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• W4200394791 abstract "Where Are We Now? Soft tissue sarcoma affects more than 13,000 patients annually and causes more than 5000 deaths per year in the United States [9]. But because these numbers represent less than 1% of all cancers diagnosed each year, the financial incentives for drug development and the research resources to study sarcoma are limited. Standard cytotoxic chemotherapy has been utilized to try to improve survival with limited success. Standard chemotherapeutic agents, therefore, remain controversial. Current research efforts have involved targeted chemotherapy agents [2] such as tyrosine kinase and mTOR inhibitors but often only in advanced metastatic disease. These drugs, initially developed for other types of cancer, are now being more widely studied to evaluate their efficacy in soft tissue sarcoma. While research continues to be ongoing, targeted chemotherapeutic agents have not demonstrated they advance cure rates. Current additional methods of evaluating new treatment paths involve the use of drugs currently approved by the Federal Drug Administration for other conditions to see if there may be efficacy in sarcoma. The study by Hutchinson et al. [3] is the first to evaluate the relationship of an oral hypoglycemic drug, metformin, on the survival of patients with soft tissue sarcoma. Metformin may increase survival in a wide variety of carcinomas such as lung, prostate, colorectal, and endometrial origin [4, 7]. The authors [3] found that even after controlling for a number of relevant confounding variables, patients who were taking metformin (most likely for their diabetes) survived longer with their soft tissue sarcomas than did patients who did not take metformin. Based on studies such as this one, further investigations are underway to learn more about the metabolic pathways affected by metformin. The direct anticancer mechanism of metformin is through the activation of the liver kinase B1 (LBK1)-adenosine monosphosphate kinase (AMPK) pathway, which activates a tumor suppressor tuberous sclerosis complex 1 and 2 (TSC 1/2) that negatively regulates the protein mTOR. Metformin-activated AMPK inhibits mTOR with other downstream effects, leading to inhibition of global cell synthesis, cell cycle progression, cell proliferation, and angiogenesis [1, 11]. Analysis of the inhibition or suppression of any one of these cellular functions may lead to a new breakthrough in sarcoma treatment. A remarkable new world is opening up that holds great promise for the future. Where Do We Need To Go? Prospective clinical trials are currently in process with the National Cancer Institute in breast, head and neck, and endometrial carcinomas [5]. These clinical trials will help answer several questions, including: Does metformin actually decrease the risk of a cancer diagnosis? Does metformin improve survival in all types of cancer or only certain types of cancer? Answers in the affirmative to either one of these questions would support asking and answering the question for more rare types of cancer such as sarcoma. High-grade soft tissue sarcoma is an aggressive cancer that is lethal in nearly 40% of those who are diagnosed. The overall survival rate of soft tissue sarcoma has not changed in a considerable way since the development of modern multidisciplinary treatment teams at tertiary referral centers in the 1980s and 1990s. Based upon the current study, one must ask, is metformin the drug we have been searching for to advance sarcoma survival? Metformin, which is a relatively well-tolerated drug with minimal side effects, has been widely studied in other forms of cancer and now needs to be evaluated in sarcoma. Because we already have 50 years of data on the relative safety of metformin, the early work is complete. For example, several studies have demonstrated that metformin is likely a radiation-potentiating agent [7, 8, 12]. It modifies epigenetic phosphorylation of histone H2AX protein and affects complex I of the electron transfer chain (ETC). The damaged ETC reduces oxygen consumption and increases reactive oxygen species (ROS) that increase DNA damage and cancer cell death. Further evaluation of the synergistic effects of radiation and metformin in soft tissue sarcoma is also warranted. Cell metabolism is also tightly linked to epigenetic modifications [11]. Laboratory research has shown that metformin alters H2BK120 ubiquitination, histone acetyltransferases/deacetylases, histone methyl transferase, and DNA methylation. These epigenetic changes alter the cell cycle, cell migration, expression of oncogenes, and the process of apoptosis. Further basic research into the mechanism of action in each of these may elucidate the pathway of metformin’s action and provide new opportunities to potentiate its effects. We should look forward to defining the long-term survival outcomes for metformin. Could treatment response to metformin finally be a prognostic indicator? Certain subtypes of soft tissue sarcoma such as synovial cell sarcoma, rhabdomyosarcoma, and angiosarcoma overexpress vascular endothelial growth factor (VEGF). In a 2020 study by Weiss et al. [10], the NRG Oncology Group and Children’s Oncology Group described the first randomized clinical trial including all age groups that evaluated the efficacy of an intracellular tyrosine kinase inhibitor of the VEGF receptor, pazopanib, in combination with standard chemoradiation in chemotherapy sensitive soft tissue sarcoma subtypes. Protocol design to study metformin could be relatively simple—researchers would need only to compare its use with a control that did not use it. Weiss et al. [10] showed that the multidisciplinary sarcoma cooperative research groups can successfully answer important questions that can potentially lead to improved care. This important process needs to happen with increasing frequency. Other agents and combinations must be evaluated to improve the possibility of finding a true treatment breakthrough. How Do We Get There? Two prospective studies should be performed to validate the SEER database findings in this month’s Clinical Orthopaedics and Related Research® [3]. The first study should longitudinally follow patients with diabetes who take metformin and those who do not. The second study should be a randomized, double-blind trial of patients who do not have diabetes. This type of study would evaluate metformin use in addition to standard treatment. Such a study would need to be a national or even international collaboration between sarcoma research groups. Since the utilization of systemic chemotherapy is controversial, there may need to be several arms of the study to try to adequately handle confounding variables. The PARITY study [6] has demonstrated that international collaboration in sarcoma research can be done. Could a study on metformin be next? Radiation therapy is standard of care in most large soft tissue sarcomas. The randomized trials above could potentially determine the benefit of radiation synergy with metformin. Could the addition of a second radiation potentiation agent such as pazopanib be beneficial as well? Examining the basic science of the interactions of metformin has great promise and can lead to translational treatment advances in the treatment of patients with soft tissue sarcoma. Evidence suggests that the presence of mTOR is necessary to activate hypoxic inducible factor (HIF-1). HIF-1 is a key regulator of gene transcription that affects the ability of cells to adapt to hypoxia and can cause cancer cell resistance when radiation therapy is utilized. AMPK indirectly inhibits HIF-1 activity and cancer cell growth under hypoxic conditions [7]. Further study of the interactions of mTOR, HIF-1, and AMPK will be needed to understand how changing the microenvironment around the sarcoma can improve outcomes. This should be a feasible approach because metformin is very inexpensive and widely used but not an enticing target for new revenue generation for the pharmaceutical industry." @default.
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• W4200394791 date "2021-12-27" @default.
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• W4200394791 title "CORR Insights®: Is Metformin Use Associated with Prolonged Overall Survival In Patients with Soft Tissue Sarcoma? A SEER-Medicare Study" @default.
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