year-old and were treated at Department of Hematology, West China Hospital were included in this study. Thirty-three cases of them chose imatinib (IM) as the first-line treatment regimen and 2 cases of them chose nilotinib (NIL) as the first-line treatment regimen, while the other 17 cases were treated with interferon before IM. The therapeutic response, overall survival (OS), event-free survival (EFS), comorbidity and drug-related adverse reactions of all the patients were analyzed by retrospective method, in order to summarize the efficacy and safety of TKI in the treatment of CML in elderly patients. Results ① The rates of cumulative complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR) and major molecular response (MMR) were 100.0% (52/52), 82.7 % (43/52), 80.8 % (42/52) and 71.2 % (37/52), respectively. The rates of OS of 1-year, 5-year and 10-year were 100.0%, 95.1% and 75.3%, respectively, while the rates of EFS of 1-year, 5-year and 10-year were 92.3%, 73.3% and 51.4%, respectively. ② Twenty-five patients had comorbidities. The scores of Charlson comorbidity index (CCI) of these 52 patients were all less than 2 scores. There were no significant differences in the incidence of cumulative CCyR, MCyR, MMR, grade Ⅲ hematologic and non-hematologic adverse reactions between 32 patients with CCI score=0 and 20 patients with CCI score>0 (χ2=0.948, 0.525, 0.021, 0.288, 0.021; P>0.05). ③ In 50 patients who received treatment of IM, the incidence rates of Ⅲ-Ⅳ grade neutropenia, thrombocytopenia and anemia were 16.0 % (8/50), 28.0% (14/50) and 18.0% (9/50), respectively. While 14 patients occurred Ⅲ-Ⅳ grade non-hematologic adverse reactions, with the incidence rate of 28.0% (14/50). Due to intolerance of IM, 5 cases (10.0%, 5/50) of the patients received the second-line TKI treatment. Conclusions TKI is an effective and safe treatment for the elderly patients who have chronic phrase CML. Mild comorbidities have no influence on the therapy. Key words: Leukemia, myelogenous, chronic, BCR-ABL positive; Tyrosine kinase inhibitor; Aged; Drug-related side effects and adverse reactions; Comorbidity

Ligand-based and e-pharmacophore modeling, 3D-QSAR and hierarchical virtual screening to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3)

The clinical efficacy of multiple kinase inhibitors has caught the interest of Pharmaceutical and Biotech researchers to develop potential drugs with multi-kinase inhibitory activity for complex diseases. In the present work, we attempted to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3), keys players in immune signaling, by developing ideal pharmacophores integrating Ligand-based pharmacophore models (LBPMs) and Structure-based pharmacophore models (SBPMs), thereby projecting the optimum pharmacophoric required for inhibition of both the kinases. The four point LBPM; ADPR.14 suggested the presence of one hydrogen bond acceptor, one hydrogen bond donor, one positive ionizable, and one ring aromatic feature for Syk inhibitory activity and AADH.54 proposed the necessity of two hydrogen bond acceptor, one hydrogen bond donor, and one hydrophobic feature for JAK3 inhibitory activity. To our interest, SBPMs identified additional ring aromatic features required for inhibition of both the kinases. For Syk inhibitory activity, the hydrogen bond acceptor feature indicated by LBPM was devoid of forming hydrogen bonding interaction with the hinge region amino acid residue (Ala451). Thus merging the information revealed by both LBPMs and SBPMs, ideal pharmacophore models i.e. ADPRR.14 (Syk) and AADHR.54 (JAK3) were generated. These models after rigorous statistical validation were used for screening of Asinex database. The systematic virtual screening protocol, including pharmacophore and docking-based screening, ADME property, and MM-GBSA energy calculations, retrieved final 10 hits as dual inhibitors of Syk and JAK3. Final 10 hits thus obtained can aid in the development of potential therapeutic agents for autoimmune disorders. Also the top two hits were evaluated against both the enzymes.

Targeting the receptor tyrosine kinase RET in combination with aromatase inhibitors in ER positive breast cancer xenografts.

The majority of breast cancers are estrogen receptor positive (ER+). Blockade of estrogen biosynthesis by aromatase inhibitors (AIs) is the first-line endocrine therapy for post-menopausal women with ER+ breast cancers. However, AI resistance remains a major challenge. We have demonstrated previously that increased GDNF/RET signaling in ER+ breast cancers promotes AI resistance. Here we investigated the efficacy of different small molecule RET kinase inhibitors, sunitinib, cabozantinib, NVP-BBT594 and NVP-AST487, and the potential of combining a RET inhibitor with the AI letrozole in ER+ breast cancers. The most effective inhibitor identified, NVP-AST487, suppressed GDNF-stimulated RET downstream signaling and 3D tumor spheroid growth. Ovariectomized mice were inoculated with ER+ aromatase-overexpressing MCF7-AROM1 cells and treated with letrozole, NVP-AST487 or the two drugs in combination. Surprisingly, the three treatment regimens showed similar efficacy in impairing MCF7-AROM1 tumor growth in vivo. However in vitro, NVP-AST487 was superior to letrozole in inhibiting the GDNF-induced motility and tumor spheroid growth of MCF7-AROM1 cells and required in combination with letrozole to inhibit GDNF-induced motility in BT474-AROM3 aromatase expressing cells. These data indicate that inhibiting RET is as effective as the current therapeutic regimen of AI therapy but that a combination treatment may delay cancer cell dissemination and metastasis.

EGFR protein expression using a specific intracellular domain antibody and PTEN and clinical outcomes in squamous cell lung cancer patients with EGFR-tyrosine kinase inhibitor therapy.

PurposeThe aim of this research was to examine the molecular and clinical features that are related with EGFR-tyrosine kinase inhibitor (EGFR-TKI) efficacy in previously treated patients with squamous cell carcinoma of the lung (SCCL).Materials and methodsThis retrospective study included 67 SCCL patients with obtainable lung cancer tissue and records on EGFR-TKI treatment response and survival. EGFR protein expression in lung cancer tissue was measured by immunohistochemistry with a specific antibody that recognizes the intracellular domain (ID) of EGFR. PTEN expression in lung cancer tissue was also evaluated with immunohistochemistry. PI3KCA gene amplification was detected by quantitative real-time polymerase chain reaction, and FGFR1 amplification was assessed by fluorescent in situ hybridization.ResultsEGFR ID expression (hazard ratio [HR] 0.53, P=0.022) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) (HR 0.43, P=0.022) were significantly related with progression-free survival following EGFR-TKIs treatment. PTEN expression (HR 0.52, P=0.025) was significantly related to overall survival. The group of EGFR-positive or PTEN-positive patients with ECOG PS of 0 or 1 had better clinical outcomes than patients who were EGFR-negative and PTEN-negative or who had poor ECOG PS with longer median progression-free survival (2.1 vs 1.0 months, P=0.05) and overall survival (6.2 vs 2.1 months, P=0.05).ConclusionEGFR expression using an ID-specific antibody and PTEN protein expression may be used to identify SCCL patients who might benefit from EGFR-TKI treatment.

Clinical efficacy of first-generation EGFR-TKIs in patients with advanced non-small-cell lung cancer harboring EGFR exon 20 mutations.

PurposeSubsets of non-small-cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations carry uncommon subtypes. We evaluated the efficacy of first-generation EGFR-tyrosine kinase inhibitors (TKIs; erlotinib, gefitinib, and icotinib) in patients with non-small-cell lung cancer carrying insertions and T790M and S768I mutations in EGFR exon 20.Patients and methodsPatients carrying EGFR exon 20 insertion/T790M/S768I mutations and treated with EGFR-TKIs were evaluated from 2005 to 2014 in Zhejiang Cancer Hospital. The efficacy was evaluated using the Kaplan–Meier method and compared with the log-rank test.ResultsSixty-two patients with exon 20 insertion/T790M/S768I mutations were enrolled. Mutations including exon 20 insertions and T790M and S768I mutations were observed in 29, 23, and ten patients, respectively. In total, the response rate and median progression-free survival (PFS) were 8.1% and 2.1 months, respectively. Patients with S768I mutation manifested the longest median PFS (2.7 months), followed by those with T790M (2.4 months) and exon 20 insertions (1.9 months; P=0.022). Patients with complex mutations show a better PFS than those with single mutations (2.7 months vs 1.9 months; P=0.034).ConclusionFirst-generation EGFR-TKIs are less effective in patients with exon 20 uncommon mutations than in those with common mutations. Patients with complex mutations benefited more from first-generation EGFR-TKIs than those with single mutations.

Hippo pathway effector YAP inhibition restores the sensitivity of EGFR-TKI in lung adenocarcinoma having primary or acquired EGFR-TKI resistance

The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) is significantly limited by various resistance mechanisms to those drugs. The resistance to EGFR-TKI is largely divided by two classes; acquired resistance after EGFR-TKI treatment, and primary resistance marked by cancer cell's dependence on other oncogene, such as KRAS. YAP has emerged as critical oncogene in conferring drug resistance against targeted therapy. In this study, we evaluated the role of YAP in primary and acquired EGFR-TKI resistance using gefitinib-resistant A549 and PC9 cells and their parental cell lines. Our study revealed that EGFR-TKI resistance is associated with enhanced YAP activity. Notably, YAP activation was independent of the Hippo pathway. We confirmed that AXL is a downstream target of YAP that confers EGFR-TKI resistance. And our results showed that YAP can induce ERK activation in lung adenocarcinoma. The combination of YAP inhibition with EGFR-TKI overcomes primary and acquired EGFR-TKI resistance. We also found increased YAP expression in human lung cancer after acquiring EGFR-TKI resistance. Collectively, we suggest a novel EGFR-TKI resistance mechanism involving YAP activation and suggest targeting YAP and EGFR simultaneously may be a breakthrough treatment of primary and acquired EGFR-TKI resistant lung cancer.

Activation Mechanism of Oncogenic Deletion Mutations in BRAF, EGFR, and HER2

Activating mutations in protein kinases drive many cancers. While how recurring point mutations affect kinase activity has been described, the effect of in-frame deletions is not well understood. We show that oncogenic deletions within the β3-αC loop of HER2 and BRAF are analogous to the recurrent EGFR exon 19 deletions. We identify pancreatic carcinomas with BRAF deletions mutually exclusive with KRAS mutations. Crystal structures of BRAF deletions reveal the truncated loop restrains αC in an active "in" conformation, imparting resistance to inhibitors like vemurafenib that bind the αC "out" conformation. Characterization of loop length explains the prevalence of five amino acid deletions in BRAF, EGFR, and HER2 and highlights the importance of this region for kinase activity and inhibitor efficacy.

Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis

Background &amp; Aims. At present, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment option with curative potential in patients with myelofibrosis (MF), especially in intermediate and high risk categories. The aim of the study is to perform a retrospective analysis of alloHSCT outcomes in MF patients. Materials &amp; Methods. Outcomes of allo-HSCT in 11 intermediate-2 (n = 3) and high (n = 6) risk patients (based on Dynamic International Prognostic Scoring Scale, DIPSSplus) performed in the R.M. Gorbacheva Scientific Research Institute of Pediatric Hematology and Transplantation over the period from 2005 till 2015 were analyzed in the study. Two more patients underwent allo-HSCT in MF blast phase. Two patients received ruxolitinib before allo-HSCT and 1 patient before and after allo-HSCT. Reduced intensity conditioning regimen was used in all cases. Results. Primary engraftment was documented in 8 patients. 72 % of patients achieved complete hematological remission. Molecular remission and myelofibrosis regression were confirmed in 5 patients. 5 of 11 patients were still with remission and followed-up by the date of the paper submission. The overall two-year survival was 46 %. Conclusion. Allo-HSCT is an effective treatment option for MF patients. Further trials are required to evaluate an optimal timing for allo-HSCT in MF patients and efficacy of Janus kinase (JAK) inhibitors as pre- and posttransplant therapy in MF.

Abstract A51: Targeting mTOR metabolism for glioblastoma cancer therapy

Abstract Aerobic glycolysis (the Warburg effect), first recognized almost a century ago, by Otto Warburg is a core hallmark of cancer. The Warburg effect describes a switch in glucose metabolism from oxidative phosphorylation to glycolysis. Recently links have been established between the oncogenic pathways that drive tumorigenesis and the mechanistic basis of tumor cell metabolism. The kinase mTOR is a major driver of tumor metabolism and proliferation of cancer cells, acts downstream of numerous oncogenic pathways. Several drugs targeting the mTOR pathway are being developed, however the most common drug rapamycin does not inhibit mTOR complex-2. Therefore in the current study, we examined the potential benefit of MLN0128, a novel potent mTOR ATP competitive inhibitor, as a therapeutic strategy for glioblastoma (GBM), one of the deadliest brain tumors. We studied the action of MLN0128 in human GBM tumor cells and patient derived stem cells. We show the inhibitory effect of MLN0128 in nanomolar concentrations on tumor proliferation in multiple GBM cell lines via the blockage of phospho-AKT, -ribosomal protein, -4EBP1 inhibiting both mTORC1 and mTORC2 signaling in GBM. Reduction of invasive potential and disruption of paxillin localization to focal adhesions was observed in vitro. MLN0128 treatment decreased glucose consumption and lactate production. It inhibited rate of glycolysis, glycolytic capacity and glycolytic reserve. It also inhibited ATP production, mitochondrial respiration and spare respiratory capacity. MLN0128 was superior in inhibiting metabolism compared to rapamycin. On clonogenic survival assay MLN0128 decreased GBM cell survival and increased radiosensitivity. In vivo treatment of mouse xenografts with MLN0128 downregulated mTOR targets and significantly inhibited tumor volume compared to drug and irradiation alone. Combination treatment of GBM cells with MLN0128 and other chemotherapeutic agents like carboplatin, irinotecan and TMZ showed synergistic effects when combination index was calculated in GBM tumor cells and stem cells. However, the therapeutic efficacy of TMZ combination was greater than MLN0128 combination with either carboplatin or irinotecan. Moreover, similar TMZ chemosensitivity was observed in MGMT non-methylated, TMZ in-sensitive GBM stem cells and MGMT methylated GBM cells. These findings support the rationale for clinical testing of MLN0128 in patients with GBM to provide insight towards optimizing therapeutic efficacy of mTOR kinase inhibitors with standard care. Citation Format: Anita Tandle, Tamalee Kramp, Philip Tofilon, Kevin Camphausen. Targeting mTOR metabolism for glioblastoma cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A51.

Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for patient with leptomeningeal metastasis of epidermal growth factor receptor mutant non-small cell lung cancer

Efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors for patient with leptomeningeal metastasis of epidermal growth factor receptor mutant non-small cell lung cancer