Cancer & Metabolism最新文献

{"title":"Comparative polar and lipid plasma metabolomics differentiate KSHV infection and disease states.","authors":"Sara R Privatt, Camila Pereira Braga, Alicia Johnson, Salum J Lidenge, Luke Berry, John R Ngowi, Owen Ngalamika, Andrew G Chapple, Julius Mwaiselage, Charles Wood, John T West, Jiri Adamec","doi":"10.1186/s40170-023-00316-0","DOIUrl":"10.1186/s40170-023-00316-0","url":null,"abstract":"<p><strong>Background: </strong>Kaposi sarcoma (KS) is a neoplastic disease etiologically associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV). KS manifests primarily as cutaneous lesions in individuals due to either age (classical KS), HIV infection (epidemic KS), or tissue rejection preventatives in transplantation (iatrogenic KS) but can also occur in individuals, predominantly in sub-Saharan Africa (SSA), lacking any obvious immune suppression (endemic KS). The high endemicity of KSHV and human immunodeficiency virus-1 (HIV) co-infection in Africa results in KS being one of the top 5 cancers there. As with most viral cancers, infection with KSHV alone is insufficient to induce tumorigenesis. Indeed, KSHV infection of primary human endothelial cell cultures, even at high levels, is rarely associated with long-term culture, transformation, or growth deregulation, yet infection in vivo is sustained for life. Investigations of immune mediators that distinguish KSHV infection, KSHV/HIV co-infection, and symptomatic KS disease have yet to reveal consistent correlates of protection against or progression to KS. In addition to viral infection, it is plausible that pathogenesis also requires an immunological and metabolic environment permissive to the abnormal endothelial cell growth evident in KS tumors. In this study, we explored whether plasma metabolomes could differentiate asymptomatic KSHV-infected individuals with or without HIV co-infection and symptomatic KS from each other.</p><p><strong>Methods: </strong>To investigate how metabolic changes may correlate with co-infections and tumorigenesis, plasma samples derived from KSHV seropositive sub-Saharan African subjects in three groups, (A) asymptomatic (lacking neoplastic disease) with KSHV infection only, (B) asymptomatic co-infected with KSHV and HIV, and (C) symptomatic with clinically diagnosed KS, were subjected to analysis of lipid and polar metabolite profiles RESULTS: Polar and nonpolar plasma metabolic differentials were evident in both comparisons. Integration of the metabolic findings with our previously reported KS transcriptomics data suggests dysregulation of amino acid/urea cycle and purine metabolic pathways, in concert with viral infection in KS disease progression.</p><p><strong>Conclusions: </strong>This study is, to our knowledge, the first to report human plasma metabolic differentials between in vivo KSHV infection and co-infection with HIV, as well as differentials between co-infection and epidemic KS.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"13"},"PeriodicalIF":5.9,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10470137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10307672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Magnetospirillum magneticum triggers apoptotic pathways in human breast cancer cells.","authors":"Stefano Menghini, Matej Vizovisek, Jonathas Enders, Simone Schuerle","doi":"10.1186/s40170-023-00313-3","DOIUrl":"10.1186/s40170-023-00313-3","url":null,"abstract":"<p><p>The use of bacteria in cancer immunotherapy has the potential to bypass many shortcomings of conventional treatments. The ability of anaerobic bacteria to preferentially accumulate and replicate in hypoxic regions of solid tumors, as a consequence of bacterial metabolic needs, is particularly advantageous and key to boosting their immunostimulatory therapeutic actions in situ. While several of these bacterial traits are well-studied, little is known about their competition for nutrients and its effect on cancer cells which could serve as another potent and innate antineoplastic action. Here, we explored the consequences of the iron-scavenging abilities of a particular species of bacteria, Magnetospirillum magneticum, which has been studied as a potential new class of bacteria for magnetically targeted bacterial cancer therapy. We investigated their influence in hypoxic regions of solid tumors by studying the consequential metabolic effects exerted on cancer cells. To do so, we established an in vitro co-culture system consisting of the bacterial strain AMB-1 incubated under hypoxic conditions with human breast cancer cells MDA-MB-231. We first quantified the number of viable cells after incubation with magnetotactic bacteria demonstrating a lower rate of cellular proliferation that correlated with increasing bacteria-to-cancer cells ratio. Further experiments showed increasing populations of apoptotic cells when cancer cells were incubated with AMB-1 over a period of 24 h. Analysis of the metabolic effects induced by bacteria suggest an increase in the activation of executioner caspases as well as changes in levels of apoptosis-related proteins. Finally, the level of several human apoptosis-related proteins was investigated, confirming a bacteria-dependent triggering of apoptotic pathways in breast cancer cells. Overall, our findings support that magnetotactic bacteria could act as self-replicating iron-chelating agents and indicate that they interfere with proliferation and lead to increased apoptosis of cancer cells. This bacterial feature could serve as an additional antineoplastic mechanism to reinforce current bacterial cancer therapies.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"12"},"PeriodicalIF":5.9,"publicationDate":"2023-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10344209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Restoring gluconeogenesis by TEF inhibited proliferation and promoted apoptosis and immune surveillance in kidney renal clear cell carcinoma.","authors":"Wenyuan Zhuang, Xiaokai Shi, Shenglin Gao, Xihu Qin","doi":"10.1186/s40170-023-00312-4","DOIUrl":"10.1186/s40170-023-00312-4","url":null,"abstract":"<p><strong>Background: </strong>Kidney renal clear cell carcinoma (KIRC) is the major histological subtype of kidney tumor which covers approximately 80% of the cases. Although various therapies have been developed, the clinical outcome remains unsatisfactory. Metabolic dysregulation is a key feature of KIRC, which impacts progression and prognosis of the disease. Therefore, understanding of the metabolic changes in KIRC is of great significance in improving the treatment outcomes.</p><p><strong>Methods: </strong>The glycolysis/gluconeogenesis genes were analyzed in the KIRC transcriptome from the Cancer Genome Atlas (TCGA) by the different expression genes (DEGs) test and survival analysis. The gluconeogenesis-related miRNAs were identified by ImmuLncRNA. The expression levels of indicated genes and miRNAs were validated in KIRC tumor and adjunct tissues by QPCR. The effects of miR-4477b and PCK1 on cell proliferation and apoptosis were examined using the cell viability assay, cell apoptosis assay, and clone information. The interaction of miR-4477b with TEF was tested by the luciferase report gene assay. The different gluconeogenesis statuses of tumor cells and related signatures were investigated by single-cell RNA sequencing (scRNA-seq) analysis.</p><p><strong>Results: </strong>The 11 gluconeogenesis genes were found to be suppressed in KIRC (referring as PGNGs), and the less suppression of PGNGs indicated better survival outcomes. Among the 11 PGNGs, we validated four rate-limiting enzyme genes in clinical tumor patients. Moreover, restoring gluconeogenesis by overexpressing PCK1 or TEF through miR-4477b inhibition significantly inhibited tumor cell proliferation, colony formation, and induced cell apoptosis in vitro. Independent single-cell RNA sequencing (scRNA-seq) data analysis revealed that the tumor cells had high levels of PGNG expression (PGNG + tumor cells) represented a phenotype of early stage of neoplasia and prompted immune surveillance.</p><p><strong>Conclusions: </strong>Our study suggests that the deficiency of gluconeogenesis is a key metabolic feature of KIRC, and restoring gluconeogenesis could effectively inhibit the proliferation and progression of KIRC cells.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"11"},"PeriodicalIF":5.9,"publicationDate":"2023-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10410999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10026397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long non-coding RNA CCHE1 modulates LDHA-mediated glycolysis and confers chemoresistance to melanoma cells.","authors":"Zhi Ding,&nbsp;Junyi Yang,&nbsp;Baojin Wu,&nbsp;Yingzhi Wu,&nbsp;Fanli Guo","doi":"10.1186/s40170-023-00309-z","DOIUrl":"10.1186/s40170-023-00309-z","url":null,"abstract":"<p><p>Melanoma is considered as the most common metastatic skin cancer with increasing incidence and high mortality globally. The vital roles of long non-coding RNAs (lncRNAs) in the tumorigenesis of melanoma are elucidated by emerging evidence. The lncRNA cervical carcinoma high-expressed 1 (CCHE1) was overexpressed and acted as an oncogene in a variety of cancers, while the function of CCHE1 in melanoma remains unclear. Here, we found that CCHE1 was highly expressed in melanoma and correlated with the poorer survival of melanoma patients. Depletion of CCHE1 inhibited the proliferation, induced cell apoptosis and suppressed in vivo tumor growth. To further understand the functional mechanism of CCHE1, the interacting partners of CCHE1 were identified via RNA pull-down assay followed by mass spectrometry. CCHE1 was found to bind lactate dehydrogenase A (LDHA) and acted as a scaffold to enhance the interaction of LDHA with the fibroblast growth factor receptor type 1 (FGFR1), which consequently enhanced LDHA phosphorylation and activity of LDHA. Inhibiting CCHE1 strikingly suppressed the glycolytic flux of melanoma cells and lactate generation in vivo. Further study demonstrated that CCHE1 desensitized melanoma cells to dacarbazine and inhibition of glycolysis reversed CCHE1-induced chemoresistance. These results uncovered the novel function of CCHE1 in melanoma by reprogramming the glucose metabolism via orchestrating the activity of LDHA.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"10"},"PeriodicalIF":5.9,"publicationDate":"2023-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10360318/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9857477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in hepatocellular carcinoma (HCC) cells.","authors":"Jiamin Zhong,&nbsp;Luyao Tian,&nbsp;Yannian Gou,&nbsp;Piao Zhao,&nbsp;Xiangyu Dong,&nbsp;Meichun Guo,&nbsp;Guozhi Zhao,&nbsp;Aohua Li,&nbsp;Ailing Hao,&nbsp;Tong-Chuan He,&nbsp;Jiaming Fan","doi":"10.1186/s40170-023-00310-6","DOIUrl":"https://doi.org/10.1186/s40170-023-00310-6","url":null,"abstract":"<p><strong>Background: </strong>Excessive hepatic glycogen accumulation benefits tumorigenesis and cancer cell survival. We previously reported that BMP4 has the strongest ability to promote glycogenesis among the 14 BMPs in hepatocytes and augmented hepatocellular carcinoma (HCC) cell survival under hypoxia and hypoglycemia conditions by promoting the glycolysis pathway. However, the mechanism underlying BMP4's effect on glycogenesis in HCC remains elusive.</p><p><strong>Methods: </strong>The expression of BMP4 and SLC2A1 were acquired by analyzing the TCGA-LIHC dataset, as well as by immunohistochemical analysis of the 40 pairs of human HCC samples and para-tumor tissues. Gene expressions were detected by qPCR, immunoflurorescence staining, and Western blotting. Overexpression and silencing of BMP4 were accomplished through adenoviruses Ad-B4 and Ad-siB4 infection. Hepatic glycogen was detected by PAS staining. SLC2A1 (GLUT1) function was blocked by the inhibitor BAY-876. ChIP assay was used to determine the binding of SMADs to the promoter region of SLC2A1 in HCC cells. Lastly, the in vivo effect of BMP4-regulated SLC2A1 on HCC tumor growth was assessed in a xenograft model of HCC.</p><p><strong>Results: </strong>The elevated expression of BMP4 in HCC tumor tissues was highly correlated with hepatic glycogen accumulation in clinical samples. SLC2A1 was highly expressed in HCC tumor tissue and correlated with clinical stage and prognosis. Exogenous BMP4 augmented glycogen accumulation and upregulated the expression of glycogen synthesis-related genes in Huh7 and HepG2 cells, both of which were effectively blunted by SLC2A1inhibitor BAY-876. In mechanism, BMP4 activated SMAD5 to regulate the promoter of SLC2A1to enhance its expression. The in vivo xenograft experiments revealed that BMP4 promoted glycogen accumulation and tumor growth, which were effectively diminished by BAY-876.</p><p><strong>Conclusion: </strong>These results demonstrate that BMP4 upregulates glycogen synthesis through the SMAD/SLC2A1 (GLUT1) signaling axis in HCC cells, which may be exploited as novel therapeutic targets for HCC treatment.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"9"},"PeriodicalIF":5.9,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10339511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9817691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obesity and breast cancer prognosis: pre-diagnostic anthropometric measures in relation to patient, tumor, and treatment characteristics.","authors":"Sixten Harborg,&nbsp;Maria Feldt,&nbsp;Deirdre Cronin-Fenton,&nbsp;Marie Klintman,&nbsp;Susanne O Dalton,&nbsp;Ann H Rosendahl,&nbsp;Signe Borgquist","doi":"10.1186/s40170-023-00308-0","DOIUrl":"https://doi.org/10.1186/s40170-023-00308-0","url":null,"abstract":"<p><strong>Purpose: </strong>Examine the association between obesity and clinical outcomes in early breast cancer and assess if patient, tumor, and treatment characteristics modify such associations in Malmö Diet and Cancer Study patients (MDCS).</p><p><strong>Methods: </strong>The MDCS enrolled 17,035 Swedish women from 1991 to 1996. At enrollment, participants' body mass index (BMI), waist circumference and body fat percentage measures were collected. We identified all female MDCS participants with invasive breast cancer from 1991 to 2014. Follow-up began at breast cancer diagnosis and ended at breast cancer recurrence (BCR), death, emigration, or June 8, 2020. The World Health Organization guidelines were used to classify BMI, waist circumference, and body fat percentage into three categories of healthy weight, overweight, and obesity. We fit Cox regression models to compute adjusted hazard ratios (HRs) with 95% confidence intervals (CI) of BCR according to body composition. To evaluate effect measure modification, we stratified Cox models by patient, tumor, and treatment characteristics.</p><p><strong>Results: </strong>In total, 263 BCRs were diagnosed over 12,816 person-years among 1099 breast cancer patients with a median follow-up of 11.1 years. Obesity according to BMI (HR = 1.44 [95%CI 1.00-2.07]), waist circumference (HR = 1.31 [95%CI 0.98-1.77]), and body fat percentage (HR = 1.41 [95%CI 1.02-1.98]) was associated with increased risk of BCR compared with healthy weight. Obesity was stronger associated with BCR in patients with low socioeconomic position (HR = 2.55 [95%CI 1.08-6.02]), larger tumors > 20 mm (HR = 2.68 [95%CI 1.42-5.06]), estrogen-receptor-negative breast cancer (HR = 3.13 [95%CI 1.09-8.97]), and with adjuvant chemotherapy treatment (HR = 2.06 [95%CI 1.08-4.31]).</p><p><strong>Conclusion: </strong>Higher pre-diagnostic BMI, waist circumference, and body fat percentage was associated with increased risk of BCR. The association between obesity and BCR appears dependent on patient, tumor, and treatment characteristics.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"8"},"PeriodicalIF":5.9,"publicationDate":"2023-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10294507/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10097014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual inhibition of IDO1/TDO2 enhances anti-tumor immunity in platinum-resistant non-small cell lung cancer.","authors":"Chunjing Wu,&nbsp;Sydney A Spector,&nbsp;George Theodoropoulos,&nbsp;Dan J M Nguyen,&nbsp;Emily Y Kim,&nbsp;Ashley Garcia,&nbsp;Niramol Savaraj,&nbsp;Diane C Lim,&nbsp;Ankita Paul,&nbsp;Lynn G Feun,&nbsp;Michael Bickerdike,&nbsp;Medhi Wangpaichitr","doi":"10.1186/s40170-023-00307-1","DOIUrl":"https://doi.org/10.1186/s40170-023-00307-1","url":null,"abstract":"<p><strong>Background: </strong>The impact of non-small cell lung cancer (NSCLC) metabolism on the immune microenvironment is not well understood within platinum resistance. We have identified crucial metabolic differences between cisplatin-resistant (CR) and cisplatin-sensitive (CS) NSCLC cells with elevated indoleamine 2,3-dioxygenase-1 (IDO1) activity in CR, recognized by increased kynurenine (KYN) production.</p><p><strong>Methods: </strong>Co-culture, syngeneic, and humanize mice models were utilized. C57BL/6 mice were inoculated with either Lewis lung carcinoma mouse cells (LLC) or their platinum-resistant counterpart (LLC-CR) cells. Humanized mice were inoculated with either A (human CS cells) or ALC (human CR cells). Mice were treated with either IDO1 inhibitor or TDO2 (tryptophan 2,3-dioxygenase-2) inhibitor at 200 mg/kg P.O. once a day for 15 days; or with a new-in-class, IDO1/TDO2 dual inhibitor AT-0174 at 170 mg/kg P.O. once a day for 15 days with and without anti-PD1 antibody (10 mg/kg, every 3 days). Immune profiles and KYN and tryptophan (TRP) production were evaluated.</p><p><strong>Results: </strong>CR tumors exhibited a more highly immunosuppressive environment that debilitated robust anti-tumor immune responses. IDO1-mediated KYN production from CR cells suppressed NKG2D on immune effector natural killer (NK) and CD8⁺ T cells and enhanced immunosuppressive populations of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). Importantly, while selective IDO1 inhibition attenuated CR tumor growth, it concomitantly upregulated the TDO2 enzyme. To overcome the compensatory induction of TDO2 activity, we employed the IDO1/TDO2 dual inhibitor, AT-0174. Dual inhibition of IDO1/TDO2 in CR mice suppressed tumor growth to a greater degree than IDO1 inhibition alone. Significant enhancement in NKG2D frequency on NK and CD8⁺ T cells and a reduction in Tregs and MDSCs were observed following AT-1074 treatment. PD-L1 (programmed death-ligand-1) expression was increased in CR cells; therefore, we assessed dual inhibition + PD1 (programmed cell death protein-1) blocking and report profound anti-tumor growth and improved immunity in CR tumors which in turn extended overall survival in mice.</p><p><strong>Conclusion: </strong>Our study reports the presence of platinum-resistant lung tumors that utilize both IDO1/TDO2 enzymes for survival, and to escape immune surveillance as a consequence of KYN metabolites. We also report early in vivo data in support of the potential therapeutic efficacy of the dual IDO1/TDO2 inhibitor AT-0174 as a part of immuno-therapeutic treatment that disrupts tumor metabolism and enhances anti-tumor immunity.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"7"},"PeriodicalIF":5.9,"publicationDate":"2023-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10207715/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9517239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.","authors":"Lauren K Park,&nbsp;Kian-Huat Lim,&nbsp;Jonas Volkman,&nbsp;Mina Abdiannia,&nbsp;Hannah Johnston,&nbsp;Zack Nigogosyan,&nbsp;Marilyn J Siegel,&nbsp;Janet B McGill,&nbsp;Alexis M McKee,&nbsp;Maamoun Salam,&nbsp;Rong M Zhang,&nbsp;Da Ma,&nbsp;Karteek Popuri,&nbsp;Vincent Tze Yang Chow,&nbsp;Mirza Faisal Beg,&nbsp;William G Hawkins,&nbsp;Linda R Peterson,&nbsp;Joseph E Ippolito","doi":"10.1186/s40170-023-00306-2","DOIUrl":"https://doi.org/10.1186/s40170-023-00306-2","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear.</p><p><strong>Methods: </strong>We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed.</p><p><strong>Results: </strong>Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements.</p><p><strong>Conclusions: </strong>Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"6"},"PeriodicalIF":5.9,"publicationDate":"2023-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10193807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9500806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between diabetes mellitus and reduced efficacy of pembrolizumab in non-small cell lung cancer.","authors":"Y. Leshem, Yardenna Dolev, N. Siegelmann-Danieli, S. Sharman Moser, L. Apter, G. Chodick, A. Nikolaevski-Berlin, S. Shamai, O. Merimsky, I. Wolf","doi":"10.1530/endoabs.90.p379","DOIUrl":"https://doi.org/10.1530/endoabs.90.p379","url":null,"abstract":"BACKGROUND\u0000Diabetes mellitus (DM) is a highly prevalent chronic metabolic disorder. Although DM has been associated with immune dysfunction, the effect of DM on the efficacy of immunotherapy is unknown. This study aimed to evaluate the impact of DM on the efficacy of pembrolizumab in metastatic non-small cell lung cancer (NSCLC).\u0000\u0000\u0000METHODS\u0000The authors reviewed the medical records of consecutive metastatic NSCLC patients treated with first-line pembrolizumab either alone or in combination with chemotherapy at a single tertiary center. For validation, a computerized data from Maccabi Healthcare Services, a 2.5-million-member state health service was used.\u0000\u0000\u0000RESULTS\u0000Of the 203 eligible patients, 51 (25%) had DM. Patients with DM had a significantly shorter median progression-free survival (PFS) (5.9 vs. 7.1 months, p = .004) and overall survival (OS) (12 vs. 21 months, p = .006). The shorter OS in diabetic patients was more pronounced when pembrolizumab was given alone (12 vs. 27 months, p = .03) than when combined with chemotherapy (14.3 vs. 19.4 months, p = .06). Multivariate analysis confirmed DM as an independent risk factor for shorter PFS (hazard ratio [HR], 1.67; 95% confidence interval [CI], 1.11-2.50, p = .01) and OS (HR, 1.73; 95% CI, 1.09-2.76, p = .02). In a validation cohort of 452 metastatic NSCLC patients, the time on pembrolizumab treatment was shorter in diabetic patients (p = .025), with only 19.6% of patients remaining on treatment at 12 months compared to 31.7% of the nondiabetic patients.\u0000\u0000\u0000CONCLUSIONS\u0000This study suggests immunotherapy is less beneficial in diabetic NSCLC patients. More work is needed to verify our findings and explore similar effects in other cancer entities.","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"41 1","pages":""},"PeriodicalIF":5.9,"publicationDate":"2023-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72998961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Normalization of hepatic ChREBP activity does not protect against liver disease progression in a mouse model for Glycogen Storage Disease type Ia.","authors":"Martijn G S Rutten,&nbsp;Yu Lei,&nbsp;Joanne H Hoogerland,&nbsp;Vincent W Bloks,&nbsp;Hong Yang,&nbsp;Trijnie Bos,&nbsp;Kishore A Krishnamurthy,&nbsp;Aycha Bleeker,&nbsp;Mirjam H Koster,&nbsp;Rachel E Thomas,&nbsp;Justina C Wolters,&nbsp;Hilda van den Bos,&nbsp;Gilles Mithieux,&nbsp;Fabienne Rajas,&nbsp;Adil Mardinoglu,&nbsp;Diana C J Spierings,&nbsp;Alain de Bruin,&nbsp;Bart van de Sluis,&nbsp;Maaike H Oosterveer","doi":"10.1186/s40170-023-00305-3","DOIUrl":"https://doi.org/10.1186/s40170-023-00305-3","url":null,"abstract":"<p><strong>Background: </strong>Glycogen storage disease type 1a (GSD Ia) is an inborn error of metabolism caused by a defect in glucose-6-phosphatase (G6PC1) activity, which induces severe hepatomegaly and increases the risk for liver cancer. Hepatic GSD Ia is characterized by constitutive activation of Carbohydrate Response Element Binding Protein (ChREBP), a glucose-sensitive transcription factor. Previously, we showed that ChREBP activation limits non-alcoholic fatty liver disease (NAFLD) in hepatic GSD Ia. As ChREBP has been proposed as a pro-oncogenic molecular switch that supports tumour progression, we hypothesized that ChREBP normalization protects against liver disease progression in hepatic GSD Ia.</p><p><strong>Methods: </strong>Hepatocyte-specific G6pc knockout (L-G6pc^-/-) mice were treated with AAV-shChREBP to normalize hepatic ChREBP activity.</p><p><strong>Results: </strong>Hepatic ChREBP normalization in GSD Ia mice induced dysplastic liver growth, massively increased hepatocyte size, and was associated with increased hepatic inflammation. Furthermore, nuclear levels of the oncoprotein Yes Associated Protein (YAP) were increased and its transcriptional targets were induced in ChREBP-normalized GSD Ia mice. Hepatic ChREBP normalization furthermore induced DNA damage and mitotic activity in GSD Ia mice, while gene signatures of chromosomal instability, the cytosolic DNA-sensing cGAS-STING pathway, senescence, and hepatocyte dedifferentiation emerged.</p><p><strong>Conclusions: </strong>In conclusion, our findings indicate that ChREBP activity limits hepatomegaly while decelerating liver disease progression and protecting against chromosomal instability in hepatic GSD Ia. These results disqualify ChREBP as a therapeutic target for treatment of liver disease in GSD Ia. In addition, they underline the importance of establishing the context-specific roles of hepatic ChREBP to define its therapeutic potential to prevent or treat advanced liver disease.</p>","PeriodicalId":9418,"journal":{"name":"Cancer & Metabolism","volume":"11 1","pages":"5"},"PeriodicalIF":5.9,"publicationDate":"2023-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122297/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9415655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}