scholarly journals Targeting IDH1 as a pro-senescent therapy in high-grade serous ovarian cancer

2018 ◽  
Author(s):  
Erika S. Dahl ◽  
Raquel Buj ◽  
Kelly E. Leon ◽  
Jordan M. Newell ◽  
Benjamin G. Bitler ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Aerobic Glycolysis ◽  
Gynecological Cancer ◽  
Significant Proportion ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Serous Carcinoma ◽  
Metabolic Adaptation ◽  
High Grade ◽  
Novel Therapeutic

AbstractEpithelial ovarian cancer (EOC) is the deadliest gynecological cancer. High-grade serous carcinoma (HGSC) is the most frequently diagnosed and lethal histosubtype of EOC. A significant proportion of HGSC patients relapse with chemoresistant disease. Therefore, there is an urgent need for novel therapeutic strategies for HGSC. Metabolic reprogramming is a hallmark of cancer cells, and targeting metabolism for cancer therapy may be beneficial. Here we found that in comparison to normal fallopian tube epithelial cells, HGSC cells preferentially utilize glucose in the TCA cycle and not for aerobic glycolysis. This correlated with universally increased TCA cycle enzyme expression in HGSC cells under adherent conditions. To further differentiate the necessity of TCA cycle enzymes in ovarian cancer progression, we found that only wildtype isocitrate dehydrogenase I (IDH1) is both significantly increased in HGSC cells in spheroid conditions and is associated with reduced progression-free survival. IDH1 protein expression is also increased in primary HGSC patient tumors. Pharmacological inhibition or knockdown of IDH1 decreased proliferation of multiple HGSC cell lines by inducing senescence. Mechanistically, suppression of IDH1 increased the repressive histone mark H3K9me2 at proliferation promoting gene loci (PCNA and MCM3), which led to decreased mRNA expression. Altogether, these data suggest that increased IDH1 activity is an important metabolic adaptation in HGSC and that targeting wildtype IDH1 in HGSC alters the repressive histone epigenetic landscape to induce senescence. Therefore, inhibition of IDH1 may act as a novel therapeutic approach to alter both the metabolism and epigenetics of HGSC as a pro-senescent therapy.

scholarly journals Emergence of MicroRNAs as Key Players in Cancer Cell Metabolism

2019 ◽  
Vol 65 (9) ◽  
pp. 1090-1101 ◽  
Author(s):  
Sugarniya Subramaniam ◽  
Varinder Jeet ◽  
Judith A Clements ◽  
Jennifer H Gunter ◽  
Jyotsna Batra
Keyword(s):  
Fatty Acid ◽  
Signaling Pathways ◽  
Tumor Cells ◽  
Metabolic Pathways ◽  
Acid Metabolism ◽  
Tca Cycle ◽  
Metabolic Reprogramming ◽  
Metabolic Adaptation ◽  
Novel Therapeutic

AbstractBACKGROUNDMetabolic reprogramming is a hallmark of cancer. MicroRNAs (miRNAs) have been found to regulate cancer metabolism by regulating genes involved in metabolic pathways. Understanding this layer of complexity could lead to the development of novel therapeutic approaches.CONTENTmiRNAs are noncoding RNAs that have been implicated as master regulators of gene expression. Studies have revealed the role of miRNAs in the metabolic reprogramming of tumor cells, with several miRNAs both positively and negatively regulating multiple metabolic genes. The tricarboxylic acid (TCA) cycle, aerobic glycolysis, de novo fatty acid synthesis, and altered autophagy allow tumor cells to survive under adverse conditions. In addition, major signaling molecules, hypoxia-inducible factor, phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin/phosphatase and tensin homolog, and insulin signaling pathways facilitate metabolic adaptation in tumor cells and are all regulated by miRNAs. Accumulating evidence suggests that miRNA mimics or inhibitors could be used to modulate the activity of miRNAs that drive tumor progression via altering their metabolism. Currently, several clinical trials investigating the role of miRNA-based therapy for cancer have been launched that may lead to novel therapeutic interventions in the future.SUMMARYIn this review, we summarize cancer-related metabolic pathways, including glycolysis, TCA cycle, pentose phosphate pathway, fatty acid metabolism, amino acid metabolism, and other metabolism-related oncogenic signaling pathways, and their regulation by miRNAs that are known to lead to tumorigenesis. Further, we discuss the current state of miRNA therapeutics in the clinic and their future potential.

scholarly journals Targeting progesterone signaling prevents metastatic ovarian cancer

2020 ◽  
Vol 117 (50) ◽  
pp. 31993-32004
Author(s):  
Olga Kim ◽  
Eun Young Park ◽  
Sun Young Kwon ◽  
Sojin Shin ◽  
Robert E. Emerson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Deleterious Mutation ◽  
Peritoneal Metastases ◽  
Cancer Development ◽  
Serous Carcinoma ◽  
Cancer Type ◽  
High Grade ◽  
Primary Tumors ◽  
High Risk Populations ◽  
Genetic Deletion

Effective cancer prevention requires the discovery and intervention of a factor critical to cancer development. Here we show that ovarian progesterone is a crucial endogenous factor inducing the development of primary tumors progressing to metastatic ovarian cancer in a mouse model of high-grade serous carcinoma (HGSC), the most common and deadliest ovarian cancer type. Blocking progesterone signaling by the pharmacologic inhibitor mifepristone or by genetic deletion of the progesterone receptor (PR) effectively suppressed HGSC development and its peritoneal metastases. Strikingly, mifepristone treatment profoundly improved mouse survival (∼18 human years). Hence, targeting progesterone/PR signaling could offer an effective chemopreventive strategy, particularly in high-risk populations of women carrying a deleterious mutation in the BRCA gene.

scholarly journals Tumour Versus Germline BRCA Testing in Ovarian Cancer: A Single-Site Institution Experience in the United Kingdom

Diagnostics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 547
Author(s):  
Iolia Akaev ◽  
Siavash Rahimi ◽  
Olubukola Onifade ◽  
Francis John Edward Gardner ◽  
David Castells-Rufas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Unknown Origin ◽  
Parp Inhibitors ◽  
Serous Carcinoma ◽  
High Grade ◽  
Brca1 And Brca2 ◽  
Brca Mutations ◽  
Epithelial Cancers ◽  
Pathogenic Variants ◽  
Pathogenic Mutations

The aim of this audit was to evaluate the usefulness and serviceability of testing for pathogenic mutations in BRCA1 or BRCA2 (BRCA1/2) genes in ovarian cancer (OC) patients. One hundred and thirty-five patients with more common histological sub-types of OC were retrospectively identified between 2011 and 2019. The fail rate of the molecular analysis was 7.4% (10/135). One hundred and twenty-five records were evaluated: 99 (79.2%) patients had wild-type BRCA (both somatic and germline); tumour BRCA1/2 (tBRCA1/2) pathogenic mutations were found in 20 (16%) patients with distribution between BRCA1 and BRCA2 being 40% and 60%, respectively; 13 (10.4%) patients with pathogenic variants had germline mutations; and tBRCA1/2 with variant of unknown significance (VUS), in the absence of pathogenic BRCA1 or BRCA2 variants, was detected in 6 (4.8%) patients. Our data show that expanding the molecular service to the routine first-tumour testing for patients with OC will potentially increase the detection rate of BRCA mutations, thereby providing early benefits of PARP inhibitors therapy. The tumour testing service should continue to be offered to newly diagnosed patients with high-grade epithelial cancers, including high-grade serous carcinoma, but also with carcinosarcomas and poorly-differentiated metastatic adenocarcinomas of unknown origin.

scholarly journals Precision Oncology of High-Grade Ovarian Cancer Defined through Targeted Sequencing

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5240
Author(s):  
Sandra Wessman ◽  
Beatriz Bohorquez Fuentes ◽  
Therese Törngren ◽  
Anders Kvist ◽  
Georgia Kokaraki ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Molecular Characterization ◽  
Parp Inhibitor ◽  
Clinical Information ◽  
Undifferentiated Carcinoma ◽  
Serous Carcinoma ◽  
Precision Oncology ◽  
High Grade ◽  
Histologic Diagnosis ◽  
Germline Testing

Background: We examined whether molecular characterization of high-grade epithelial ovarian cancer can inform the diagnosis and/or identify potential actionable targets. Methods: All of the consecutively sequenced high-grade ovarian tumours with consent between 2014 until 2019 were included. A total of 274 tumours underwent next generation sequencing using a targeted panel. Results: Patients with high-grade ovarian epithelial cancer were consented to prospective molecular characterization. Clinical information was extracted from their medical record. Tumour DNA was subjected to sequencing, and selected patients received PARP inhibitor therapy. Conclusions: Tumours from 274 women were sequenced, including high-grade serous carcinoma (n = 252), clear cell carcinoma (n = 4), carcinosarcoma (n = 9), endometrioid carcinoma (n = 3), undifferentiated carcinoma (n = 1), and mixed tumours (n = 5). Genomic profiling did not influence histologic diagnosis. Mutations were identified in TP53, BRCA1, BRCA2, as well as additional homologous recombination repair pathway genes BARD1, ATR, CHEK2, PALB2, RAD51D, RAD50, SLX4, FANCA, RAD51C, and RAD54L. In addition, mutations in PTEN and CDKN2A were identified. Several somatic mutations with implications for germline testing were identified, including RMI1, STK11, and CDH1. Germline testing identified 16 previously unknown BRCA1/2 carriers. Finally, 20 patients were treated with the PARP inhibitor olaparib based on the sequencing results.

scholarly journals Metabolic Reprogramming from Glycolysis to Fatty Acid Uptake and beta-Oxidation in Platinum-Resistant Cancer Cells

2021 ◽  
Author(s):  
Junjie Li ◽  
Yuying Tan ◽  
Guangyuan Zhao ◽  
Kai-Chih Huang ◽  
Horacio Cardenas ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Single Cell ◽  
Cancer Cell ◽  
Aerobic Glycolysis ◽  
Fatty Acid Uptake ◽  
Metabolic Reprogramming ◽  
De Novo Lipogenesis ◽  
Acid Uptake ◽  
Beta Oxidation

Increased aerobic glycolysis is widely considered as a hallmark of cancer. Yet, cancer cell metabolic reprograming during development of therapeutic resistance is under-studied. Here, through high-throughput stimulated Raman scattering imaging and single cell analysis, we found that cisplatin-resistant cells exhibit increased uptake of exogenous fatty acids, accompanied with decreased glucose uptake and de novo lipogenesis, indicating a reprogramming from glucose and glycolysis dependent to fatty acid uptake and beta-oxidation dependent anabolic and energy metabolism. A metabolic index incorporating measurements of glucose derived anabolism and fatty acid uptake correlates linearly to the level of resistance to cisplatin in ovarian cancer cell lines and in primary cells isolated from ovarian cancer patients. Mechanistically, the increased fatty acid uptake facilitates cancer cell survival under cisplatin-induced oxidative stress by enhancing energy production through beta-oxidation. Consequently, blocking fatty acid beta-oxidation by a small molecule inhibitor in combination with cisplatin or carboplatin synergistically suppressed ovarian cancer proliferation in vitro and growth of patient-derived xenograft in vivo. Collectively, these findings support a new way for rapid detection of cisplatin-resistance at single cell level and a new strategy for treatment of cisplatin-resistant tumors.

scholarly journals Oxidative Phosphorylation: A Target for Novel Therapeutic Strategies Against Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 337 ◽  
Author(s):  
Amruta Nayak ◽  
Arvinder Kapur ◽  
Lisa Barroilhet ◽  
Manish Patankar
Keyword(s):  
Ovarian Cancer ◽  
Oxidative Phosphorylation ◽  
Aerobic Glycolysis ◽  
Ovarian Tumors ◽  
Metabolic Adaptation ◽  
Ovarian Cancer Stem Cells ◽  
Critical Control Points ◽  
Energy Needs ◽  
Oxidative Phosphorylation Pathway ◽  
Novel Therapeutic Strategies

Aerobic glycolysis is an important metabolic adaptation of cancer cells. There is growing evidence that oxidative phosphorylation is also an active metabolic pathway in many tumors, including in high grade serous ovarian cancer. Metastasized ovarian tumors use fatty acids for their energy needs. There is also evidence of ovarian cancer stem cells privileging oxidative phosphorylation (OXPHOS) for their metabolic needs. Metformin and thiazolidinediones such as rosiglitazone restrict tumor growth by inhibiting specific steps in the mitochondrial electron transport chain. These observations suggest that strategies to interfere with oxidative phosphorylation should be considered for the treatment of ovarian tumors. Here, we review the literature that supports this hypothesis and describe potential agents and critical control points in the oxidative phosphorylation pathway that can be targeted using small molecule agents. In this review, we also discuss potential barriers that can reduce the efficacy of the inhibitors of oxidative phosphorylation.

scholarly journals Genomics and molecular mechanisms of high grade serous ovarian cancer: the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium

2019 ◽  
Vol 29 (Suppl 2) ◽  
pp. s7-s11
Author(s):  
Erinn B Rankin
Keyword(s):  
Ovarian Cancer ◽  
Cancer Research ◽  
Dna Repair ◽  
Molecular Mechanisms ◽  
New Technologies ◽  
Serous Carcinoma ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Poster Presentations ◽  
Oral Presentations

ObjectiveThe aim of this study was to review current research efforts in genomics and molecular mechanisms of high grade serous ovarian cancer, presented at the 12th Biennial Rivkin Center Ovarian Cancer Research Symposium, held at the University of Washington.MethodsThe 12th Biennial Rivkin Center Ovarian Cancer Research Symposium brought together leaders in the field to discuss recent advances in ovarian cancer research and therapy.ResultsThe genomics and molecular mechanisms of ovarian cancer session featured invited speaker presentations by Dr Alan D’ Andrea on ‘Deoxyribonucleic acid (DNA) repair in ovarian cancer’ and Dr Kathleen Cho on ‘Modeling the genomics of high grade serous carcinoma in the mouse’. Eight additional oral presentations and 46 poster presentations were selected from the submitted abstracts that highlighted current research efforts in p53, DNA repair, genomic instability and modeling disease in mice, and organoids in high grade serous ovarian cancer.ConclusionsNew technologies utilizing clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (CAS9) approaches in mice, organoids, and cell based screens continue to advance our knowledge of key molecular drivers of ovarian cancer initiation, progression, and drug resistance. Improved understanding of the mechanisms of poly ADP ribose polymerase inhibitor resistance may lead to new therapeutic strategies to enhance outcomes in women with high grade serous ovarian cancer.

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