A phase 1 study evaluating the combination of an allosteric AKT inhibitor (MK-2206) and trastuzumab in patients with HER2-positive solid tumors.

INTRODUCTION: Trastuzumab is effective in human epidermal growth factor receptor 2 (HER2)-over-expressing breast and gastric cancers. However, patients may develop resistance through downstream signaling via the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. This phase 1 trial was conducted to determine the safety and tolerability of the investigational AKT inhibitor MK-2206, to prepare for future studies to determine whether the combination with trastuzumab could inhibit compensatory signaling. METHODS: Patients with HER2+ treatment-refractory breast and gastroesophageal cancer were enrolled. Treatment consisted of standard doses of intravenous trastuzumab and escalating dose levels of oral MK-2206 using either an every-other-day (45 mg and 60 mg QOD) or once-weekly (135 mg and 200 mg QW) schedule. RESULTS: A total of 34 patients with HER2+ disease were enrolled; 31 received study-drug. The maximum tolerated dose (MTD) for MK-2206 in combination with trastuzumab was 60 mg for the QOD schedule and 135 mg for the QW schedule, although a true MTD was not established due to early termination of the trial. The most common treatment-emergent toxicities included fatigue, hyperglycemia, and dermatologic rash, consistent with prior experience; one death unrelated to treatment was reported. There was one complete response in a patient with metastatic breast cancer, one patient achieved a partial response, and 5 patients had stable disease for at least 4 months, despite progression on multiple prior trastuzumab- and lapatinib-based therapies. Results also indicate that trastuzumab does not affect the pharmacokinetics of MK-2206. CONCLUSIONS: Results suggest the AKT inhibitor MK-2206 can be safely combined with trastuzumab, and is associated with clinical activity, supporting further investigation. TRIAL REGISTRATION: ClinicalTrials.gov; identifier: NCT00963547.

Resistance exercise and postprandial lipemia: The dose effect of differing volumes of acute resistance exercise bouts.

INTRODUCTION: Resistance exercise has been shown to reduce postprandial lipemia, but no dose-response effect has been established. PURPOSE: The purpose of this study was to determine whether prior resistance exercise exhibited a dose-response effect on postprandial lipemia, while controlling for energy balance. METHODS: Subjects were healthy resistance-trained men (n = 4) and women (n = 6) aged 23.4 +/- 2.5 years. Subjects participated in 4 different treatment conditions consisting of control (no exercise), 1 set, 3 sets, and 5 sets of 8 resistance exercises in a repeated-measures design. On day 1, each exercise was performed at 75% of the subject's 1-repetition maximum for 10 repetitions. This was followed by consumption of a postexercise meal equal in caloric volume designed to maintain energy balance. On day 2, after a 12-hour overnight fast (approximately 13 hours postexercise) in the General Clinical Research Center, subjects consumed a high-fat meal consisting of 1.7 g fat, 1.65 g carbohydrate, 0.25 g-protein per kilogram of fat-free mass and equal to 95 kJ of energy per kilogram of fat-free mass. Blood collections occurred before meal, and at 0.5, 1, 2, 3, 4, 5, and 6 hours after meal consumption and were analyzed for triacylglycerol (TAG), glucose, and insulin concentrations. The lipemic response was evaluated as the area under curve (AUC) for TAG versus time. Glucose and insulin AUCs were also calculated. RESULTS: No significant differences were observed among treatments for postprandial lipemia (mmol/L per 6 hours) as measured by the TAG AUC (control 2.96 +/- 0.79, 1 set 2.52 +/- 0.60, 3 sets 2.61 +/- 0.59, 5 sets 2.45 +/- 0.58). Similarly, no differences were observed for insulin or glucose AUC or for insulin sensitivity between treatments. There was a sex effect with TAG AUC significantly lower in women for control, 1 set, and 3 sets. Conclusion The results of this investigation suggest no dose-response attenuation of the postprandial lipemic response to a high-fat meal after previous resistance exercise.

Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

PURPOSE: KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. EXPERIMENTAL DESIGN: We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. RESULTS: Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. CONCLUSION: Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748).

A conceptual application of health behavior theory in the design and implementation of a successful surgical weight loss program.

Obesity (BMI > or =30 kg/m(2)) is recognized as a primary risk factor in the pathogenesis of several leading causes of morbidity and mortality, most notably hypertension, diabetes, and coronary artery disease. Despite numerous preventive approaches, the number of Americans who are overweight and obese has reached pandemic proportions and continues to increase. Moreover, the "fat are becoming fatter" as evidenced by the increasing prevalence of morbidly obese individuals (BMI > or =40 kg/m(2)). For the morbidly obese individual with potentially life-threatening comorbidities, the support for and use of surgical treatment options as a corrective mechanism is growing. Weight reduction results for bariatric surgery average 30-80% of excess body weight, depending on the length of the follow-up and the surgical technique. The demonstrated effectiveness of surgical treatment as a weight-reduction method coupled with the increasing prevalence of severe obesity is certain to increase the popularity of surgical treatment options. With this increased popularity, comes a responsibility for health-care professionals to guard against patients' perception of surgical treatment as a panacea. To counter this possibility, three recommendations are presented as components of a treatment paradigm by a multidisciplinary team of health professionals, which incorporate surgical and non-surgical treatment components, increase patient responsibility, promote lifelong health behavior change and effect permanent weight loss.

Aerobic exercise alters postprandial lipemia in African American versus White women.

PURPOSE: To determine whether ethnicity influences postprandial lipemia after a bout of aerobic exercise. METHODS: Randomized crossover design. Healthy White (W; n=6) and African American (AA; n=6) women (age, W 27.0+/-3.3 yr, AA 21.6+/-1.4 yr; body-mass index, W 25.0+/-0.93 kg/m2, AA 25.8+/-0.79 kg/m2) participated in 2 treatments (control and exercise), each conducted over 2 d. On d 1, participants rested (control) or walked at 60% of maximal oxygen uptake for 90 min (exercise) and then consumed a meal. On d 2, after a 12-hr overnight fast, participants consumed an oral fat-tolerance test (OFTT) meal of 1.7 g fat, 1.65 g carbohydrate, and 0.25 g protein per kg fat-free mass. Blood was collected pre-meal and at 0.5, 1, 2, 3, 4, 5, and 6 hr post-OFTT and analyzed for triacylglycerol (TAG), glucose, and insulin. Areas under the curve (AUCs) were calculated for each blood variable. RESULTS: A significantly lower TAG AUC was observed for AA (0.86+/-0.24 mmol x L(-1) x 6 hr(-1)) after exercise than for W (2.25+/- .50 mmol x L(-1) x 6 hr(-1)). Insulin AUC was significantly higher for AA after exercise (366.2+/-19.9 mmol x L(-1) x 6 hr(-1)) than for the control (248.1+/-29.2 mmol x L(-1) x 6 hr(-1)). CONCLUSIONS: The data indicate that exercise performed approximately 13 hr before an OFTT significantly reduces postprandial lipemia in AA compared with W. It appears that AA women have an increased ability to dispose of TAG after exercise and a high-fat meal.

Effects of different macronutrient consumption following a resistance-training session on fat and carbohydrate metabolism.

The effect of consuming meals of different macronutrient content on substrate oxidation following resistance exercise was examined in 9 resistance-trained men (26.2 +/- 2.4 years). Subjects completed 3 resistance exercise bouts of 8 exercises and 1 warm-up set (50% of 10 repetition maximum [RM]), which were followed by 3 sets of 10 repetitions (72.7 +/- 1.9% 10RM), with 60 seconds of rest between sets. Forty-five minutes after exercise, subjects consumed meals of high fat (HF, 37% carbohydrate, 18% protein, and 45% fat), high carbohydrate (HC, 79% carbohydrate, 20% protein, and 1% fat), or water (CON). Fat and carbohydrate oxidation were determined at 15-minute periods after meal consumption for 165 minutes. Blood was collected at preexercise (pre), premeal (0 minutes), and 15, 30, 45, 60, 90, 120, 150, and 180 minutes postmeal and was analyzed for insulin, glucose, triacylglycerols, and glycerol. There were no significant differences among the meal conditions for fat and carbohydrate oxidation. Insulin and glucose concentrations were significantly higher (p < 0.05) following HC at 15, 30, 45, 60, and 90 minutes compared to HF and CON. Triacylglycerol concentrations were significantly higher (p < 0.05) following HF at 90, 120, 150, and 180 minutes compared to HC and CON. Fat and carbohydrate oxidation were not affected by differences in macronutrient meal consumption after an acute bout of resistance training. Different macronutrient consumption does influence insulin, glucose, and triacylglycerol concentrations after resistance exercise.