Clinical research progress of metformin's anti-tumor effect in 2019

Progress of metformin antitumor clinical trials < br / > as of November 2019, ClinicalTrials.gov There were 1726 registered clinical trials of metformin, of which 69.24% (1195 / 1726) were most related to diabetes treatment, followed by tumor prevention or treatment, accounting for 19.18% (331 / 1726)In terms of time distribution, metformin research in the field of anti-tumor has attracted great attention since the last decade, and the research heat has continued to maintain< br / > Fig1 clinical trial time and indication distribution of metformin < br / > data source: ClinicalTrials.gov , Flint creation < br / > ClinicalTrials.gov Among the registered clinical trials, there are 7 anti-tumor studies of metformin in non diabetic patients, and the research information is shown in Table 1< br / > Table 1 evidence of anti-tumor clinical trials of metformin < br / > source: reference [1] < br / > research shows that Ki-67, a tumor proliferation marker, decreased significantly in metformin groupTwo studies showed that metformin had no significant effect on Ki-67Another study found that Ki-67 level increased after metformin treatmentIn addition, a prostate cancer study found that after metformin administration, prostate cancer cells secreted protein prostate specific antigen (PSA) levels decreasedThe above results support the antitumor effect of metforminHowever, more large-scale randomized controlled trials are needed to further confirm the effect of metformin in different tumors< br / > the research progress of metformin combined therapy strategy < br / > the anti-tumor mechanism of metformin has not been fully elucidatedAt present, there are two main aspects [2]: (1) inhibition of tumor cell energy and biosynthetic substrate supply by targeting electron respiratory chain complex I, It can induce metabolic stress and eventually lead to cell death; (2) activate AMPK to regulate the metabolic process of tumor cells and other survival signal pathway activities to play an anti-tumor rolePreclinical studies have found that the above mechanisms enable metformin to combine with other drugs to play a better anti-tumor potentialAt present, some corresponding clinical evidence has also been obtained< br / > 1Metformin combined with radiotherapy and chemotherapy < br / > pre clinical study found that [3], metformin can significantly increase the chemosensitivity of a series of tumor cells, including breast cancer, endometrial cancer, ovarian cancer, etc.; at the same time, in vitro research evidence shows that metformin may be conducive to protect some serious side effects caused by chemotherapy, For example, ototoxicity caused by cisplatin and cardiotoxicity caused by adriamycin< br / > the results of clinical trials show that metformin may play different roles in different tumors In metastatic pancreatic cancer [4] and advanced pancreatic cancer [5], the addition of metformin had no significant effect on the original chemotherapy, but in non-small cell lung cancer, metformin combined therapy significantly prolonged the survival of patients [6] < br / > Table 2 evidence of metformin combined with chemotherapy in anti-tumor clinical trials < br / > Fig 2 in non-small cell lung cancer, metformin combined treatment significantly prolonged the survival of patients < br / > picture source: reference [6] < br / > 2, metformin combined with targeted drugs < br / > acquired resistance is an important reason for limiting the clinical application of targeted drugs, At present, it is believed that the target drug resistance is often related to the compensatory change of survival signal pathway, in addition, the resistant cells are likely to have compensatory change of metabolic pathway < br / > the results of in vitro study showed that [7], EGFR-TKIs resistant breast cancer cells have compensatory changes in glucose metabolism pathway; metformin can effectively increase the sensitivity of EGFR-TKI resistant lung cancer cells to erlotinib and gefitinib, and inhibit the epithelial stromal transformation of resistant cells [8] < br / > the results of clinical trials showed that metformin combined with first / second-line TKIs could significantly prolong the progression free survival of patients with non-small cell lung cancer complicated with type 2 diabetes However, in non-diabetic NSCLC patients, metformin combined with TKIs did not show favorable results [10] < br / > Table 3: evidence of clinical trials of metformin combined with targeted therapy for anti-tumor < br / > Table 4: in patients with non-small cell lung cancer combined with type 2 diabetes mellitus, metformin combined with TKIs significantly prolonged the progression free survival period < br / > data source: reference [9] < br / > Figure 3: in patients with non-small cell lung cancer combined with TKIs, no favorable results were shown < br / > picture source: reference [10] < br / > but in patients with lung adenocarcinoma [11], metformin combined with tyrosine kinase inhibitor Elotinib, avastini and gefitinib significantly improved the median disease-free and median survival of patients < br / > Fig 4 the combination of metformin and TKIs significantly improved the median disease-free and median survival time of lung adenocarcinoma patients < br / > photo source: reference [11] < br / > metformin can inhibit the activity of mTOR by activating AMPK In the advanced pancreatic neuroendocrine tumor patients with diabetes mellitus, metformin combined with etor inhibitor everolimus can effectively improve the disease-free survival period [12] < br / > Fig 5 in advanced pancreatic neuroendocrine tumor patients with diabetes mellitus, metformin combined with everolimus can effectively improve the disease-free survival period of patients < br / > picture source: reference [12] < br / > in addition, three clinical trials (nct01840007, nct01638676, nct02143050) have tried to explore the clinical application of metformin combined with B-Raf inhibitor strategy in melanoma, At present, the three clinical trials are in recruitment status, and there is no result report < br / > 3 Metformin combined with immunotherapy < br / > in the past decade, tumor immunotherapy has subverted the traditional concept of treatment, especially the discovery and application of immunocheckpoint molecules It was found in preclinical studies that [13] the oxygen consumption capacity of tumor and the oxygen content in its microenvironment were related to its sensitivity to PD-1 inhibitors Improving the hypoxia state of tumor microenvironment by metformin can effectively enhance the sensitivity of tumor cells to PD-1 inhibitors In addition, metformin can inhibit the maturation of PD-L1 protein in tumor cells, promote its degradation, reduce the expression of PD-L1, and improve the sensitivity of tumor cells to toxic T cells < br / > at present, there is a clinical study report of metformin combined immunotherapy [15] Compared with immunosuppressant alone, metformin combined with immunosuppressant increased the objective remission rate of orr (68.2% vs 54.5%, P = 0.31), disease control rate of DCR (77.3% vs 60.6%, P = 0.19), median survival time of OS (46.7 vs 28 months), and median progression free survival time of PFS (19.8 vs may), especially the number of metastases (0.59 vs 5 months) 1.51, P = 0.009) < br / > Fig 6: immunosuppressant combined with metformin in metastatic melanoma shows the trend of prolonging the median and median progression free survival of patients < br / > photo source: reference [15] < br / > although there is no significant difference between the groups due to the limited sample size, this study still provides supporting evidence for the prospect of metformin combined with immunosuppressant More clinical trials are currently being recruited, as shown in Table 4 < br / > Table 4 registered clinical trials of metformin combined with immunotherapy for anti-tumor < br / > clinical evidence of metformin tumor prevention < br / > a multicenter, double-blind, randomized controlled phase III clinical trial (umin000006254) [16] for patients with single or multiple colorectal adenomas resection, low-dose metformin was given, One year later, colonoscopy showed that compared with placebo, metformin significantly reduced the incidence of polyps (38.0% vs.56.5%, P = 0.034) and adenomas (30.6% vs.51.6%, P = 0.016), suggesting that metformin is likely to have a chemopreventive effect on colorectal cancer < br / > summary < br / > a large number of preclinical research results have provided evidence of metformin anti-tumor from the level of cells and animal models With the discovery of cell metabolism characteristics and various biological functions, especially the interaction between cell metabolism and immune and inflammatory signals, the application scope of metformin may be further expanded At present, more large-scale clinical studies are still needed to clarify the different effects of metformin in different tumors, and provide clinical evidence for its individual treatment, combined treatment and tumor prevention < br / > References: < br / > [1] Vancouver a, bu P, Bhagwat m, et al Metformin as an anticoncer agent [J] Trends pharmaceutical SCI., 2018 < br / > [2] Morales D R, Morris a D metformin in cancer treatment and prevention [J] Annual review of medicine, 2015 < br / > [3] Peng m, Darko K o, Tao T, et al Combination of metformin withchemotherapeutic drugs via different molecular mechanisms[J] Cancer TreatmentReviews, 2017 [4] Dugnani E, Cereda S, et al (Ir)relevance ofmetformin treatment in patients with metastatic pancreatic cancer: anopen-label, randomized phase 2 trial[J] Clinical Cancer Research, 2015 [5]Kordes, Sil, Pollak, Michael N, Zwinderman, Aeilko H, etal Metformin in patients with advanced pancreatic cancer: a double-blind,randomised, placebo-controlled phase 2 trial[J] Lancet Oncology, 2015 [6]Marrone K A, Zhou X, Forde P M, et al A Randomized PhaseII Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients withChemotherapy-Naïve Advanced or Metastatic Nonsquamous Non-Small Cell LungCancer[J] The Oncologist, 2018 [7] Komurov K, Tseng J T, Muller M, et al Theglucose-deprivation network counteracts lapatinib-induced toxicity in resistantErbB2-positive breast cancer cells[J].Mol Syst Biol., 2012 [8] Li L, Han R, Xiao H, et al Metformin SensitizesEGFR-TKI-Resistant Human Lung Cancer Cells In Vitro and In Vivo throughInhibition of IL-6 Signaling and EMT Reversal[J] Clinical Cancer Research,2014 [9] Chen H, Yao W, Chu Q, et al Synergistic effects ofmetformin in combination with EGFR-TKI in treatment of patients with advancednon-small cell lung cancer and type 2 diabetes[J].Cancer Letters, 2015 [10] Li L, Jiang L, Wang Y, et al Combination of Metforminand Gefitinib as First-Line Therapy for Nondiabetic Advanced NSCLC Patientswith EGFR Mutations: A Randomized, Double-Blind Phase II Trial[J] Clin CancerRes., 2019 [11] Arrieta O, Barrón F, Padilla M S, et al Effect ofMetformin Plus Tyrosine Kinase Inhibitors Compared With Tyrosine KinaseInhibitors Alone in Patients With Epidermal Growth Factor Receptor-Mutated LungAdenocarcinoma: A Phase 2 Randomized Clinical Trial[J] JAMA Oncol, 2019 [12] Pusceddu S, Vernieri C, Maio M D, et al Metformin UseAssociates With Longer Progression-free Survival of Patients With Diabetes andPancreatic Neuroendocrine Tumors Receiving Everolimus and/or SomatostatinAnalogues[J] Gastroenterology, 2018 [13] Scharping N E, Menk A V, Whetstone R D, et al Efficacyof PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of TumorHypoxia[J] Cancer Immunology Research, 2017 [14] Cha J H, Yang W H, Xia W, et al Metformin PromotesAntitumor Immunity via Endoplasmic-Reticulum-Associated Degradation ofPD-L1[J] Mol Cell, 2018 [15] Zubair A M, Mercado R R, Keisuke S Efficacy ofmetformin in combination with immune checkpointinhibitors(anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma[J] Journalfor ImmunoTherapy of Cancer, 2018 [16] Higurashi T, Hosono K, Takahashi H , et al Metforminfor chemoprevention of metachronous colorectal adenoma or polyps inpost-polypectomy patients without diabetes: a multicenter double-blind,p