Insulin stimulates glucose uptake in skeletal muscle cells and fat cells by promoting the rapid translocation of GLUT4 glucose transporters to the plasma membrane. Recent work from our laboratory supports the concept that insulin also stimulates the intrinsic activity of GLUT4 through a signaling pathway that includes p38 MAPK. Here we show that regulation of GLUT4 activity by insulin develops during maturation of skeletal muscle cells into myotubes in concert with the ability of insulin to stimulate p38 MAPK. In L6 myotubes expressing GLUT4 that carries an exofacial myc-epitope (L6-GLUT4myc), insulin-stimulated GLUT4myc translocation equals in magnitude the glucose uptake response. Inhibition of p38 MAPK with SB203580 reduces insulinstimulated glucose uptake without affecting GLUT4myc translocation. In contrast, in myoblasts, the magnitude of insulin-stimulated glucose uptake is significantly lower than that of GLUT4myc translocation and is insensitive to SB203580. Activation of p38 MAPK by insulin is considerably higher in myotubes than in myoblasts, as is the activation of upstream kinases MKK3/ MKK6. In contrast, the activation of all three Akt isoforms and GLUT4 translocation are similar in myoblasts and myotubes. Furthermore, GLUT4myc translocation and phosphorylation of regulatory sites on Akt in L6-GLUT4myc myotubes are equally sensitive to insulin, whereas glucose uptake and phosphorylation of regulatory sites on p38 MAPK show lower sensitivity to the hormone. These observations draw additional parallels between Akt and GLUT4 translocation and between p38 MAPK and GLUT4 activation. Regulation of GLUT4 activity by insulin develops upon muscle cell differentiation and correlates with p38 MAPK activation by insulin.

BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell's ability to evade programmed cell death. Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family. BH3 profiling is reviewed. Historical therapeutic agents are addressed, and currently investigated BH3 mimetics are described with attention to clinical significance. The limitations of BCL-2 family targeted drugs with regard to on-target and off-target toxicities are explored. Agents under development for targeting MCL-1 and other BCL-2 family members are discussed. Expert opinion: ABT-199 (venetoclax) and other BH3 mimetics have entered the clinical arena and show promising results in both hematologic and solid malignancies. Use of agents targeting this system will likely expand, and likely a number of malignant diseases will be successfully targeted resulting in improved treatment responses and patient survival.

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Activating epidermal growth factor receptor (EGFR) mutations in metastatic non-small cell lung cancer (NSCLC) are associated with a high response rate to EGFR tyrosine kinase inhibitor (TKI). The current guidelines recommend routine EGFR mutational analysis prior to initiating first line systemic therapy. The clinical characteristics including smoking status, histologic type, sex and ethnicity are known to be associated with the incidence of EGFR mutations. We retrospectively analyzed 277 patients with metastatic NSCLC within Kaiser Permanente Northern California (KPNC); among these patients, 83 were positive for EGFR mutations. We performed both univariate and multivariable logistic regressions to identify predictors of EGFR mutations. We found that histologic grade was significantly associated with the incidence of EGFR mutation, regardless of ethnicity, sex and smoking status. In grade I (well differentiated) and II (moderately differentiated), histology was associated with significantly higher incidence of EGFR mutations compared to grade II–III (moderate-to-poorly differentiated) and III (poorly differentiated). Ever-smokers with grade III lung adenocarcinoma had 1.8% incidence of EGFR mutations. This study indicates that histologic grade is a predictive factor for the incidence of EGFR mutations and suggests that for patients with grade II–III or III lung adenocarcinoma, prompt initiation of first-line chemotherapy or immunotherapy is appropriate while awaiting results of EGFR mutational analysis, particularly for patients with history of smoking.

Background: Mantle cell lymphoma (MCL) is a moderately aggressive and incurable small to medium size B cell lymphoma. There is no standardized treatment for this disease. The conventional chemotherapy results in a high incidence of treatment related toxicity with frequent disease relapse. Cladribine is a hypomethylating agent that indirectly downregulate DNA methylation to suppress tumorigenesis. Combination of Cladribine and Rituximab showed a synergetic effect in treating B cell lymphomas. Velcade (Bortezomib) is a FDA approved proteasome inhibitor to treat relapsed/refractory MCL. In this phase 1 study, we evaluated the safety and efficiency of Valcade, Cladribine, and Rituximab (VCR) combination treatment in newly diagnosed and relapsed/refractory MCL. Patients and Methods: This is a single arm, open label, investigator initiated Phase 1 study conducted at PennState Hershey Cancer Institute. This study employed a standard 3+3 dose-escalation scheme designed to determine the maximum tolerated dose (MTD) of Cladribine in VCR regimen. The treatment scheme and Cladribine dose escalation levels (1, 2, and 3) are as follows: the therapy consisted of 6 28-day cycles. At first cycle of the treatment, Rituximab 375 mg/m2 infusion started on day 5 of the first week and then given weekly for 3 weeks; in the next 5 cycles Rituximab was given on day 5 of each cycle, and then every 2 months as the maintenance therapy. Cladribine 3-5 mg/m2 (3 mg/m2 for level 1, 4 mg/m2 for level 2, and 5 mg/m2 for level 3) infusion was given on days 1-5 for 6 cycles. If the patient's was older than 70 years old, Cladribine was only given on days 1-3 of each cycle. Velcade 1.6 mg/m2 subcutaneous injection was given on days 12, 19 and 26 for cycles 1-3, then Day 5 and 19 during Cycles 4-6, then once per month as maintenance therapy until toxicity or progression of the disease. The primary endpoint of this study was to investigate the dose-limiting toxicity (DLT), safety, and efficiency of this regimen in patients with MCL. The secondary endpoints included remission rate (RR), progression-free survival (PFS) and overall survival (OS). The analysis was done by intent to treat. This study is registered with clinicaltrials.gov (NCT01439750). Results: No subject experienced dose limited toxicity (DLT) at either level 1 or 2, one possible DLT (infectious colitis) was observed on a subject during 2nd cycle at level 3. Then no additional DLTs were seen in 3 subjects added to level 3. Overall, this study recruited 13 subjects, with a median age of 64 years old (range from 55 to 83), and a total of 11 male and 2 females. Ten subjects were never previously treated, while 3 either relapsed or failed previous treatments. The majority of subjects tolerated this regimen well. The patient with a history of DLT became the only mortality of this cohort 7 months later as a result of multiple organ failure. The overall remission (OR) rate was 85% (11/13) and complete remission (CR) rate was 62% (8/13). In newly diagnosed subject cohort, the RR and OS rates were 100% (9/9), PFR was 89% (8/9), and CR rate was 78% (7/9), of which 2 patients have been followed for more than 3 years and 4 patients for more than 2 years. However, in relapsed/refractory subject cohort, 1 subject achieved CR for 7 months but then relapsed, 2 subjects had no response. There were 2 blastoid subjects, one was newly diagnosed and achieved CR. No severe systemic toxicity was observed in this study. Bone marrow suppression caused prolonged anemia and thrombocytopenia were the most common toxicity (3/13 with ≤grade 2). Low grade peripheral neuropathies (≤grade 2) were observed in 15% (2/13). Mild fatigue was a frequent complaint. Correlative studies measured cyclin D1 expression levels using mononuclear cells as opposed to formalin-preserved tissue, a technique which allows for monitoring the levels over time. Although limited by a small sample size, the results indicated that the G/G (or A/A) genotype at G870A polymorphism site as well as a rapid decline of cyclin D1 and D1a during treatment may be correlated to a less aggressive disease course. Further studies are needed to explore the underlining mechanism. Conclusions: The VCR combination is a well tolerated, low toxicity and effective regimen for MCL, especially for untreated MCL. Cladribine 5 mg/m2 is a tolerable dose with manageable toxicity. A phase II trial to further evaluate the activity and toxicity of VCR regimen is warranted. Disclosures No relevant conflicts of interest to declare.