Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer

Brown, Jennifer N.; Chan, Daniel; Shank, Jessica; Griffith, Kent A.; Fan, Huihui; Szulawski, Robert; Yang, Kun; Reynolds, R. Kevin; Johnston, Carolyn; McLean, Karen; Uppal, Shitanshu; Liu, J Rebecca; Cabrera, Lourdes; Taylor, S.E.; Orr, Brian; Modugno, Francesmary; Mehta, Pooja; Bregenzer, Michael E.; Mehta, Geeta; Shen, Hui; Coffman, Lan; Buckanovich, Ronald J.

doi:10.1172/jci.insight.133247

Cited by 110 publications

(99 citation statements)

References 68 publications

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“…It is important to note that much of the clinical data suggesting the benefit of metformin regarding patient outcomes are still predominantly in retrospective analyses, which makes it difficult to determine how the drug may be best utilized in therapeutic strategies. However, recent prospective clinical data do in fact support an improvement in the overall survival of patients with ovarian cancer treated with metformin [ 16 ], which in this study, were associated with the ability of metformin to both inhibit ALDH + /CD133 + cancer stem-like cells (CSCs) and increase CSC sensitivity to carboplatin ex vivo. Unfortunately, to date, only the study by Li et al ( Section 2.3 and Section 2.4 above) has investigated the effects of metformin on immune cell function in patients with ovarian cancer, and formal prospective clinical trials evaluating the impact of the drug on the immune TME have yet to be conducted.…”

Section: Resultsmentioning

confidence: 62%

“…Consistently, a subsequent meta-analysis of numerous retrospective studies showed a nearly twofold decrease in the risk of mortality across seven cohorts (cumulative odds ratio of 0.55), as well as a small but significant decrease in the incidence of ovarian cancer in several others [ 15 ]. Several prospective clinical trials have been initiated to determine the efficacy of metformin in the treatment of ovarian cancer, which are summarized in Supplementary Table S1 , including one with recently published findings showing that metformin improved the overall survival and demonstrated a potential for the drug to promote platinum sensitivity in cancer stem cells ex vivo [ 16 ]. Interestingly, in another recently published prospective study, metformin was associated with decreased occurrence in adenomatous polyp reformation in colorectal cancer [ 17 ], further supporting its potential utility in preventing early tumor development and preventing tumor progression.…”

Section: Introductionmentioning

confidence: 99%

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Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

Tsogas

Majerczyk

Hart

2021

IJMS

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Growing evidence suggests that the immune component of the tumor microenvironment (TME) may be highly involved in the progression of high-grade serous ovarian cancer (HGSOC), as an immunosuppressive TME is associated with worse patient outcomes. Due to the poor prognosis of HGSOC, new therapeutic strategies targeting the TME may provide a potential path forward for preventing disease progression to improve patient survival. One such postulated approach is the repurposing of the type 2 diabetes medication, metformin, which has shown promise in reducing HGSOC tumor progression in retrospective epidemiological analyses and through numerous preclinical studies. Despite its potential utility in treating HGSOC, and that the immune TME is considered as a key factor in the disease’s progression, little data has definitively shown the ability of metformin to target this component of the TME. In this brief review, we provide a summary of the current understanding of the effects of metformin on leukocyte function in ovarian cancer and, coupled with data from other related disease states, posit the potential mechanisms by which the drug may enhance the anti-tumorigenic effects of immune cells to improve HGSOC patient survival.

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Section: Resultsmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

Tsogas

Majerczyk

Hart

2021

IJMS

View full text Add to dashboard Cite

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“…It has also been shown that mitochondria function normally even in glycolysis-dependent cancer cells, and that glutamine metabolism and FAO are activated [ 50 , 51 , 52 , 54 , 55 ]. In vitro and in vivo experiments have shown that inhibitors of mitochondrial OXPHOS, such as metformin, phenformin, and menadione, suppress CSC traits [ 132 , 163 , 164 , 165 , 166 , 167 ]. Also, since mitochondria are derived from a prokaryote that originally parasitized eukaryotic cells, it is known that its function can be inhibited by treatment with various antibiotics [ 17 , 18 , 19 , 20 , 168 , 169 , 170 ].…”

Section: Therapeutic Strategies For Targeting Csc Metabolismmentioning

confidence: 99%

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

Tanabe

Sahara

2020

Cancers

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Numerous findings have indicated that CSCs, which are present at a low frequency inside primary tumors, are the main cause of therapy resistance and cancer recurrence. Although various therapeutic methods targeting CSCs have been attempted for eliminating cancer cells completely, the complicated characteristics of CSCs have hampered such attempts. In analyzing the biological properties of CSCs, it was revealed that CSCs have a peculiar metabolism that is distinct from non-CSCs to maintain their stemness properties. The CSC metabolism involves not only the catabolic and anabolic pathways, but also intracellular signaling, gene expression, and redox balance. In addition, CSCs can reprogram their metabolism to flexibly respond to environmental changes. In this review, we focus on the flexible metabolic mechanisms of CSCs, and highlight the new therapeutics that target CSC metabolism.

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“…A recent phase II clinical trial show a median PFS of 18.0 months (95% CI = 14.0–21.6) with a relapse-free survival at 18 months of 59.3% (95% CI = 38.6–70.5) and a median OS of 57.9 months (95% CI = 28.0-not estimable) for metformin users in non-diabetic OC patients [ 129 ]. The same authors demonstrate that metformin is a CSC targeting agent, since metformin-treated ex vivo tumours exhibit an average 2.4-fold decrease in ALDH + /CD133 + cells and an increased sensitivity to cisplatin compared to non-metformin-treated cells [ 129 ].…”

Section: Drug Repurposing For Ovarian Cancer Therapymentioning

confidence: 99%

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

Nunes

Abreu

Bartosch

et al. 2020

IJMS

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The main challenge in ovarian cancer treatment is the management of recurrences. Facing this scenario, therapy selection is based on multiple factors to define the best treatment sequence. Target therapies, such as bevacizumab and polymerase (PARP) inhibitors, improved patient survival. However, despite their achievements, ovarian cancer survival remains poor; these therapeutic options are highly costly and can be associated with potential side effects. Recently, it has been shown that the combination of repurposed, conventional, chemotherapeutic drugs could be an alternative, presenting good patient outcomes with few side effects and low costs for healthcare institutions. The main aim of this review is to strengthen the importance of repurposed drugs as therapeutic alternatives, and to propose an in vitro model to assess the therapeutic value. Herein, we compiled the current knowledge on the most promising non-oncological drugs for ovarian cancer treatment, focusing on statins, metformin, bisphosphonates, ivermectin, itraconazole, and ritonavir. We discuss the primary drug use, anticancer mechanisms, and applicability in ovarian cancer. Finally, we propose the use of these therapies to perform drug efficacy tests in ovarian cancer ex vivo cultures. This personalized testing approach could be crucial to validate the existing evidences supporting the use of repurposed drugs for ovarian cancer treatment.

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Phase II clinical trial of metformin as a cancer stem cell-targeting agent in ovarian cancer

Cited by 110 publications

References 68 publications

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

Possible Role of Metformin as an Immune Modulator in the Tumor Microenvironment of Ovarian Cancer

The Metabolic Heterogeneity and Flexibility of Cancer Stem Cells

Recycling the Purpose of Old Drugs to Treat Ovarian Cancer

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