Faculty Bibliography

PURPOSE: This prospective cohort study evaluates associations between healthful behaviors consistent with WCRF/AICR cancer prevention guidelines and obesity-related cancer risk, as a third of cancers are estimated to be preventable. METHODS: The study sample consisted of adults from the Framingham Offspring cohort (n = 2,983). From 1991 to 2008, 480 incident doctor-diagnosed obesity-related cancers were identified. Data on diet, measured by a food frequency questionnaire, anthropometric measures, and self-reported physical activity, collected in 1991 was used to construct a 7-component score based on recommendations for body fatness, physical activity, foods that promote weight gain, plant foods, animal foods, alcohol, and food preservation, processing, and preparation. Multivariable Cox regression models were used to estimate associations between the computed score, its components, and subcomponents in relation to obesity-related cancer risk. RESULTS: The overall score was not associated with obesity-related cancer risk after adjusting for age, sex, smoking, energy, and preexisting conditions (HR 0.94, 95 % CI 0.86-1.02). When score components were evaluated separately, for every unit increment in the alcohol score, there was 29 % lower risk of obesity-related cancers (HR 0.71, 95 % CI 0.51-0.99) and 49-71 % reduced risk of breast, prostate, and colorectal cancers. Every unit increment in the subcomponent score for non-starchy plant foods (fruits, vegetables, and legumes) among participants who consume starchy vegetables was associated with 66 % reduced risk of colorectal cancer (HR 0.44, 95 % CI 0.22-0.88). CONCLUSIONS: Lower alcohol consumption and a plant-based diet consistent with the cancer prevention guidelines were associated with reduced risk of obesity-related cancers in this population.

Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of interleukin-8 and VEGF due to GRM1-mediated activation of the AKT-mTOR-HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in posttreatment as compared with pretreatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers proangiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients.

BACKGROUND: Obesity-related dysregulation of the insulin-glucose axis is hypothesized in carcinogenesis. We studied impaired fasting glucose (IFG) and other markers of insulin-glucose metabolism in the Framingham Heart Study-Offspring Cohort, which uniquely tracks these markers and cancer >37 years. METHODS: Participants were recruited between 1971 and 1975 and followed until 2008 (n = 4,615; mean age 66.8 years in 2008). Serum glucose, insulin, and hemoglobin A1c were determined from fasting blood in quart-annual exams. Lifestyle and demographic information was self-reported. HRs and 95% confidence intervals (CI) of cancer risk were computed using time-dependent survival analysis (SASv9.3), while accounting for temporal changes for relevant variables. RESULTS: We identified 787 obesity-related cancers, including 136 colorectal, 217 breast, and 219 prostate cancers. Absence versus presence of IFG 10 to 20 years and 20+ years before the event or last follow-up was associated with 44% (95% CI, 1.15-1.79) and 57% (95% CI, 1.17-2.11) increased risk of obesity-related cancers, respectively. When time-dependent variables were used, after adjusting for age, sex, smoking, alcohol, and body mass index, IFG was associated with a 27% increased risk of obesity-related cancer (HR = 1.27; CI, 1.1-1.5). Associations were stronger in smokers (HR = 1.41; CI, 1.13-1.76). Increased risk was noted among persons with higher insulin (HR = 1.47; CI, 1.15-1.88) and hemoglobin A1c (HR = 1.54; CI, 1.13-2.10) for the highest (>/=5.73%) versus lowest (2-fold increase in colorectal cancer risk was observed for all blood biomarkers of insulin-glucose metabolism, particularly with earlier IFG exposure. Nonsignificant increased risk of breast and prostate cancer was observed for blood biomarkers. CONCLUSIONS: Earlier IFG exposure (>10 years before) increased obesity-related cancer risk, particularly for colorectal cancer. IMPACT: Our study explicitly recognizes the importance of prolonged IFG exposure in identifying links between glucose dysregulation and obesity-related cancers. Cancer Epidemiol Biomarkers Prev; 22(10); 1-12. (c)2013 AACR.

Longitudinal associations between leisure-time physical activity (LTPA) and overall cancer mortality were evaluated within the Third National Health and Nutrition Examination Survey (NHANES III; 1988-2006; n = 15,535). Mortality status was ascertained using the National Death Index. Self-reported LTPA was divided into inactive, regular low-to-moderate and vigorous activity. A frequency-weighted metabolic equivalents (METS/week) variable was also computed. Hazard ratios (HRs) and 95% confidence intervals (CI) were calculated for overall cancer mortality in the whole sample, by body mass index categories and insulin resistance (IR) status. Nonsignificant protective associations were observed for regular low-to-moderate and vigorous activity, and for the highest quartile of METS/week (HRs range: 0.66-0.95). Individuals without IR engaging in regular vigorous activity had a 48% decreased risk of cancer mortality (HR: 0.52; 95% CI: 0.28-0.98) in multivariate analyses. Conversely, nonsignificant positive associations were observed in people with IR. In conclusion, regular vigorous activity may reduce risk of cancer mortality among persons with normal insulin-glucose metabolism in this national sample.

In the preclinical setting, phosphorylation and subsequent proteosomal degradation of the proapoptotic protein BIM confers resistance to paclitaxel in solid tumors with RAS/RAF/MAPK pathway activation. Concurrent administration of the proteasome inhibitor bortezomib enables paclitaxel-induced BIM accumulation, restoring cancer cell apoptosis in vitro and producing tumor regression in mice in vivo. A phase I study was conducted to determine the maximum tolerated dose (MTD) of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors commonly exhibiting mitogen-activated protein kinase (MAPK) pathway activation were treated weekly with paclitaxel and bortezomib. Starting doses were 40 mg/m(2) for paclitaxel and 0.7 mg/m(2) for bortezomib. A modified continual reassessment method adapted for 2-drug escalation was used for MTD determination with 3-patient cohorts treated at each dose level. MTD was reached at 60 mg/m(2) paclitaxel and 1.0 mg/m(2) bortezomib, the recommended phase II dose. Therapy was overall well tolerated. Most frequently observed toxicities included anemia (in 43.75% of patients, one grade 3 event), fatigue (in 43.75% of patients, one grade 3 event beyond cycle 1), and neuropathy (in 31.25% of patients, one grade 3 event after cycle 1). Of 15 evaluable patients, one non-small-cell lung carcinoma (NSCLC) patient with paclitaxel exposure at the adjuvant setting had a partial response and five patients had stable disease (SD); median disease stabilization was 143.5 days; three NSCLC patients had SD lasting 165 days or longer. Thus, rationally designed weekly treatment with paclitaxel and bortezomib in solid tumors with MAPK pathway activation, including previously taxane-treated malignancies, is a tolerable regimen with preliminary signals of antitumor activity worthy of further investigation.

BACKGROUND: Previous studies suggest that obesity is associated with higher prostate cancer progression and mortality despite an association with lower prostate cancer incidence. This study aims to better understand these apparently inconsistent relationships among obese men by combining evidence from 3 nationally representative cross-sectional surveys. METHODS: We evaluated relationships between obesity and 1) testosterone concentrations in the Third National Health and Nutrition Examination Survey (NHANES III; n=845); 2) prostate-specific antigen (PSA) in NHANES 2001-2004 (n=2458); and 3) prostate biopsy rates in the National Health Interview Survey (NHIS 2000; n=4789) population. Mean testosterone, PSA concentrations, and biopsy rates were computed for Body Mass Index (BMI) categories. RESULTS: Testosterone concentrations were inversely associated with obesity (P-trend <.0001) in NHANES III. In NHANES 2001-2004, obese (BMI >35) versus lean (BMI <25) men were less likely to have PSA concentrations that reached the biopsy threshold of >4 ng/mL (3% vs 8%; P <.0001). Among NHIS participants, all BMI groups had similar rates of PSA testing (P=.24). However, among men who had PSA tests, 11% of men with BMI >30 versus 16% with BMI <25, achieved a PSA threshold of 4 ng/mL; P=.01. Furthermore, biopsy rates were lower among men with BMI >30 versus BMI <25 in NHIS participants (4.6% vs 5.8%; P=.05). CONCLUSIONS: Obesity was associated with lower PSA-driven biopsy rates. These data support further studies to test the hypothesis that obesity affects prostate cancer detection independent of prostate cancer risk by decreasing the PSA-driven biopsy rates.

Insulin and glucose may influence cancer mortality via their proliferative and anti-apoptotic properties. Using longitudinal data from the nationally representative Third National Health and Nutrition Examination Survey (NHANES III; 1988-1994), with an average follow-up of 8.5 years to death, we evaluated markers of glucose and insulin metabolism, with cancer mortality, ascertained using death certificates or the National Death Index. Plasma glucose, insulin, C-peptide, and lipid concentrations were measured. Anthropometrics, lifestyle, medical, and demographic information was obtained during in-person interviews. After adjusting for age, race, sex, smoking status, physical activity, and body mass index, for every 50 mg/dl increase in plasma glucose, there was a 22% increased risk of overall cancer mortality. Insulin resistance was associated with a 41% (95% confidence interval (CI) (1.07-1.87; p = 0.01) increased risk of overall cancer mortality. These associations were stronger after excluding lung cancer deaths for insulin-resistant individuals (HR: 1.67; 95% CI: 1.15-2.42; p = 0.01), specifically among those with lower levels of physical activity (HR: 2.06; 95% CI: 1.4-3.0; p = 0.0001). Similar associations were observed for other blood markers of glucose and insulin, albeit not statistically significant. In conclusion, hyperglycemia and insulin resistance may be 'high-risk' conditions for cancer mortality. Managing these conditions may be effective cancer control tools

Studies suggest inverse associations between obesity and prostate-specific antigen (PSA). However, there is little evidence whether factors related to obesity, including lifestyle (diet and physical activity) and physiologic factors (insulin resistance and metabolic syndrome), influence PSA. We used dietary, physical activity, and serum PSA, insulin, glucose, and lipid data for men >40 years from the National Health and Nutrition Examination Survey (2001-2004; N = 2,548). Energy, fat, and carbohydrate intakes were estimated from a 24-hour dietary recall. Men were considered as having metabolic syndrome based on the Adult Treatment Panel III criteria. Leisure-time physical activity and doctor-diagnosed hypertension were self-reported. Body mass index was calculated from measured weight and height. We computed the geometric mean PSA (ng/mL), adjusted for age, race, and body mass index, by tertile of energy, fat, and carbohydrate intake and level of physical activity, and among men with and without insulin resistance and metabolic syndrome in the whole population and by race. The geometric mean PSA (95% confidence interval) among men in the lowest tertile of energy was 1.05 (0.97-1.1) relative to 0.85 (0.8-0.9) in the highest tertile (P = 0.0002) in the whole population. The PSA concentrations were lower among overweight men with higher versus lower energy intake (P = 0.001). The PSA concentrations in men with insulin resistance was lower [0.87 (0.8-0.9)] relative to men without insulin resistance [0.98 (0.9-1.1)] at P = 0.04. All associations were in similar directions within racial subgroups. No associations were observed between the other lifestyle and physiologic factors. Additional studies are required to confirm these results and to investigate the potential mechanisms that may explain these relationships.

OBJECTIVE: To examine the expression profiles of luteinized granulosa cells isolated from women with normal or diminished ovarian reserve undergoing in vitro fertilization. DESIGN: Expression profiling by complementary DNA microarray analysis. SETTING: Women undergoing in vitro fertilization-embryo transfer in a university-based fertility clinic. PATIENT(S): Eighteen women with normal or decreased ovarian reserve. INTERVENTION(S): All patients were given gonadotropin stimulation in preparation for IVF with granulosa cells isolated at the time of follicular aspiration. MAIN OUTCOME MEASURE(S): Expression profiles of luteinized granulosa cells isolated from each woman were determined by using DNA microarray analysis. RESULT(S): Changes in patterns of gene expression in granulosa cells were observed between women with normal and diminished ovarian reserve. These genes included several anonymous expressed sequence tags and also expressed sequence tags that correspond to known genes. CONCLUSION(S): Expression profiling of granulosa cells by DNA microarray may yield signature patterns that reflect the status of ovarian reserve and the competence of granulosa cells