Metformin in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Phase 2 Trial (SAKK 08/09)

Rothermundt, Christian; Hayoz, Stefanie; Templeton, Arnoud J.; Winterhalder, Ralph; Strebel, Räto T.; Bärtschi, Daniela; Pollak, Michael; Lui, L.; Endt, Kathrin; Schiess, Ralph; Rüschoff, Jan H.; Cathomas, Richard; Gillessen, Silke

doi:10.1016/j.eururo.2013.12.057

Cited by 102 publications

(71 citation statements)

References 30 publications

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“…A preliminary phase-II trial suggested metformin may slow the progression of advanced prostate cancer. 27) Understanding the mechanisms of this activity is critical prior to clinical evaluation. It has been shown that the type 1 insulin-like growth factor receptor (IGF-IR) up regulation induced by androgen was inhibited by metformin via disrupting membrane-initiated androgen signaling.…”

Section: Discussionmentioning

confidence: 99%

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo

Wang

Huang

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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Metformin is a commonly used drug for the treatment of type II diabetes and atorvastatin is the most prescribed cholesterol-lowering statin. The present study investigated the effects and mechanisms of metformin and atorvastatin in combination on human prostate cancer cells cultured in vitro and grown as xenograft tumor in vivo. Metformin in combination with atorvastatin had stronger effects on growth inhibition and apoptosis in PC-3 cells than either drug alone. The combination also potently inhibited cell migration and the formation of tumorspheres. Metformin and atorvastatin in combination had a potent inhibitory effect on nuclear factor-kappaB (NF-κB) activity and caused strong decreases in the expression of its downstream anti-apoptotic gene Survivin. Moreover, strong decreases in the levels of phospho-Akt and phosphorextracellular signal-regulated kinase (Erk)1/2 were found in the cells treated with the combination. The in vivo study showed that treatment of severe combined immunodeficient (SCID) mice with metformin or atorvastatin alone resulted in moderate inhibition of tumor growth while the combination strongly inhibited the growth of the tumors. Results of the present study indicate the combination of metformin and atorvastatin may be an effective strategy for inhibiting the growth of prostate cancer and should be evaluated clinically.Key words prostate cancer; atorvastatin; metformin; apoptosis; combination Prostate cancer is one of the common types of malignant disease in males in the world and is the second leading cause of cancer-related death in the United States. The American Cancer Society estimates for 2016 approximately 180890 new cases will be diagnosed and 26120 men will die of the disease, accounting for about 8.3% of male cancer-related deaths. 1)Androgen deprivation therapy is an effective treatment for advanced prostate cancer. Unfortunately, almost all patients treated with androgen deprivation therapy will progress to castration-resistant prostate cancer (CRPC).2,3) Docetaxel is the most commonly prescribed first-line chemotherapy for CRPC. 4) Although docetaxel provides a modest (2.4-month) increase in median overall survival, many patients with CRPC cannot tolerate this cytotoxic chemotherapy due to advanced age, medical comorbidities, or limited bone marrow reserves. 5)Therefore, the identification of an effective alternative therapy with less toxicity may lead to increased survival and an improved QOL.Metformin is a well-established agent for the treatment of type II diabetes. In addition to its efficacy in lowering glucose levels, recent reports indicate it may have antitumor effects in various cancers, including prostate cancer. 6) Diabetic patients receiving metformin have been shown to have a reduced cancer incidence and a decrease in cancer-specific mortality.7) Further, epidemiologic evidence revealed a decreased incidence of prostate cancer in men taking metformin, 8,9) and both animal and in vitro models demonstrate its activity in prostate cancer cell lines. 10,11) Finall...

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Section: Discussionmentioning

confidence: 99%

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells in Vitro and in Vivo

Wang

Huang

Zhang

et al. 2017

Biological & Pharmaceutical Bulletin

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“…More importantly, metformin is a potent activator of the adenosinmonophosphate-activated protein kinase (AMPK) in epithelial cells [8]. A recent report found a significant PSA response to metformin exposure in men with castration-resistant PCa [9] possibly through disruption of the androgen receptor protein synthesis [10]. Although the molecular mechanism of metformin to hamper PCa growth seems to be plausible, case-control studies found mixed results [11][12][13][14].…”

Section: Introductionmentioning

confidence: 96%

Influence of metformin use on PSA values, free-to-total PSA, prostate cancer incidence and grade and overall survival in a prospective screening trial (ERSPC Aarau)

et al. 2014

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“…However, these findings are supported by other clinical trials such as that by Rothermundt et al where metformin was used pre-chemotherapy in a chemotherapy naïve CRPC population over 12 weeks. The authors reported a decline in HOMA-IR by 26%, prolongation of PSA doubling time in 52.3%, overall decline in IGF-1 and IGFBP3, and reasonable tolerability [151,166]. Insulin and glucose levels were lower without statistical significance.…”

Section: Hyperinsulinaemia and Risk Of Cancer Progressionmentioning

confidence: 98%

“…Treatment was associated with prolongation of PSA doubling time (88 vs 111 days), decline of PSA and a decrease in the homeostatic model assessment (HOMA) index (-25.9%, 95% CI -41.7 to 47, P=0.6), IGF-1 (-13.8%, 95% CI -22.5 to -5.7) and IGFBP-3 levels (-278%, 95% CI -437.0 to -39.5) [166].…”

Section: Metformin and Adtmentioning

confidence: 99%

“…Apart from a cancer specific advantage, a prospective clinical trial of metformin in conjunction with ADT, caloric restriction and exercise, also reported a reduction in adverse effects of ADT such as alteration in abdominal girth, weight, body mass index and systolic blood pressure [151]. In a recent phase II trial of chemotherapy naïve CRPC patients, metformin use was associated with prolongation of PSA doubling time, decline of PSA and decrease in the homeostatic model assessment index, IGF-1 and IGFBP-3 levels [166]. The prospect of repurposing a commonly used medication to combat cancer is certainly exciting, and this has resulted in the recent registration of many clinical trials involving metformin in the treatment of cancer (62)(63)(64)(65).…”

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confidence: 99%

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Androgen Deprivation Therapy (ADT), Metabolic Syndrome and Metastatic Prostate Cancer: In Vivo and In Vitro Assessments of Effects of Metformin

Rhee¹

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Research Title -In vivo In this translational research PhD project, we conducted a randomized, placebo-controlled clinical trial named ADT and Adjuvant Metformin (ADMET) trial to determine the metabolic and therapeutic effects of treating hyperinsulinaemia in men starting ADT using a diabetic medication called metformin. Men who had been diagnosed with metastatic PCa and commencing ADT as a standard strategy provided the opportunity to study the physiological and pathological impact of the acute rise in insulin levels resulting from the iatrogenic hypogonadism [6]. To assess for the therapeutic benefits of metformin, we used a variety of novel technologies such as circulating tumour cell (CTC) enumeration, culture, transcriptomic analysis, and molecular imaging.The clinical trial was commenced in September 2014 and was completed in March 2017. It concluded that hyperinsulinaemia and MS is a phenomenon that affects most patients when using ADT, although the changes can be ameliorated by metformin. The use of medication was associated with the reduced need for treatment of MS with agents such as statins and progression to CRPC. Further, the trial confirmed that insulin resistance at the time of starting treatment is associated with early development of CRPC and progression of the disease.Progression free survival was also demonstrated using a novel molecular imaging called Prostate Specific

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Metformin in Chemotherapy-naive Castration-resistant Prostate Cancer: A Multicenter Phase 2 Trial (SAKK 08/09)

Cited by 102 publications

References 30 publications

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

Influence of metformin use on PSA values, free-to-total PSA, prostate cancer incidence and grade and overall survival in a prospective screening trial (ERSPC Aarau)

Androgen Deprivation Therapy (ADT), Metabolic Syndrome and Metastatic Prostate Cancer: In Vivo and In Vitro Assessments of Effects of Metformin

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