Publications by authors named "Michael N Pollak"

147 Publications

A hydride transfer complex reprograms NAD metabolism and bypasses senescence.

Mol Cell 2021 09;81(18):3848-3865.e19

CRCHUM, 900 Saint-Denis St, Montréal, QC H2X 0A9, Canada; Département de Biochimie et Médecine Moléculaire, Université de Montréal, Montréal, QC H3C 3J7, Canada. Electronic address:

Metabolic rewiring and redox balance play pivotal roles in cancer. Cellular senescence is a barrier for tumorigenesis circumvented in cancer cells by poorly understood mechanisms. We report a multi-enzymatic complex that reprograms NAD metabolism by transferring reducing equivalents from NADH to NADP. This hydride transfer complex (HTC) is assembled by malate dehydrogenase 1, malic enzyme 1, and cytosolic pyruvate carboxylase. HTC is found in phase-separated bodies in the cytosol of cancer or hypoxic cells and can be assembled in vitro with recombinant proteins. HTC is repressed in senescent cells but induced by p53 inactivation. HTC enzymes are highly expressed in mouse and human prostate cancer models, and their inactivation triggers senescence. Exogenous expression of HTC is sufficient to bypass senescence, rescue cells from complex I inhibitors, and cooperate with oncogenic RAS to transform primary cells. Altogether, we provide evidence for a new multi-enzymatic complex that reprograms metabolism and overcomes cellular senescence.
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http://dx.doi.org/10.1016/j.molcel.2021.08.028DOI Listing
September 2021

Association of Adiponectin and Vitamin D With Tumor Infiltrating Lymphocytes and Survival in Stage III Colon Cancer.

JNCI Cancer Spectr 2021 Oct 23;5(5):pkab070. Epub 2021 Jul 23.

Division of Oncology and Mayo Clinic Comprehensive Cancer Center, Rochester, MN, USA.

Background: Adipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival.

Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided.

Results: We found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median=6845 vs 8984 ng/mL; = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index >30 kg/m) vs nonobese patients (median=6608 vs 12 351 ng/mL;  < .001), in men vs women (median=8185 vs 11 567 ng/mL;  < .001), in Blacks vs Whites or Asians (median=6412 vs 8847 vs 7858 ng/mL;  < .03), and in those with fewer lymph node metastases (N1 vs N2: median=7768 vs 9253 ng/mL;  = .01). Insufficiency of 25(OH)D (<30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS.

Conclusions: Lower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.
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http://dx.doi.org/10.1093/jncics/pkab070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410141PMC
October 2021

Pre- and Postoperative Circulating IGF-I, IGFBP-3, and IGFBP-7 Levels in Relation to Endocrine Treatment and Breast Cancer Recurrence: A Nested Case-Control Study.

Front Oncol 2021 9;11:626058. Epub 2021 Mar 9.

Department of Clinical Sciences Lund, Oncology, Lund University and Skåne University Hospital, Lund, Sweden.

Insulin-like growth factor-I (IGF-I) and its binding proteins (BPs) have been associated with breast cancer risk, especially high IGF-I concentrations and the biologically active fraction estimated as the IGF-I/IGFBP-3 molar ratio. The relation of circulating IGF-I and IGFBP-3 concentrations with risk of breast cancer recurrence has been less documented. In addition a new member to a sub-group of the IGFBP-superfamily was recently identified, the low affinity IGFBP-7. To date, the role of systemic IGFBP-7 in breast cancer progression has not been investigated. Our purpose was to establish whether circulating IGF-I, IGFBP-3, and IGFBP-7 levels are related to recurrence-risk in breast cancer. A case-control study was nested within the population-based BCBlood cohort of 853 breast cancer patients diagnosed 2002-2010 in Sweden and followed through 2012. In total, 95 patients with recurrence and 170 controls were matched on age and tumor characteristics. Plasma IGF analytes and tumor membrane IGF-I receptor (IGF-IR) positivity were analyzed and recurrence-risk was evaluated with conditional logistic regression. Preoperative tertiles of IGF-I and IGFBP-3 were both positively associated with recurrence-risk, but not IGFBP-7. The trend was of borderline significance for IGF-I, T1:REF, T2 OR:1.6, T3 OR: 2.2 adjusted =0.057 and significant for IGFBP-3 T1:REF, T2 OR:1.2, T3 OR: 2.1 adjusted =0.042. The models were adjusted for age, anthropometric factors, smoking, and treatments. There was a significant interaction between IGFBP-7 and IGF-IR positivity on recurrence, where the highest IGFBP-7 highest IGFBP-7 tertile conferred increased recurrence-risk in patients with IGF-IR positive tumors but not in those with IGF-IR negative tumors ( =0.024). By the 1-year visit, age-adjusted IGF-I levels were reduced by 17% while IGFBP-3 and IGFBP-7 were stable. IGF-I levels were significantly reduced by radiotherapy in all patients and by tamoxifen in patients with ER tumors. Postoperative changes >10% (n=208) in IGF-I, IGFBP-3, IGFBP-7, or the IGF-I/IGFBP-3 ratio did not predict recurrence after adjustment for preoperative levels, age, anthropometric factors, smoking, and treatments. In conclusion, this study suggests that preoperative IGF-I and IGFBP-3 levels, but not postoperative changes, might provide independent prognostic information and influence breast cancer recurrence. The role of IGFBP-7 in breast cancer merits further study.
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http://dx.doi.org/10.3389/fonc.2021.626058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986849PMC
March 2021

Pilot Study Assessing Tolerability and Metabolic Effects of Metformin in Patients With Li-Fraumeni Syndrome.

JNCI Cancer Spectr 2020 Dec 18;4(6):pkaa063. Epub 2020 Jul 18.

Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.

Background: Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for cancer cell proliferation and decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction for cancer in patients with LFS, but its safety in nondiabetic patients with germline pathogenic variants has not been documented.

Methods: This study assessed safety and tolerability of metformin in nondiabetic LFS patients and measured changes in metabolic profiles. Adult patients with LFS and germline variant received 14 weeks of metformin. Blood samples were obtained for measurement of serum insulin-like growth factor-1, insulin, and insulin-like growth factor binding protein 3. Hepatic mitochondrial function was assessed with fasting exhaled CO after ingestion of C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided.

Results: We enrolled 26 participants: 20 females and 6 males. The most common adverse events were diarrhea (50.0%) and nausea (46.2%). Lactic acidosis did not occur, and there were no changes in fasting glucose. Cumulative mean C exhalation was statistically significantly suppressed by metformin ( = .001). Mean levels of insulin-like growth factor binding protein 3 and insulin-like growth factor-1 were statistically significantly lowered ( = .02). Lipid metabolites and branched-chain amino acids accumulated.

Conclusions: Metformin was safe and tolerable in patients with LFS. It suppressed hepatic mitochondrial function as expected in these individuals. This study adds to the rationale for development of a pharmacologic risk-reduction clinical trial of metformin in LFS.
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http://dx.doi.org/10.1093/jncics/pkaa063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746650PMC
December 2020

IGF-Binding Proteins, Adiponectin, and Survival in Metastatic Colorectal Cancer: Results From CALGB (Alliance)/SWOG 80405.

JNCI Cancer Spectr 2021 Feb 27;5(1):pkaa074. Epub 2020 Aug 27.

Department of Medical Oncology, Dana-Farber/Partners CancerCare, Boston, MA, USA.

Background: Energy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.

Methods: Baseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute-sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). values are 2-sided.

Results: Median follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS ( = .03).

Conclusions: Among patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.
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http://dx.doi.org/10.1093/jncics/pkaa074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785047PMC
February 2021

Effect of Exercise or Metformin on Biomarkers of Inflammation in Breast and Colorectal Cancer: A Randomized Trial.

Cancer Prev Res (Phila) 2020 12 28;13(12):1055-1062. Epub 2020 Aug 28.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Observational studies report that physical activity and metformin are associated with improved clinical outcome in patients with cancer. Inflammation is one biological mechanism hypothesized to mediate these associations. In this phase II, multicenter, 2 × 2 factorial trial, 139 patients with breast and colorectal cancer who completed standard therapy were randomized to one of four treatment groups for 12 weeks: exercise alone, metformin alone, exercise and metformin, or control. Inflammation outcomes included high-sensitivity C-reactive protein (hs-CRP), soluble tumor necrosis factor alpha receptor two (sTNFαR2), and IL6. The primary modeling strategy evaluated the trial product estimand that was quantified using a generalized linear mixed model. Compared with control, exercise alone reduced hs-CRP [-30.2%; 95% confidence interval (CI), -50.3, -1.0] and IL6 (-30.9%; 95% CI, -47.3, -9.5) but did not change sTNFαR2 (1.0%; 95% CI, -10.4, 13.9). Compared with control, metformin alone did not change hs-CRP (-13.9%; 95% CI, -40.0, 23.4), sTNFαR2 (-10.4%; 95% CI, -21.3, 2.0), or IL6 (-22.9%; 95% CI, -42.3, 2.0). Compared with control, exercise and metformin reduced sTNFαR2 (-13.1%; 95% CI, -22.9, -1.0) and IL6 (-38.7%; 95% CI, -52.3, -18.9) but did not change hs-CRP (-20.5%; 95% CI, -44.0, 12.7). The combination of exercise and metformin was not synergistic for hs-CRP, sTNFαR2, or IL6. In survivors of breast and colorectal cancer with low baseline physical activity and without type 2 diabetes, exercise and metformin reduced measures of inflammation that are associated with cancer recurrence and mortality.
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http://dx.doi.org/10.1158/1940-6207.CAPR-20-0188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718298PMC
December 2020

Repression of LKB1 by Sensitizes -Dependent Lymphoma to Biguanide Treatment.

Cell Rep Med 2020 May 19;1(2):100014. Epub 2020 May 19.

Goodman Cancer Research Centre, McGill University, Montreal, QC H3A 1A3, Canada.

Cancer cells display metabolic plasticity to survive stresses in the tumor microenvironment. Cellular adaptation to energetic stress is coordinated in part by signaling through the liver kinase B1 (LKB1)-AMP-activated protein kinase (AMPK) pathway. Here, we demonstrate that miRNA-mediated silencing of LKB1 confers sensitivity of lymphoma cells to mitochondrial inhibition by biguanides. Using both classic (phenformin) and newly developed (IM156) biguanides, we demonstrate that elevated expression in lymphoma cells promotes increased apoptosis to biguanide treatment and . This effect is driven by the -dependent silencing of LKB1, which reduces AMPK activation in response to complex I inhibition. Mechanistically, biguanide treatment induces metabolic stress in lymphoma cells by inhibiting TCA cycle metabolism and mitochondrial respiration, exposing metabolic vulnerability. Finally, we demonstrate a direct correlation between expression and biguanide sensitivity in human cancer cells. Our results identify expression as a potential biomarker for biguanide sensitivity in malignancies.
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http://dx.doi.org/10.1016/j.xcrm.2020.100014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249503PMC
May 2020

Plasma Biomarkers of Insulin and the Insulin-like Growth Factor Axis, and Risk of Colorectal Adenoma and Serrated Polyp.

JNCI Cancer Spectr 2019 Sep 1;3(3):pkz056. Epub 2019 Aug 1.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA.

Background: Hyperinsulinemia, high insulin-like growth factor 1 (IGF1) levels, and low IGF binding protein 1 (IGFBP1) levels have been implicated in the relationship between obesity and increased risk of colorectal cancer (CRC). However, it remains inconclusive whether circulating biomarkers of insulin and the IGF axis are associated with conventional adenoma and serrated polyp, the two distinct groups of CRC precursors.

Methods: We prospectively examined the associations of plasma C-peptide, IGF1, IGFBP1, IGFBP3, and IGF1 to IGFBP3 ratio with conventional adenoma and serrated polyp among 11 072 women from the Nurses' Health Studies. Multivariable logistic regression was used to calculate the odds ratio (OR) per 1-SD increase in each biomarker for overall risk of conventional adenoma and serrated polyp and according to polyp feature.

Results: During 20 years of follow-up, we documented 1234 conventional adenomas and 914 serrated polyps. After adjusting for various lifestyle factors (including body mass index), higher concentrations of IGFBP1 were associated with lower risk of serrated polyp (OR = 0.84, 95% confidence interval = 0.75 to 0.95, =.005). The association was particularly strong for large serrated polyp (≥10 mm) located in the distal colon and rectum (OR = 0.59, 95% confidence interval = 0.39 to 0.87, =.01). In contrast, we did not find any statistically significant association between the biomarkers and conventional adenoma.

Conclusions: A higher plasma level of IGFBP1 was associated with lower risk of serrated polyp. Our findings support a potential role of IGFBP1 in the serrated pathway of CRC in women.
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http://dx.doi.org/10.1093/jncics/pkz056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050032PMC
September 2019

Genetic and Circulating Biomarker Data Improve Risk Prediction for Pancreatic Cancer in the General Population.

Cancer Epidemiol Biomarkers Prev 2020 05 22;29(5):999-1008. Epub 2020 Apr 22.

Program in Genetic Epidemiology and Statistical Genetics, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Pancreatic cancer is the third leading cause of cancer death in the United States, and 80% of patients present with advanced, incurable disease. Risk markers for pancreatic cancer have been characterized, but combined models are not used clinically to identify individuals at high risk for the disease.

Methods: Within a nested case-control study of 500 pancreatic cancer cases diagnosed after blood collection and 1,091 matched controls enrolled in four U.S. prospective cohorts, we characterized absolute risk models that included clinical factors (e.g., body mass index, history of diabetes), germline genetic polymorphisms, and circulating biomarkers.

Results: Model discrimination showed an area under ROC curve of 0.62 via cross-validation. Our final integrated model identified 3.7% of men and 2.6% of women who had at least 3 times greater than average risk in the ensuing 10 years. Individuals within the top risk percentile had a 4% risk of developing pancreatic cancer by age 80 years and 2% 10-year risk at age 70 years.

Conclusions: Risk models that include established clinical, genetic, and circulating factors improved disease discrimination over models using clinical factors alone.

Impact: Absolute risk models for pancreatic cancer may help identify individuals in the general population appropriate for disease interception.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020898PMC
May 2020

Cancer Immunoprevention: A Case Report Raising the Possibility of "Immuno-interception".

Cancer Prev Res (Phila) 2020 04;13(4):351-356

Cancer Prevention Centre, Jewish General Hospital, Montreal, Quebec, Canada.

Immune checkpoint blockade therapy provides substantial benefits for subsets of patients with advanced cancer, but its utility for cancer prevention is unknown. Lynch syndrome (MIM 120435) is characterized by defective DNA mismatch repair and predisposition to multiple cancers. A variant of Lynch syndrome, Muir-Torre syndrome (MIM 158320), is characterized by frequent gastrointestinal tumors and hyperplastic or neoplastic skin tumors. We report the case of a man with Muir-Torre syndrome who had 136 cutaneous or visceral hyperplastic or neoplastic lesions over a period of 19 years (mean 7.5 neoplasms/year, range 2-26) prior to receiving pembrolizumab immunotherapy as part of multi-modality treatment for invasive bladder cancer. He not only had a complete response of the bladder cancer, but also was noted to have an absence of new cancers during a 22-month follow-up period. This case adds to the rationale for exploring the utility of immune checkpoint blockade for cancer prevention, particularly for patients with DNA repair deficits.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0528DOI Listing
April 2020

Prospective Association of Energy Balance Scores Based on Metabolic Biomarkers with Colorectal Cancer Risk.

Cancer Epidemiol Biomarkers Prev 2020 05 24;29(5):974-981. Epub 2020 Feb 24.

Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.

Background: Energy balance-related factors, such as body mass index (BMI), diet, and physical activity, may influence colorectal cancer etiology through interconnected metabolic pathways, but their combined influence is less clear.

Methods: We used reduced rank regression to derive three energy balance scores that associate lifestyle factors with combinations of prediagnostic, circulating levels of high-sensitivity C-reactive protein (hsCRP), C-peptide, and hemoglobin A (HbA) among 2,498 participants in the Cancer Prevention Study-II Nutrition Cohort. Among 114,989 participants, we verified 2,228 colorectal cancer cases. We assessed associations of each score with colorectal cancer incidence and by tumor molecular phenotypes using Cox proportional hazards regression.

Results: The derived scores comprised BMI, physical activity, screen time, and 14 food groups, and explained 5.1% to 10.5% of the variation in biomarkers. The HR and 95% confidence interval (CI) for quartile 4 versus 1 of the HbA+C peptide-based score and colorectal cancer was 1.30 (1.15-1.47), the hsCRP-based score was 1.35 (1.19-1.53), and the hsCRP, C-peptide, and HbA-based score was 1.35 (1.19-1.52). The latter score was associated with non-CIMP tumors (HR: 1.59; 95% CI: 1.17-2.16), but not CIMP-positive tumors ( = 0.04).

Conclusions: These results further support hypotheses that systemic biomarkers of metabolic health-inflammation and abnormal glucose homeostasis-mediate part of the relationship between several energy balance-related modifiable factors and colorectal cancer risk.

Impact: Results support cancer prevention guidelines for maintaining a healthful body weight, consuming a healthful diet, and being physically active. More research is needed on these clusters of exposures with molecular phenotypes of tumors.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1382DOI Listing
May 2020

Transcriptomic analysis of human primary breast cancer identifies fatty acid oxidation as a target for metformin.

Br J Cancer 2020 01 10;122(2):258-265. Epub 2019 Dec 10.

Department of Oncology, University of Oxford, Churchill Hospital, Oxford, OX3 7LE, UK.

Background: Epidemiological studies suggest that metformin may reduce the incidence of cancer in patients with diabetes and multiple late phase clinical trials assessing the potential of repurposing this drug are underway. Transcriptomic profiling of tumour samples is an excellent tool to understand drug bioactivity, identify candidate biomarkers and assess for mechanisms of resistance to therapy.

Methods: Thirty-six patients with untreated primary breast cancer were recruited to a window study and transcriptomic profiling of tumour samples carried out before and after metformin treatment.

Results: Multiple genes that regulate fatty acid oxidation were upregulated at the transcriptomic level and there was a differential change in expression between two previously identified cohorts of patients with distinct metabolic responses. Increase in expression of a mitochondrial fatty oxidation gene composite signature correlated with change in a proliferation gene signature. In vitro assays showed that, in contrast to previous studies in models of normal cells, metformin reduces fatty acid oxidation with a subsequent accumulation of intracellular triglyceride, independent of AMPK activation.

Conclusions: We propose that metformin at clinical doses targets fatty acid oxidation in cancer cells with implications for patient selection and drug combinations.

Clinical Trial Registration: NCT01266486.
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http://dx.doi.org/10.1038/s41416-019-0665-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986920PMC
January 2020

A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction among Individuals with History of Colorectal Adenomas and Elevated Body Mass Index.

Cancer Prev Res (Phila) 2020 02 9;13(2):203-212. Epub 2019 Dec 9.

Department of Medicine, University of California, Irvine, California.

Obesity is associated with risk of colorectal adenoma (CRA) and colorectal cancer. The signaling pathway activated by metformin (LKB1/AMPK/mTOR) is implicated in tumor suppression in Apc mice via metformin-induced reduction in polyp burden, increased ratio of pAMPK/AMPK, decreased pmTOR/mTOR ratio, and decreased pS6/S6 ratio in polyps. We hypothesized that metformin would affect colorectal tissue S6 among obese patients with recent history of CRA. A phase IIa clinical biomarker trial was conducted via the U.S. National Cancer Institute-Chemoprevention Consortium. Nondiabetic, obese subjects (BMI ≥30) ages 35 to 80 with recent history of CRA were included. Subjects received 12 weeks of oral metformin 1,000 mg twice every day. Rectal mucosa biopsies were obtained at baseline and end-of-treatment (EOT) endoscopy. Tissue S6 and Ki-67 immunostaining were analyzed in a blinded fashion using Histo score (Hscore) analysis. Among 32 eligible subjects, the mean baseline BMI was 34.9. Comparing EOT to baseline tissue S6 by IHC, no significant differences were observed. Mean (SD) Hscore at baseline was 1.1 (0.57) and 1.1 (0.51) at EOT; median Hscore change was 0.034 ( = 0.77). Similarly, Ki-67 levels were unaffected by the intervention. The adverse events were consistent with metformin's known side-effect profile. Among obese patients with CRA, 12 weeks of oral metformin does not reduce rectal mucosa pS6 or Ki-67 levels. Further research is needed to determine what effects metformin has on the target tissue of origin as metformin continues to be pursued as a colorectal cancer chemopreventive agent.
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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025666PMC
February 2020

Study protocol of a phase II clinical trial of oral metformin for the intravesical treatment of non-muscle invasive bladder cancer.

BMC Cancer 2019 Nov 21;19(1):1133. Epub 2019 Nov 21.

Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.

Background: Non-muscle-invasive bladder cancer (NMIBC) is the most common neoplasm of the urinary tract and requires life-long invasive surveillance to detect disease recurrence. Currently, there are no effective oral therapies that delay disease recurrence or progression. We recently demonstrated that in mice, metformin accumulates unchanged in the urine. Urothelial cells are exposed to metformin concentrations ~ 240-fold higher than in serum. This was effective in the treatment of mouse bladder cancer models.

Methods: We describe the protocol of a multi-centre, open-label, phase II clinical trial of metformin in up to 49 evaluable patients with intermediate-risk NMIBC with the aim to determine the overall response to administration of oral metformin for 3 months on a marker tumour deliberately left following transurethral resection of multiple, papillary NMIBC tumours. All patients will receive metformin orally at doses up to 3000 mg per day. Metformin treatment will start within 2 weeks following transurethral resection of all tumours except one marker lesion. After 3 months of metformin treatment, the effect of metformin on the marker lesion is evaluated by cystoscopy and biopsy under anaesthesia. Residual tumour, if present at this evaluation, will be resected. In case of complete disappearance of the marker lesion, the former tumour area will be biopsied. The primary outcome is the complete response rate of the marker lesion, as determined by decentralised scoring of pre- and post-treatment cystoscopy images by expert independent urologists. Secondary outcomes are the partial response rate, overall safety of metformin and the duration of the time to recurrence.

Discussion: Preclinical studies show the potential role of oral metformin treatment in the management of NMIBC. It could offer an alternative to current adjuvant intravesical treatment. If positive, the reported results of this study could warrant further phase III trials to compare the efficacy of metformin against current treatments of intravesical installations with chemotherapy or Bacillus Calmette-Guérin (BCG).

Trial Registration: This trial is registered in ClinicalTrials.gov under NCT03379909.
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http://dx.doi.org/10.1186/s12885-019-6346-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873510PMC
November 2019

Cancer Prevention: A Message from the New Editors-in-Chief.

Cancer Prev Res (Phila) 2019 01 27;12(1):1-2. Epub 2018 Dec 27.

Department of Oncology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.

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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0349DOI Listing
January 2019

A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup.

Geroscience 2018 12 27;40(5-6):419-436. Epub 2018 Aug 27.

UConn Center on Aging, University of Connecticut School of Medicine, Farmington, CT, 06030, USA.

Recent advances indicate that biological aging is a potentially modifiable driver of late-life function and chronic disease and have led to the development of geroscience-guided therapeutic trials such as TAME (Targeting Aging with MEtformin). TAME is a proposed randomized clinical trial using metformin to affect molecular aging pathways to slow the incidence of age-related multi-morbidity and functional decline. In trials focusing on clinical end-points (e.g., disease diagnosis or death), biomarkers help show that the intervention is affecting the underlying aging biology before sufficient clinical events have accumulated to test the study hypothesis. Since there is no standard set of biomarkers of aging for clinical trials, an expert panel was convened and comprehensive literature reviews conducted to identify 258 initial candidate biomarkers of aging and age-related disease. Next selection criteria were derived and applied to refine this set emphasizing: (1) measurement reliability and feasibility; (2) relevance to aging; (3) robust and consistent ability to predict all-cause mortality, clinical and functional outcomes; and (4) responsiveness to intervention. Application of these selection criteria to the current literature resulted in a short list of blood-based biomarkers proposed for TAME: IL-6, TNFα-receptor I or II, CRP, GDF15, insulin, IGF1, cystatin C, NT-proBNP, and hemoglobin A1c. The present report provides a conceptual framework for the selection of blood-based biomarkers for use in geroscience-guided clinical trials. This work also revealed the scarcity of well-vetted biomarkers for human studies that reflect underlying biologic aging hallmarks, and the need to leverage proposed trials for future biomarker discovery and validation.
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http://dx.doi.org/10.1007/s11357-018-0042-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294728PMC
December 2018

Simultaneous Extraction of RNA and Metabolites from Single Kidney Tissue Specimens for Combined Transcriptomic and Metabolomic Profiling.

J Proteome Res 2018 09 23;17(9):3039-3049. Epub 2018 Aug 23.

Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology , Stuttgart , Germany and University of Tübingen, Tübingen, Germany.

Tissue analysis represents a powerful tool for the investigation of disease pathophysiology. However, the heterogeneous nature of tissue samples, in particular of neoplastic, may affect the outcome of such analysis and hence obscure interpretation of results. Thus, comprehensive isolation and extraction of transcripts and metabolites from an identical tissue specimen would minimize variations and enable the economic use of biopsy material which is usually available in limited amounts. Here we demonstrate a fast and simple protocol for combined transcriptomics and metabolomics analysis in homogenates prepared from one single tissue sample. Metabolites were recovered by protein precipitation from lysates originally prepared for RNA isolation and were analyzed by LC-QTOF-MS after HILIC and RPLC separation, respectively. Strikingly, although ion suppression was observed, over 80% of the 2885 detected metabolic features could be extracted and analyzed with high reproducibility (CV ≤ 20%). Moreover fold changes of different tumor and nontumor kidney tissues were correlated to an established metabolomics protocol and revealed a strong correlation ( r ≥ 0.75). In order to demonstrate the feasibility of the combined analysis of RNA and metabolites, the protocol was applied to kidney tissue of metformin treated mice to investigate drug induced alterations.
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http://dx.doi.org/10.1021/acs.jproteome.8b00199DOI Listing
September 2018

Uncoupling Hepatic Oxidative Phosphorylation Reduces Tumor Growth in Two Murine Models of Colon Cancer.

Cell Rep 2018 07;24(1):47-55

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address:

Obesity is associated with colon cancer pathogenesis, but the underlying mechanism is actively debated. Here, we confirm that diet-induced obesity promotes tumor growth in two murine colon cancer models and show that this effect is reversed by an orally administered controlled-release mitochondrial protonophore (CRMP) that acts as a liver-specific uncoupler of oxidative phosphorylation. This agent lowered circulating insulin, and the reduction of tumor growth was abrogated by an insulin infusion raising plasma insulin to the level of high-fat-fed mice. We also demonstrate that hyperinsulinemia increases glucose uptake and oxidation in vivo in tumors and that CRMP reverses these effects. This study provides evidence that perturbations of whole-organism energy balance or hepatic energy metabolism can influence neoplastic growth. Furthermore, the data show that glucose uptake and utilization by cancers in vivo are not necessarily constitutively high but rather may vary according to the hormonal milieu.
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http://dx.doi.org/10.1016/j.celrep.2018.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056247PMC
July 2018

Incretin-based Drugs and the Incidence of Colorectal Cancer in Patients with Type 2 Diabetes.

Epidemiology 2018 03;29(2):246-253

Background: Evidence on the safety of the incretin-based drugs (glucagon-like peptide-1 [GLP-1] analogues and dipeptidyl peptidase-4 [DPP-4] inhibitors) with respect to colorectal cancer is contradictory. The objective of this study was to determine whether use of incretin-based drugs is associated with risk of incident colorectal cancer in patients with type 2 diabetes.

Methods: Using data from the UK Clinical Practice Research Datalink, we identified a cohort of 112,040 patients newly treated with antidiabetic drugs between 1 January 2007 and 31 March 2015. We modeled use of GLP-1 analogues and DPP-4 inhibitors as time-varying variables and compared them with use of sulfonylureas. We lagged exposures by 1 year for latency and to reduce reverse causality and detection bias. We used time-dependent Cox proportional hazards models to estimate hazard ratios with 95% confidence intervals of incident colorectal cancer associated with the use of GLP-1 analogues and DPP-4 inhibitors overall, by cumulative duration of use and by time since initiation.

Results: During 388,619 person-years of follow-up, there were 733 incident colorectal cancer events (incidence rate: 1.9 per 1,000 person-years). Use of GLP-1 analogues was not associated with colorectal cancer incidence (hazard ratio: 1.0; 95% confidence interval = 0.7, 1.6), nor was use of DPP-4 inhibitors (hazard ratio: 1.2; 95% confidence interval = 1.0, 1.5). There was no evidence of a duration-response relation for either drug.

Conclusions: The results of this large population-based study indicate that use of incretin-based drugs is not associated with colorectal cancer incidence among patients with type 2 diabetes.
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http://dx.doi.org/10.1097/EDE.0000000000000793DOI Listing
March 2018

Effects of Rapid Weight Loss on Systemic and Adipose Tissue Inflammation and Metabolism in Obese Postmenopausal Women.

J Endocr Soc 2017 Jun 25;1(6):625-637. Epub 2017 Apr 25.

Department of Medicine, Weill Cornell Medical College, New York, New York 10065.

Context: Obesity is associated with subclinical white adipose tissue inflammation, as defined by the presence of crown-like structures (CLSs) consisting of dead or dying adipocytes encircled by macrophages. In humans, bariatric surgery-induced weight loss leads to a decrease in CLSs, but the effects of rapid diet-induced weight loss on CLSs and metabolism are unclear.

Objective: To determine the effects of rapid very-low-calorie diet-induced weight loss on CLS density, systemic biomarkers of inflammation, and metabolism in obese postmenopausal women.

Design: Prospective cohort study.

Setting: Rockefeller University Hospital, New York, NY.

Participants: Ten obese, postmenopausal women with a mean age of 60.6 years (standard deviation, ±3.6 years).

Main Outcome Measures: Effects on CLS density and gene expression in abdominal subcutaneous adipose tissue, cardiometabolic risk factors, white blood count, circulating metabolites, and oxidative stress (urinary isoprostane-M) were measured.

Results: Obese subjects lost approximately 10% body weight over a mean of 46 days. CLS density increased in subcutaneous adipose tissue without an associated increase in proinflammatory gene expression. Weight loss was accompanied by decreased fasting blood levels of high-sensitivity C-reactive protein, glucose, lactate, and kynurenine, and increased circulating levels of free fatty acids, glycerol, -hydroxybutyrate, and 25 hydroxyvitamin D. Levels of urinary isoprostane-M declined.

Conclusion: Rapid weight loss stimulated lipolysis and an increase in CLS density in subcutaneous adipose tissue in association with changes in levels of circulating metabolites, and improved systemic biomarkers of inflammation and insulin resistance. The observed change in levels of metabolites (, lactate, -hydroxybutyrate, 25 hydroxyvitamin D) may contribute to the anti-inflammatory effect of rapid weight loss.
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http://dx.doi.org/10.1210/js.2017-00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5686624PMC
June 2017

Menstrual cycle characteristics and steroid hormone, prolactin, and growth factor levels in premenopausal women.

Cancer Causes Control 2017 Dec 31;28(12):1441-1452. Epub 2017 Oct 31.

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA.

Purpose: Menstrual cycle characteristics are markers of endocrine milieu. However, associations between age at menarche and adulthood sex steroid hormone levels have been inconsistent, and data on menstrual characteristics and non-sex steroid hormones are sparse.

Methods: We assessed the relations of menstrual characteristics with premenopausal plasma sex steroid hormones, sex hormone binding globulin (SHBG), prolactin, and growth factors among 2,745 premenopausal women (age 32-52) from the Nurses' Health Study II. Geometric means and tests for trend were calculated using multivariable general linear models.

Results: Early age at menarche was associated with higher premenopausal early-follicular free estradiol (percent difference < 12 vs. > 13 years = 11%), early-follicular estrone (7%), luteal estrone (7%), and free testosterone (8%) (all p  < 0.05). Short menstrual cycle length at age 18-22 was associated with higher early-follicular total (< 26 vs. > 39 days = 18%) and free estradiol (16%), early-follicular estrone (9%), SHBG (7%), lower luteal free estradiol (- 14%), total (- 6%), and free testosterone (- 15%) (all p  < 0.05). Short adult menstrual length was associated with higher early-follicular total estradiol (< 26 vs. > 31 days = 14%), SHBG (10%), lower luteal estrone (- 8%), progesterone (- 9%), total (- 11%) and free testosterone (- 25%), and androstenedione (- 14%) (all p  < 0.05). Irregularity of menses at 18-22 was associated with lower early-follicular total (irregular vs. very regular = - 14%) and free estradiol (- 14%), and early-follicular estrone (- 8%) (All p  < 0.05). Irregularity of adult menstrual cycle was associated with lower luteal total estradiol (irregular vs. very regular = - 8%), SHBG (- 3%), higher total (8%), and free testosterone (11%) (all p  < 0.05).

Conclusions: Early-life and adulthood menstrual characteristics are moderately associated with mid-to-late reproductive year's hormone concentrations. These relations of menstrual characteristics with endogenous hormone levels could partially account for associations between menstrual characteristics and reproductive cancers or other chronic diseases.
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http://dx.doi.org/10.1007/s10552-017-0971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5718047PMC
December 2017

Trajectories of IGF-I Predict Mortality in Older Adults: The Cardiovascular Health Study.

J Gerontol A Biol Sci Med Sci 2018 06;73(7):953-959

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia.

Background: Disruption of insulin-like growth factor-I (IGF-I) increases health and life span in animal models, though this is unconfirmed in humans. If IGF-I stability indicates homeostasis, the absolute level of IGF-I may be less clinically relevant than maintaining an IGF-I setpoint.

Methods: Participants were 945 U.S. community-dwelling individuals aged ≥65 years enrolled in the Cardiovascular Health Study with IGF-I levels at 3-6 timepoints. We examined the association of baseline IGF-I level, trajectory slope, and variability around the trajectory with mortality.

Results: There were 633 deaths over median 11.3 years of follow-up. Lower IGF-I levels, declining or increasing slope, and increasing variability were each individually associated with higher mortality (all p < .001). In an adjusted model including all three trajectory parameters, baseline IGF-I levels <70 ng/mL (hazard ratio [HR] 1.58, 95% CI 1.28-1.96 relative to IGF-I levels of 170 ng/mL), steep declines and steep increases in trajectory slope (HR 2.22, 1.30-3.80 for a 15% decline; HR 1.40, 1.07-1.84 for a 10% decline; HR 1.80, 1.12-2.89 for a 15% increase; HR 1.31, 1.00-1.72 for a 10% increase, each vs no change), and variability ≥10% (HR 1.59, 1.09-2.32 for ≥ 30%; HR 1.36, 1.06-1.75 for 20%; and HR 1.17, 1.03-1.32 for 10% variability, each vs 0%) in IGF-I levels were independently associated with mortality.

Conclusions: In contrast to data from animal models, low IGF-I levels are associated with higher mortality in older humans. Irrespective of the actual IGF-I level, older individuals with stability of IGF-I levels have lower mortality than those whose IGF-I levels fluctuate over time.
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http://dx.doi.org/10.1093/gerona/glx143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001890PMC
June 2018

Circulating resistin levels and risk of multiple myeloma in three prospective cohorts.

Br J Cancer 2017 Oct 22;117(8):1241-1245. Epub 2017 Aug 22.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Background: Resistin is a polypeptide hormone secreted by adipose tissue. A prior hospital-based case-control study reported serum resistin levels to be inversely associated with risk of multiple myeloma (MM). To date, this association has not been investigated prospectively.

Methods: We measured resistin concentrations for pre-diagnosis peripheral blood samples from 178 MM cases and 358 individually matched controls from three cohorts participating in the MM cohort consortium.

Results: In overall analyses, higher resistin levels were weakly associated with reduced MM risk. For men, we observed a statistically significant inverse association between resistin levels and MM (odds ratio, 0.44; 95% confidence interval (CI) 0.24-0.83 and 0.54; 95% CI 0.29-0.99, for the third and fourth quartiles, respectively, vs the lowest quartile; P=0.03). No association was observed for women.

Conclusions: This study provides the first prospective evidence that low circulating resistin levels may be associated with an increased risk of MM, particularly for men.
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http://dx.doi.org/10.1038/bjc.2017.282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5674102PMC
October 2017

Circulating Adiponectin Levels Differ Between Patients with Multiple Myeloma and its Precursor Disease.

Obesity (Silver Spring) 2017 08 11;25(8):1317-1320. Epub 2017 Jun 11.

Myeloma Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Objective: An increased risk of multiple myeloma (MM) has been observed among individuals with low prediagnostic circulating levels of adiponectin, a metabolic hormone that is typically underexpressed among those with overweight or obesity. To assess whether adiponectin may influence myeloma development or progression to frank MM, circulating adiponectin levels were compared across patients with different stages of MM and its precursor, monoclonal gammopathy of undetermined significance (MGUS).

Methods: Adiponectin was measured in 213 patients with MGUS, smoldering MM, or fully developed MM. Differences in adiponectin levels across patient groups were assessed using multivariate linear regression.

Results: Relative to MGUS patients, adiponectin levels were statistically significantly lower among those with smoldering and fully developed MM, both overall (16%-20% decrease; P = 0.048) and among those with IgG/IgA isotypes (26%-28% decrease; P = 0.004). Among MGUS patients, adiponectin levels were significantly lower for those with the higher-risk IgM isotype compared with those who had IgG/IgA isotypes (42% decrease; P = 0.036).

Conclusions: The findings of this study, the largest to investigate adiponectin levels in patients with different stages of MM and the first to evaluate associations with clinical characteristics, suggest that reduced expression of adiponectin may be associated with progression from MGUS to MM.
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http://dx.doi.org/10.1002/oby.21894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611818PMC
August 2017

Circulating levels of obesity-related markers and risk of renal cell carcinoma in the PLCO cancer screening trial.

Cancer Causes Control 2017 Jul 8;28(7):801-807. Epub 2017 May 8.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, 9609 Medical Center Drive, Bethesda, MD, 20892, USA.

Purpose: Obesity is an established risk factor for renal cell carcinoma (RCC). It is unclear what biologic mechanisms underlie this association, although recent evidence suggests that the effects of circulating hormones such as insulin-like growth factors (IGF) and adipokines may play a role.

Methods: To address this question, we conducted a nested case-control study of RCC (252 cases, 252 controls) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial investigating associations with pre-diagnostic serum levels of total adiponectin, high-molecular-weight (HMW) adiponectin, IGF-1, IGF-binding protein-3 (IGFBP-3), and C-peptide. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were estimated using conditional logistic regression.

Results: After adjustment for potential confounders, non-significant associations with RCC were observed for total adiponectin (OR for highest vs. lowest quartile = 0.65, 95% CI 0.37-1.14; p  = 0.35), HMW adiponectin (0.67, 0.38-1.17; p  = 0.36), IGF-1 (1.35, 0.77-2.39; p  = 0.17), IGFBP-3 (1.47, 0.83-2.62; p  = 0.53), and C-peptide (1.52, 0.86-2.70; p  = 0.15). In a joint analysis with body mass index (BMI, kg/m), obese individuals (BMI ≥30) with above-median levels of IGFBP-3 had a significantly higher risk versus those with BMI <25 and below-median IGFBP-3 (OR 2.42, 1.11-5.26), whereas obese individuals with low IGFBP-3 did not (1.18, 0.53-2.64) (p  = 0.35).

Conclusions: The results of this study, while not clearly supporting associations with these obesity-related hormones, suggest that the association between obesity and RCC may be partially modified through mechanisms related to elevated IGFBP-3.
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http://dx.doi.org/10.1007/s10552-017-0901-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535804PMC
July 2017

Cancer, obesity, and diabetes: TKIs exert multiple effects on glucose homeostasis.

Authors:
Michael N Pollak

Nat Rev Clin Oncol 2017 05 19;14(5):268. Epub 2017 Apr 19.

Departments of Oncology and Medicine, McGill University, and the Segal Cancer Centre, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montreal, Quebec H3T 1E2, Canada.

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http://dx.doi.org/10.1038/nrclinonc.2017.57DOI Listing
May 2017

Cancer, obesity, diabetes, and antidiabetic drugs: is the fog clearing?

Nat Rev Clin Oncol 2017 02 9;14(2):85-99. Epub 2016 Aug 9.

Departments of Oncology and Medicine, McGill University, McIntyre Medical Building, 3655 Sir William Osler, Montreal, Quebec H3G 1Y6, Canada.

The prevalence of obesity, of type 2 diabetes mellitus (T2DM), and of cancer are all increasing globally. The relationships between these diseases are complex, and thus difficult to elucidate; nevertheless, evidence supports the hypothesis that obesity increases the risks of both T2DM and certain cancers. Further complexity arises from controversial evidence that specific drugs used in the treatment of T2DM increase or decrease cancer risk or influence cancer prognosis. Herein, we review the current evidence from studies that have addressed these relationships, and summarize the methodological challenges that are frequently encountered in such research. We also outline the physiology that links obesity, T2DM, and neoplasia. Finally, we outline the practical principles relevant to the increasingly common challenge of managing patients who have been diagnosed with both diabetes and cancer.
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http://dx.doi.org/10.1038/nrclinonc.2016.120DOI Listing
February 2017

Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink.

BMJ 2016 Oct 20;355:i5340. Epub 2016 Oct 20.

Centre for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine, H-425.1, Montréal H3T 1E2, Canada

Objective:  To determine whether the use of glucagon-like peptide-1 (GLP-1) analogues, compared with the use of dipeptidylpeptidase-4 (DPP-4) inhibitors, is associated with an increased risk of incident breast cancer in patients with type 2 diabetes.

Design:  Population based cohort study.

Setting:  Clinical Practice Research Datalink, UK.

Participants:  44 984 women aged at least 40 years, who were newly treated with glucose lowering drugs between 1 January 2007 and 31 March 2015, with follow-up until 31 March 2016.

Main Outcomes And Measures:  Time varying use of GLP-1 analogues compared with use of DPP-4 inhibitors, with exposures lagged by one year for latency purposes. Time dependent Cox proportional hazards models were used to estimate adjusted hazard ratios with 95% confidence intervals of incident breast cancer associated with use of GLP-1 analogues overall, by cumulative duration of use, and time since initiation.

Results:  The cohort was followed for a mean of 3.5 years (standard deviation 2.2), with 549 incident events of breast cancer recorded (crude incidence 3.5 (95% confidence interval 3.3 to 3.8) per 1000 person years). Overall, compared with use of DPP-4 inhibitors, use of GLP-1 analogues was not associated with an increased risk of breast cancer (incidence 4.4 v 3.4 per 1000 person years; hazard ratio 1.40 (95% confidence interval 0.91 to 2.16)). Hazard ratios gradually increased with longer durations of use, with a peak between two to three years of GLP-1 use (2.66 (95% confidence interval 1.32 to 5.38)), and returned closer to the null after more than three years of use (0.98 (0.24 to 4.03)). A similar pattern was observed with time since initiation of GLP-1 analogues.

Conclusions:  In this population based cohort study, use of GLP-1 analogues was not associated with an overall increased risk of breast cancer. Although it is not possible to rule out a tumour promoter effect, the observed duration-response associations are likely the result of a transient increase in detection of breast cancers in GLP-1 analogue users.
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http://dx.doi.org/10.1136/bmj.i5340DOI Listing
October 2016

Pancreatic Cancer Risk Associated with Prediagnostic Plasma Levels of Leptin and Leptin Receptor Genetic Polymorphisms.

Cancer Res 2016 12 25;76(24):7160-7167. Epub 2016 Oct 25.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Leptin is an adipokine involved in regulating energy balance, which has been identified as a potential biologic link in the development of obesity-associated cancers, such as pancreatic cancer. In this prospective, nested case-control study of 470 cases and 1,094 controls from five U.S. cohorts, we used conditional logistic regression to evaluate pancreatic cancer risk by prediagnostic plasma leptin, adjusting for race/ethnicity, diabetes, body mass index, physical activity, plasma C-peptide, adiponectin, and 25-hydroxyvitamin D. Because of known differences in leptin levels by gender, analyses were conducted separately for men and women. We also evaluated associations between 32 tagging SNPs in the leptin receptor (LEPR) gene and pancreatic cancer risk. Leptin levels were higher in female versus male control participants (median, 20.8 vs. 6.7 ng/mL; P < 0.0001). Among men, plasma leptin was positively associated with pancreatic cancer risk and those in the top quintile had a multivariable-adjusted OR of 3.02 [95% confidence interval (CI), 1.27-7.16; P = 0.02] compared with men in the bottom quintile. Among women, circulating leptin was not associated with pancreatic cancer risk (P = 0.21). Results were similar across cohorts (P = 0.88 for two male cohorts and 0.35 for three female cohorts). In genetic analyses, rs10493380 in LEPR was associated with increased pancreatic cancer risk among women, with an OR per minor allele of 1.54 (95% CI, 1.18-2.02; multiple hypothesis-corrected P = 0.03). No SNPs were significantly associated with risk in men. In conclusion, higher prediagnostic levels of plasma leptin were associated with an elevated risk of pancreatic cancer among men, but not among women. Cancer Res; 76(24); 7160-7. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-1699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181854PMC
December 2016

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.

Aging Cell 2016 Oct 21;15(5):811-24. Epub 2016 Jun 21.

Leiden University Medical Center, Medical Statistics and Bioinformatics, Leiden, 2300 RC, The Netherlands.

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.
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http://dx.doi.org/10.1111/acel.12490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5013013PMC
October 2016
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