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Targeting Obesity for Endometrial Cancer Treatment

Targeting Obesity for Endometrial Cancer Treatment. Victoria Bae-Jump, MD, PhD Associate Professor Division of Gynecologic Oncology University of North Carolina at Chapel Hill. Disclosure – Novatarg, Merck. Endometrial Cancer and Obesity. 4 th most common cancer among women in the U.S.

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Targeting Obesity for Endometrial Cancer Treatment

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  1. Targeting Obesity for Endometrial Cancer Treatment Victoria Bae-Jump, MD, PhD Associate Professor Division of Gynecologic Oncology University of North Carolina at Chapel Hill

  2. Disclosure – Novatarg, Merck

  3. Endometrial Cancer and Obesity 4th most common cancer among women in the U.S. Obesity, diabetes and insulin resistance are well-known risk factors Each increase in BMI of 5 kg/m2 significantly increases a woman’s risk of developing endometrial cancer.1 Obese women with endometrial cancer have up to a 6.25 increased risk of death.2 1Renehan et. al., Lancet, 371: 569-578 (2008). 2Calle et. al., N Engl J Med, 348: 1625-38 (2003). 1/3/2020 3

  4. Obesity and Endometrial Cancer

  5. Hypothesis • The metabolic consequences of obesity may be crucial in endometrial cancer pathogenesis. • Biologically and metabolically distinct cancers than those that arise in a non-obese environment. • Obesity-driven endometrial cancers may have unique vulnerabilities that could be targeted for treatment. • Metformin • Biguanide • Pre-clinical/epidemiologic studies suggest anti-tumorigenic effects

  6. Metformin’s Anti-tumorigenic Effects • Indirect – improvement in insulin resistance, decrease in circulating insulin and glucose levels • Direct – inhibits mitochondrial complex 1, AMPK activation, leading to inhibition of mTOR pathway, inhibition of lipid and fatty acid synthesis

  7. Metformin and Endometrial Cancer Mouse Model Palpable 1 cm tumor 3 weeks 6 weeks LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer Obese (High fat diet) versus Lean (Low fat diet) Metformin versus Placebo

  8. p=0.033 RESULTS p=0.04

  9. Metabolomics: Obese vs Lean Tumors • Striking differences between obese and lean tumors • 251 up- or down-regulated metabolites • Aggressive phenotype of endometrial cancer in obese mice accompanied by alterations in metabolism • Upregulation of lipid biosynthesis • Upregulation of energy metabolism • Upregulation of protein biosynthesis INCREASE DECREASE

  10. ↑ lipid biosynthesis ↑ apo-lipoproteins – increased lipid transport ↑ lipases – release free fatty acids Proteomics: Obese vs Lean Tumors * *p< 0.05

  11. Proteomics: Obese vs Lean Tumors * ↑ protein biosynthesis ↑ proteases – increased protein degradation to provide amino acids ↑ ribosomal subunits and ribosomal stabilizing proteins – increased protein biosynthetic capacity *p< 0.05

  12. Obesity-Driven Alterations in Endometrial Cancer

  13. Obesity and Metformin in LKB1/p53 Mice • Metformin inhibited tumor size/volume in both the obese and lean mice. • Metformin-induced decreases in tumor size/volume in obese mice were significantly greater than in the lean mice (85% versus 61%, respectively, p=0.033). • Metformin’s anti-tumorigenic efficacy may be dependent on obese/insulin resistant states.

  14. Metabolomics - Metformin • Metformin treatment reversed detrimental effects of obesity • Decreased lipid biosynthesis • Increased 3-hydroxybutyrate • Fatty acids and lipids being degraded • Decreased protein turn-over and biosynthesis INCREASE DECREASE

  15. ↑ proteins involved in lipid oxidation/degradation ↑ Lipid-oxidation enzymes ↑ Peroxisome proliferator-activated receptor (PPAR) responsive proteins Proteomics- Metformin in Obese * all p-values significant

  16. ↑ proteins involved in beta-oxidation ↑ proteins involved in fatty acid degradation Excess free fatty acids shunted to beta-oxidation as opposed to lipid biosynthesis Proteomics- Metformin in Obese * all p-values significant

  17. Effect of Metformin on Obesity-Driven Alterations

  18. Preoperative Window Study – Metformin and Endometrial Cancer (UNC) • 20 patients enrolled1 • Endometrioid Histology • BMI > or = 30 • Metformin 850 mg QD • Mean of 14.7 days of treatment, stopped 24 hours prior to hysterectomy/BSO and surgical staging • Ki-67 staining decreased significantly with metformin treatment (mean of 21.9%, signed rank test, p=0.008). • Inhibited targets of the mTOR pathway. 1 1Schuler, KM, Rambally, BS, Difurio, MJ, Sampey, BP, Gehrig, PA, Makowski, L and Bae-Jump, VL. Anti-proliferative and metabolic effects of metformin in a pre-operative window clinical trial for endometrial cancer, Cancer Medicine, 4(2), 161-73 (2016).

  19. A B Metformin inhibited cell proliferation in EC patients. Obese EC patients (n=20) underwent short-term metformin treatment (mean of 14.7 days) in a pre-operative window study. Percent Ki-67 staining, a marker of cell proliferation, decreased significantly with metformin treatment (mean decrease of 21.9%, p=0.008). Endometrium (A) pre-treatment and (B) post-treatment in a patient that responded to metformin treatment, as shown by a decrease in Ki-67 staining.

  20. All early stage, G1-3 • 3 G1 toxicities – mild abdominal pain, loose stools, flatulence • No difference in age, BMI, HgBA1C, stage, grade, or number of days on treatment between responders and non-responders. • Glucose levels decreased in responders and non-responders to metformin but were only statistically significant in responders (p=0.007).

  21. Predictors of Response • Determine any molecular or metabolic biomarkers that could predict response to metformin treatment • Compare responders to non-responders • Immunohistochemical analysis • AMPK, mTOR and insulin pathway derivatives • Metformin transporters • Metabolomic profiling • Baseline and change pre- to post-treatment

  22. Molecular differences in Responders versus Non-Responders • Baseline MATE2 expression approached significance in predicting response to metformin (p=0.0625)

  23. Global Biochemical Serum Profiles • Metformin treatment significantly altered the serum concentrations of 173 metabolites (37 up and 136 down). • 114 metabolites in responders and 67 metabolites in non-responders. • Responders to metformin had seemed to be more sensitive to metformin’s beneficial effects on: • Lipid metabolism • Amino acid metabolism • Gut microbiome-associated metabolites lipid metabolites amino acid metabolites gut microbial metabolites

  24. Baseline Metabolic Differences in Serum Between Responders and Non-responders to Metformin Treatment Higher pre-metformin treatment levels of amino acids, dipeptides, glycolytic intermediates, arachidonic acid, monohydroxy fatty acids and lysolipids in responders when compared to non-responders (p<0.05).

  25. Parallels Between Mouse and Human Data Mouse Endometrial Tumors Human Endometrial Tumors • Metformin inhibited fatty acid synthesis in both human and mouse endometrial tumors. • More pronounced in obese vs lean mice. • More pronounced in responders vs non-responders.

  26. Open Clinical Trials of Metformin in Endometrial Hyperplasia with Atypia/Cancer

  27. Open Clinical Trials of Metformin in Endometrial Hyperplasia/Cancer

  28. GOG 286B:A randomized phase II/III study of paclitaxel/carboplatin/METFORMIN VERSUS paclitaxel/carboplatin/PLACEBO as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer Paclitaxel 175 mg/m2 over 3 hr day 1 Carboplatin AUC 5 day 1q3w + Placebo Advanced and Recurrent Endometrial Cancer (n=540 patients) R Paclitaxel 175 mg/m2 over 3 hr day 1 Carboplatin AUC 5 day 1q3w Metformin 850 mg po BID PI: Victoria Bae-Jump Clinical Primary Endpoints: Progression free survival for the phase II. Overall survival for the phase III. Re-open to Phase 3 in December 2016.

  29. GOG 286B: A randomized phase II/III study of paclitaxel/carboplatin/METFORMIN VERSUS paclitaxel/carboplatin/PLACEBO as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer (NCT02065687) • Outcomes – Clinical: Secondary Endpoints • To estimate the proportion of patients with objective response rate (RR) in the population of patients with measurable disease by treatment. • To estimate the duration of response in the population of patients with measurable disease who respond by treatment. • To estimate overall survival (OS) and relative hazards of death for each treatment arm if the study stops after the phase II trial is completed. If the study continues with a phase III clinical trial, then PFS will be a secondary endpoint. • To determine the nature, frequency and degree of toxicity as assessed by CTCAE for each treatment arm. • To estimate possible differences in RR, PFS, OS, and toxicity rates for the treatment regimens by the patients’ level of obesity.

  30. GOG 286B: A randomized phase II/III study of paclitaxel/carboplatin/METFORMIN VERSUS paclitaxel/carboplatin/PLACEBO as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer (NCT02065687) • Outcomes – Biomarker Endpoints • To explore the association of metabolic factors (BMI, hip-to-waist ratio, diabetes status, HgBA1C, fasting insulin and glucose levels, HOMA scores) with treatment response to metformin/paclitaxel/carboplatin. • Metabolomic profiling • To correlate expression of the metformin transporter proteins (i.e. OCT 1-3, MATE 1/2 and PMAT) and key targets of the metformin/insulin/mTOR signaling pathway with treatment response to metformin/paclitaxel/carboplatin. • Immunohistochemical analysis: Transporter proteins, insulin and mTOR pathway targets • Next generation sequencing: PTEN mutations, PIK3CA mutations/amplifications and PIK3R1/PIK3R2 mutations • Next generation sequencing: Genetic variants of transporter proteins.

  31. GOG 286B: A randomized phase II/III study of paclitaxel/carboplatin/METFORMIN VERSUS paclitaxel/carboplatin/PLACEBO as initial therapy for measurable stage III or IVA, stage IVB, or recurrent endometrial cancer (NCT02065687) • Outcomes – Patient Reported Outcomes Endpoints • To estimate differences in physical functioning, physical activity, and fatigue between treatment arms. • To explore the association between metabolic factors (i.e., BMI, hip-to-waist ratio, diabetes status, HgbA1C, fasting insulin and glucose levels, HOMA scores), physical functioning, physical activity, and fatigue. • Physical Function – Physical Function subscale of SF-36 • Fatigue – Functional Assessment of Chronic Illness-Therapy Scale (FACIT-F ) • Physical Activity – Short form of the International Physical Activity Questionnaire (IPAQ) • Patients will complete the questionnaires at 4 times (0, 6, 15 and 26 weeks).

  32. Conclusions • Endometrial tumors arising in the setting of obesity are metabolically different than their lean counterparts – may have different targets for treatment. • Pre-clinical data suggests that metformin have efficacy in obesity-driven endometrial cancer - multiple clinical trials are in progress. • Other pharmacologic interventions – novel biguanides, statins, phenformin, orlistat, cox-2 inhibitors….

  33. Thank you! • Grant Support (past and present): • NIH/NCI K23 Mentored Patient-Oriented Research Career Development Award Grant • American Gynecological & Obstetrical Society Bridge Grant • Gynecologic Cancer Foundation/Florence & Marshall Schwid Ovarian Cancer Research Grant • NC TraCS $50K Pilot Grant Program • UNC Nutrition Obesity Research Center, Pilot and Feasibility Research Grant • V Foundation Grant • Marsha Rivkin Center for Ovarian Cancer Research Pilot Project Grant • Department of Defense (DOD) Ovarian Cancer Research Program Grants • NIH/NCI R03 • North Carolina Biotechnology Center (NCBC) Collaborative Funding Grant • American Cancer Society Research Scholar Grant My Laboratory (Past and Present): • Chunxiao Zhou, MD, PhD (Lab Manager) • Gynecologic Oncology Fellows 2007 – present • Hui Guo • Lu Zhang • Yajie Yin • Guangxu Xu • Collaborators: • Dhiren Thakker, PhD • Liza Makowski, PhD • Neil David Hayes, MD, PhD • Paola Gehrig, MD • Siobhan O’Connor, MD • Lisa Abaid, MD • Douglas Lee, PhD • Thomas Conrad, PhD • Larry Maxwell, MD

  34. The Becky Black Memorial Fund to Fight Endometrial Cancer

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