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: An NRG Oncology/GOG study

Bae‐Jump, Victoria L.; Sill, M. W.; Gehrig, Paola A.; Moxley, Katherine M.; Hagemann, Andrea R.; Waggoner, Steven; O’Cearbhaill, Roisin E.; McDonald, Megan; DiSilvestro, Paul; Sperduto, Paul W.; Aghajanian, Carol

doi:10.1016/j.ygyno.2020.06.013

Cited by 13 publications

(6 citation statements)

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“…The addition of metformin to everolimus and letrozole, however, resulted in similar results to previous trials of everolimus and letrozole and standard of care hormonal therapy [55]. Furthermore, GOG 286 (NCT02065687), a randomized phase II/III study of paclitaxel/carboplatin with and without metformin in Stage III or IVA, Stage IVB, or recurrent EC showed no additional benefit to the addition of metformin [56]. Novel studies are also looking at the role of a ketogenic diet in newly diagnosed, obese and overweight EC patients (NCT03285152), an intervention which has been shown to be safe in regards to blood lipid levels [57].…”

Section: Management Of Ec Patients and Therapies Targeting The Pten Pathwaysupporting

confidence: 53%

Diagnosis and management of an endometrial cancer patient with Cowden syndrome

Manning‐Geist

Gatius

Liu

et al. 2021

Gynecologic Oncology

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Section: Management Of Ec Patients and Therapies Targeting The Pten Pathwaysupporting

confidence: 53%

Diagnosis and management of an endometrial cancer patient with Cowden syndrome

Manning‐Geist

Gatius

Liu

et al. 2021

Gynecologic Oncology

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“…Metformin is currently being explored in the treatment of endometrial cancer in combination with hormonal and targeted therapies as well as chemotherapy; however, it should be noted that metformin did not improve on the efficacy of standard-ofcare paclitaxel/carboplatin in advanced and recurrent endometrial cancer in NRG Oncology GOG286B (27), despite promising pre-clinical data in endometrial cancer cell lines and animal models (25,26). Efforts are underway to develop new and improved pharmacologic versions of metformin for the treatment of diabetes mellitus, and it is logical that these same drugs may also have greater anti-tumorigenic benefits than metformin.…”

Section: Introductionmentioning

confidence: 99%

The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

et al. 2021

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ObjectivesAnti-diabetic biguanide drugs such as metformin may have anti-tumorigenic effects by behaving as AMPK activators and mTOR inhibitors. Metformin requires organic cation transporters (OCTs) for entry into cells, and NT-1044 is an AMPK activator designed to have greater affinity for two of these transporters, OCT1 and OCT3. We sought to compare the effects of NT-1044 on cell proliferation in human endometrial cancer (EC) cell lines and on tumor growth in an endometrioid EC mouse model.MethodsCell proliferation was assessed in two EC cell lines, ECC-1 and Ishikawa, by MTT assay after exposure to NT-1044 for 72 hours of treatment. Apoptosis was analyzed by Annexin V-FITC and cleaved caspase 3 assays. Cell cycle progression was evaluated by Cellometer. Reactive oxygen species (ROS) were measured using DCFH-DA and JC-1 assays. For the in vivo studies, we utilized the LKB1fl/flp53fl/fl mouse model of endometrioid endometrial cancer. The mice were treated with placebo or NT-1044 or metformin following tumor onset for 4 weeks.ResultsNT-1044 and metformin significantly inhibited cell proliferation in a dose-dependent manner in both EC cell lines after 72 hours of exposure (IC50 218 μM for Ishikawa; 87 μM for ECC-1 cells). Treatment with NT-1044 resulted in G1 cell cycle arrest, induced apoptosis and increased ROS production in both cell lines. NT-1044 increased phosphorylation of AMPK and decreased phosphorylation of S6, a key downstream target of the mTOR pathway. Expression of the cell cycle proteins CDK4, CDK6 and cyclin D1 decreased in a dose-dependent fashion while cellular stress protein expression was induced in both cell lines. As compared to placebo, NT-1044 and metformin inhibited endometrial tumor growth in obese and lean LKB1fl/flp53fl/fl mice.ConclusionsNT-1044 suppressed EC cell growth through G1 cell cycle arrest, induction of apoptosis and cellular stress, activation of AMPK and inhibition of the mTOR pathway. In addition, NT-1044 inhibited EC tumor growth in vivo under obese and lean conditions. More work is needed to determine if this novel biguanide will be beneficial in the treatment of women with EC, a disease strongly impacted by obesity and diabetes.

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“…The use of metformin has been evaluated in a randomized phase II/III trial in combination with chemotherapy in the setting of advanced disease. Four hundred and sixty-nine pretreated endometrial cancer patients, who were randomized to receive carboplatin-paclitaxel +metformin versus carboplatin-paclitaxel +placebo, showed similar response rates (median overall survival 30 vs 35 months; objective response rate 62% vs 60%) 38…”

Section: Future Perspectives: Innovative Combinations or New Compoundsmentioning

confidence: 99%

“…Four hundred and sixty-nine pretreated endometrial cancer patients, who were randomized to receive carboplatinpaclitaxel +metformin versus carboplatin-paclitaxel +placebo, showed similar response rates (median overall survival 30 vs 35 months; objective response rate 62% vs 60%). 38…”

Section: Reviewmentioning

confidence: 99%

Management of stage III and IVa uterine cancer

Nero

Tronconi

Giudice

et al. 2022

Int J Gynecol Cancer

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The prognosis of patients with advanced endometrial cancer is poor with limited therapeutic options. Nevertheless, the integration of molecular features in the clinico-pathological classification of endometrial cancer has significantly refined prognostic risk groups, representing a major breakthrough not only in the management of the disease but also in treatment perspectives. New therapeutic compounds such as target therapies, immunotherapy, and hormonal therapies have emerged for this clinical setting. Furthermore, molecular-driven clinical trials may improve significantly the efficacy of new treatments selecting those patients who are highly likely to respond. This review aims at describing the state of the art of advanced stage III-IVa endometrial cancer management, providing also the most interesting clinical perspectives.

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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: An NRG Oncology/GOG study

Cited by 13 publications

References 0 publications

Diagnosis and management of an endometrial cancer patient with Cowden syndrome

Diagnosis and management of an endometrial cancer patient with Cowden syndrome

The Effects of NT-1044, a Novel AMPK Activator, on Endometrial Cancer Cell Proliferation, Apoptosis, Cell Stress and In Vivo Tumor Growth

Management of stage III and IVa uterine cancer

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