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    Research Grants Awarded

    The Impact Of Obesity And Obesity Treatments On Breast Cancer

    Grant Mechanism:
    Promise Grant

    Scientific Abstract:
    BACKGROUND: Obesity is a known risk factor for breast cancer (BC), particularly in postmenopausal women. At least 3 signaling pathways together explain the association of obesity with BC: insulin/insulin-like-growth-factor (IGF-1), adipokines and estrogens. There is crosstalk leading to amplification of mitogenic signal. Estrogen signaling may be especially important in obese postmenopausal patients with estrogen receptor-positive (ER+) BC. Therefore, obesity and these signaling pathways are therapeutic targets for obese BC patients. We propose to investigate anti-obesity and insulin-sensitizing treatments in the context of BC. These treatments affect the involved pathways differently, and may thus have different impacts on BC. Preliminary data also show that metformin and rosiglitazone (drugs that treat hyperinsulinemia) have direct inhibitory effects on BC cells. So far, there is a gap in knowledge about the optimal treatment of obesity in BC patients, and this proposal is to address this issue. HYPOTHESIS: Specific obesity treatments can improve survival of obese BC subjects by their effects on insulin/IGF-1, adipokine, and estrogen signaling. SPECIFIC AIMS: 1) To determine whether obesity affects tumor biological processes that may lead to tumor progression, and to determine if any treatments of obesity or related signaling can improve survival in mouse models of obesity and BC. 2) To investigate prospectively the effect of metformin and rosiglitazone on tumor progression in obese postmenopausal BC patients on aromatase inhibitor (AI) therapy. STUDY DESIGN: The Ay/a mouse is a model of diabetes and obesity, and the FGFR4 -/- mouse is a model of obesity with metabolic syndrome. These mice will be bred with MMTV-TGFalpha mice to generate models of obesity and ER+ BC. In Specific Aim 1, Part 1, we shall determine the impact of obesity on BC development and survival using the MMTV-TGFalpha/FGFR4-/- model. Sections of BC will be immunostained with anti-poly (ADP-ribose) polymerase p85, anti-phospho-histone H3 and anti-CD31 antibodies for apoptosis, cell proliferation and angiogenesis, respectively. Angiogenesis, proliferation and apoptosis of BC will be compared in BC samples from obese mice with those from lean mice MMTV-TGFalpha/FGFR4+/+. In Part 2, to investigate the impact of anti-obesity treatments on BC carcinogenesis, obese mice (Ay/a & FGFR4 -/-) with the MMTV-TGFalpha transgene will be randomized at 6 weeks of age into 7 treatment groups: placebo, caloric restriction, rosiglitazone, metformin, exenatide, orlistat and sibutramine. The time to detection of breast tumors will be analyzed using the Kaplan-Meier method. In Part 3, to investigate the impact on cancer progression, obese mice with the MMTV-TGFalpha transgene will be randomized to the same 7 treatment groups upon detection of BC. The effects of each specific obesity treatment will be evaluated by comparing the tumor growth curves and animal survival curve of the specific treatment group to the placebo group. The survival since treatment initiation will be analyzed using the Kaplan-Meier method. In all 3 parts of Aim 1, insulin, C-peptide, IGF-1, IGF-2, IGFBP3, glucose, glycohemoglobin, estradiol, progesterone, SHBG, leptin, adiponectin, TNF-alpha and IL-6 will be measured in serum or plasma at baseline and then periodically. Tumor lysates will be examined using protein microarray technology to measure activation of signaling along the IGF1R/IRS/Akt/ mTOR/S6/HIF-1 pathway using phospho-specific antibodies. Body fat percentage of each animal will be measure by X-ray absorptiometry. Cox proportional hazard models will evaluate the impact of genotypes, anti-obesity and insulin-sensitizing treatments, hormonal & metabolic parameters, signaling pathway activity as well as body fat percentage as predictors of survival, carcinogenesis or tumor progression. In Specific Aim 2, an open-label prospective phase I/II clinical trial will recruit obese postmenopausal patients with metastatic BC and randomize to 2 arms: exemestane alone (standard of care) versus exemestane in combination with metformin and rosiglitazone (treatment). This trial uses an adaptive randomization method that depends on the latest available outcomes from the trial. In phase I, toxicity and pharmacokinetics of the new drug combination will be evaluated. In phase II, the difference in progression-free survival will be compared between the 2 arms. Correlative studies serum insulin, IGF-1, glycohemoglobin, leptin, estradiol, progesterone, SHBG and adipokines (adiponectin, TNF-?, IL-6) will be measured at baseline and followed every 3 months during enrollment. Elective biopsy samples before and after treatments will be examined angiogenesis, apoptosis, cell proliferation by immunocytochemistry, and signaling pathway activity by lysate microarray technology. A Cox proportional hazards model will examine the significance of factors such as body mass index, hormones, adipokines, and etc. on the time to progression between the 2 groups. IMPACT: We expect that our mouse models for BC and obesity will elucidate a benefit of specific anti-obesity or insulin-sensitizing treatments. These animal data will generate new hypotheses for future clinical trials. The clinical trial will determine if metformin plus rosiglitazone improves outcome in obese postmenopausal patients with ER+ metastatic BC undergoing exemestane therapy. Positive results would support a future phase III confirmatory trial to change the standard of care and improve the survival of obese women with ER+ BC.

    Lay Abstract:
    This research proposal addressed a rising problem in breast cancer patients with world-wide significance. Breast cancer is the most common cancer in women, and the second leading cause of female cancer death. Approximately 200,000 women are yearly diagnosed with breast cancer, and it is expected to be responsible for 40910 deaths in 2007 in the US. Among the identified risk factors for breast cancer, obesity in postmenopausal women and use of estrogen are two readily modifiable risk factors. Unfortunately, the prevalence of obesity is rapidly increasing and has reached epidemic proportions world wide. Our proposal addresses this important issue of the impact of obesity on breast cancer. The molecular basis for the link between obesity and breast cancer is formed by the complex interaction of at least three signaling pathways: insulin/insulin-like growth factor-1 (IGF-1), adipokines (cytokines secreted by fat cells such as leptin, adiponectin?) and estrogens. There is crosstalk among the pathways leading to amplification of cancer growth signal. Estrogen signaling may be especially important in obese postmenopausal patients with estrogen receptor-positive (hormone-responsive) breast cancer. Therefore, obesity and these signaling pathways are therapeutic targets for obese breast cancer patients. In this proposal, we investigate the potential therapeutic implications based on this current knowledge. HYPOTHESIS: Specific obesity treatments can improve survival of obese BC subjects by their effects on insulin/IGF-1, adipokine, and estrogen signaling. SPECIFIC AIM 1 is test the hypothesis above using two mouse models of estrogen receptor-positive breast cancer and obesity. This Aim consists of 3 parts: Part 1 will compare the survival fat mice with breast cancer to that of lean mice with breast cancer. The mice will be examined to see if the fat mice die faster than the lean mice due to increased breast cancer progression. Whether obesity affects tumor biological processes that may lead to tumor progression (i.e., cell division, resistance to cell death and blood vessel formation in the tumor) will be determined. Part 2 will compare the impact of different anti-obesity (appetite suppression with sibutramine, calorie restricting diet, inhibition of fat absorption with orlistat, appetite suppression with exenatide) and insulin-sensitizing (activation of AMP activated kinase with metformin, activation of PPAR? transcription factor) treatments on the formation of breast cancer in two mouse models of obesity and breast cancer. The mice will be treated when they are 6 weeks old until the breast cancers are large to see if these treatments delay the formation of breast cancer compared with the untreated control fat mice. These experiments will determine whether anti-obesity and insulin-sensitizing treatments delay breast cancer formation due to the differences in insulin/IGF-1, adipokine, and estrogen signaling. Part 3 is similar to Part 2 except that the treatments will begin when breast tumors are detected lasting until the death or euthanasia of the mice. While Part 2 examines formation of breast cancer, Part 3 examines the impact of the treatments on the progression of cancer after the tumors have formed. SPECIFIC AIM 2 is to investigate prospectively the effect of metformin and rosiglitazone on tumor progression in obese postmenopausal BC patients on aromatase inhibitor (AI) therapy in a Phase I/II clinical trial. Obese postmenopausal females with metastatic hormone-responsive breast cancer will be randomized to 2 arms: exemestane alone (standard of care) versus exemestane in combination with metformin and rosiglitazone (treatment). Phase I will determine the highest tolerated dose of the combination. Phase II will test whether the combination stabilizes the cancer longer than exemestane alone. Correlative studies will study the hormone and metabolic profiles and signaling in elective biopsy samples. We propose an integrated program of mouse model studies and a clinical trial to test this hypothesis. This program is to be carried out by a multidisciplinary and multi-institutional team with expertise in endocrinology and metabolism, medical oncology, cellular and molecular oncology, transgenic mouse models, statistics, pathology and patient advocacy. The clinical trial and animal study components are integrated not only intellectually but also in tangible terms of personnel, materials and supplies and laboratory equipment. Our obese breast cancer model studies will open new avenues to elucidate benefits of specific obesity treatments in improving the survival of obese breast cancer patients. After 5 years, our data will identify the treatments beneficial to obese breast cancer patients and help to design new clinical trials that may change the clinical management of obese breast cancer patients in 10 years. The clinical trial addresses the pressing question of whether adding rosiglitazone and metformin will improve survival of obese postmenopausal hormone-sensitive breast cancer patients on AI therapy. If this clinical trial finds that metformin plus rosiglitazone improves outcome in obese postmenopausal patients with hormone-sensitive metastatic breast cancer undergoing exemestane therapy, a phase III large scale confirmatory trial can follow in the next 5 years. Therefore, within 10 years, this research may change the standard of care and introduce this novel 3-drug combination as a standard therapy for this obese subpopulation of breast cancer patients.