Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Gastric Cancer
Published in: Gastric Cancer 6/2020

Open Access 01-11-2020 | Ramucirumab | Original Article

Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel-ramucirumab

Authors: Annamaria Ruzzo, Francesco Graziano, Irene Bagaloni, Maria Di Bartolomeo, Michele Prisciandaro, Giuseppe Aprile, Elena Ongaro, Bruno Vincenzi, Giuseppe Perrone, Daniele Santini, Lorenzo Fornaro, Caterina Vivaldi, Gianluca Tomasello, Fotios Loupakis, Sara Lonardi, Matteo Fassan, Michele Valmasoni, Donatella Sarti, Paola Lorenzini, Vincenzo Catalano, Renato Bisonni, Michela Del Prete, Guido Collina, Mauro Magnani

Published in: Gastric Cancer | Issue 6/2020

Login to get access

Abstract

Introduction

For energy production, cancer cells maintain a high rate of glycolysis instead of oxidative phosphorylation converting glucose into lactic acid. This metabolic shift is useful to survive in unfavorable microenvironments. We investigated whether a positive glycolytic profile (PGP) in gastric adenocarcinomas may be associated with unfavorable outcomes under an anticancer systemic therapy, including the anti-angiogenic ramucirumab.

Materials and methods

Normal mucosa (NM) and primary tumor (PT) of 40 metastatic gastric adenocarcinomas patients who received second-line paclitaxel-ramucirumab (PR) were analyzed for mRNA expression of the following genes: HK-1, HK-2, PKM-2, LDH-A, and GLUT-1. Patients were categorized with PGP when at least a doubling of mRNA expression (PT vs. NM) in all glycolytic core enzymes (HK-1 or HK-2, PKM-2, LDH-A) was observed. PGP was also related to TP53 mutational status.

Results

Mean LDH-A, HK-2, PKM-2 mRNA expression levels were significantly higher in PT compared with NM. 18 patients were classified as PGP, which was associated with significantly worse progression-free and overall survival times. No significant association was observed between PGP and clinical-pathologic features, including TP53 positive mutational status, in 28 samples.

Conclusions

Glycolytic proficiency may negatively affect survival outcomes of metastatic gastric cancer patients treated with PR systemic therapy. TP53 mutational status alone does not seem to explain such a metabolic shift.
Appendix
Available only for authorised users
Literature
1.
Ngo DC, Ververis K, Tortorella SM, Karagiannis TC. Introduction to the molecular basis of cancer metabolism and the Warburg effect. Mol Biol Rep. 2015;42:819–23.PubMed
2.
3.
Feng Y, Xiong Y, Qiao T, Li X, Jia L, Han Y. Lactate dehydrogenase A: a key player in carcinogenesis and potential target in cancer therapy. Cancer Med. 2018;7:6124–36.PubMedPubMedCentral
4.
Herling A, König M, Bulik S, Holzhütter HG. Enzymatic features of the glucose metabolism in tumor cells. FEBS J. 2011;278:2436–59.PubMed
5.
Chaneton B, Gottlieb E. Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer. Trends Biochem Sci. 2012;37:309–16.PubMed
6.
Graziano F, Ruzzo A, Giacomini E, Ricciardi T, Aprile G, Loupakis F, et al. Glycolysis gene expression analysis and selective metabolic advantage in the clinical progression of colorectal cancer. Pharmacogenomics J. 2017;17:258–64.PubMed
7.
Jiménez-Valerio G, Casanovas O. Angiogenesis and metabolism: entwined for therapy resistance. Trends Cancer. 2017;3:10–8.PubMed
8.
Abdullah SE, Perez-Soler R. Mechanisms of resistance to vascular endothelial growth factor blockade. Cancer. 2012;118:3455–67.PubMed
9.
Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to anti-angiogenic therapy in cancer-alterations to anti-VEGF pathway. Int J Mol Sci. 2018;19(4):E1232.PubMed
10.
Wilde L, Roche M, Domingo-Vidal M, Tanson K, Philip N, Curry J, Martinez-Outschoorn U. Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development. Semin Oncol. 2017;44:198–203.PubMedPubMedCentral
11.
Paolicchi E, Gemignani F, Krstic-Demonacos M, Dedhar S, Mutti L, Landi S. Targeting hypoxic response for cancer therapy. Oncotarget. 2016;7:13464–78.PubMedPubMedCentral
12.
Lord S, Funes JM, Harris AL, Quintela-Fandino M. Antiangiogenic resistance and cancer metabolism: opportunities for synthetic lethality. Curr Drug Targets. 2016;17:1714–27.PubMed
13.
Abdel-Wahab AF, Mahmoud W, Al-Harizy RM. Targeting glucose metabolism to suppress cancer progression: prospective of anti-glycolytic cancer therapy. Pharmacol Res. 2019;150:104511.PubMed
14.
Casak SJ, Fashoyin-Aje I, Lemery SJ, Zhang L, Jin R, Li H, et al. FDA approval summary: ramucirumab for gastric cancer. Clin Cancer Res. 2015;21:3372–6.PubMed
15.
Zhang C, Liu J, Liang Y, Wu R, Zhao Y, Hong X, et al. Tumour-associated mutant p53 drives the Warburg effect. Nat Commun. 2013;4:2935.PubMedPubMedCentral
16.
Eriksson M, Ambroise G, Ouchida AT, Lima Queiroz A, Smith D, Gimenez-Cassina A et al. Effect of mutant p53 proteins on glycolysis and mitochondrial metabolism. Mol Cell Biol. 2017;37(24)e00328–17.PubMedPubMedCentral
17.
Itahana Y, Itahana K. Emerging Roles of p53 Family Members in Glucose Metabolism. Int J Mol Sci. 2018;19.
18.
Sabapathy K, Lane DP. Therapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others. Nat Rev Clin Oncol. 2018;15:13–30.PubMed
19.
Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17.PubMedPubMedCentral
20.
Di Bartolomeo M, Niger M, Tirino G, Petrillo A, Berenato R, Laterza MM, et al. Ramucirumab as second-line therapy in metastatic gastric cancer: real-world data from the RAMoss study. Target Oncol. 2018;13(2):227–34.PubMed
21.
Guescini M, Sisti D, Rocchi MB, Stocchi L, Stocchi V. A new real-time PCR method to overcome significant quantitative inaccuracy due to slight amplification inhibition. BMC Bioinformatics. 2008;9:326.PubMedPubMedCentral
22.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T) Method. Methods. 2001;25:402–8.PubMed
23.
Shi L, Jones WD, Jensen RV, Harris SC, Perkins RG, Goodsaid FM, et al. The balance of reproducibility, sensitivity, and specificity of lists of differentially expressed genes in microarray studies. BMC Bioinformatics. 2008;9:S10.PubMedPubMedCentral
24.
Petersen D, Chandramouli GV, Geoghegan J, Hilburn J, Paarlberg J, Kim CH, et al. Three microarray platforms: an analysis of their concordance in profiling gene expression. BMC Genomics. 2005;6:63.PubMedPubMedCentral
25.
Hariparsad N, Ramsden D, Palamanda J, Dekeyser JG, Fahmi OA, Kenny JR, et al. Considerations from the IQ induction working group in response to drug-drug interaction guidance from regulatory agencies: focus on downregulation, CYP2C induction, and CYP2B6 positive control. Drug Metab Dispos. 2017;45:1049–59.PubMed
26.
Robinson JT, Thorvaldsdóttir H, Wenger AM, Zehir A, Jill P. Variant review with the integrative genomics viewer (IGV). Cancer Res. 2017;77:e31–e3434.PubMedPubMedCentral
27.
Poeta ML, Manola J, Goldwasser MA, Forastiere A, Benoit N, Califano JA, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med. 2007;357:2552–611.PubMedPubMedCentral
28.
Yu M, Chen S, Hong W, Gu Y, Huang B, Lin Y, et al. Prognostic role of glycolysis for cancer outcome: evidence from 86 studies. J Cancer Res Clin Oncol. 2019;145:967–99.PubMed
29.
Berlth F, Mönig S, Pinther B, Grimminger P, Maus M, Schlösser H, et al. Both GLUT-1 and GLUT-14 are independent prognostic factors in gastric adenocarcinoma. Ann Surg Oncol. 2015;22(Suppl 3):S822–S831831.PubMed
30.
Kawamura T, Kusakabe T, Sugino T, Watanabe K, Fukuda T, Nashimoto A, et al. Expression of glucose transporter-1 in human gastric carcinoma: association with tumor aggressiveness, metastasis, and patient survival. Cancer. 2001;92:634–41.PubMed
31.
Schlößer HA, Drebber U, Urbanski A, Haase S, Baltin C, Berlth F, et al. Glucose transporters 1, 3, 6, and 10 are expressed in gastric cancer and glucose transporter 3 is associated with UICC stage and survival. Gastric Cancer. 2017;20:83–91.PubMed
32.
Qiu MZ, Han B, Luo HY, Zhou ZW, Wang ZQ, Wang FH, et al. Expressions of hypoxia-inducible factor-1α and hexokinase-II in gastric adenocarcinoma: the impact on prognosis and correlation to clinicopathologic features. Tumour Biol. 2011;32:159–66.PubMed
33.
Rho M, Kim J, Jee CD, Lee YM, Lee HE, Kim MA, et al. Expression of type 2 hexokinase and mitochondria-related genes in gastric carcinoma tissues and cell lines. Anticancer Res. 2007;27:251–8.PubMed
34.
Gao Y, Xu D, Yu G, Liang J. Overexpression of metabolic markers HK1 and PKM2 contributes to lymphatic metastasis and adverse prognosis in Chinese gastric cancer. Int J Clin Exp Pathol. 2015;8:9264–71.PubMedPubMedCentral
35.
Lim JY, Yoon SO, Seol SY, Hong SW, Kim JW, Choi SH, et al. Overexpression of the M2 isoform of pyruvate kinase is an adverse prognostic factor for signet ring cell gastric cancer. World J Gastroenterol. 2012;18:4037–43.PubMedPubMedCentral
36.
Wang J, Yuan W, Chen Z, Wu S, Chen J, Ge J, et al. Overexpression of G6PD is associated with poor clinical outcome in gastric cancer. Tumour Biol. 2012;33:95–101.PubMed
37.
Kim JG, Lee SJ, Chae YS, Kang BW, Lee YJ, Oh SY, et al. Association between phosphorylated AMP-activated protein kinase and MAPK3/1 expression and prognosis for patients with gastric cancer. Oncology. 2013;85:78–85.PubMed
38.
Sun X, Sun Z, Zhu Z, Li C, Zhang J, Xu H, et al. Expression of SIP1 is strongly correlated with LDHA and shows a significantly poor outcome in gastric cancer. Tumour Biol. 2015;36:7521–30.PubMed
39.
Kim HS, Lee HE, Yang HK, Kim WH. High lactate dehydrogenase 5 expressioncorrelates with high tumoral and stromal vascular endothelial growth factor expression in gastric cancer. Pathobiology. 2014;81:78–85.PubMed
40.
Kolev Y, Uetake H, Takagi Y, Sugihara K. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol. 2008;15:2336–444.PubMed
41.
42.
Smith TA. Mammalian hexokinases and their abnormal expression in cancer. Br J Biomed Sci. 2000;57:170–8.PubMed
43.
Wilson JE. Isozymes of mammalian hexokinase: structure, subcellular localization and metabolic function. J Exp Biol. 2003;206:2049–57.
44.
Bocci G, Di Paolo A, Danesi R. The pharmacological bases of the antiangiogenic activity of paclitaxel. Angiogenesis. 2013;16:481–92.PubMedPubMedCentral
45.
El Hassouni B, Granchi C, Vallés-Martí A, Supadmanaba IGP, Bononi G, Tuccinardi T, et al. The dichotomous role of the glycolytic metabolism pathway in cancer metastasis: Interplay with the complex tumor microenvironment and novel therapeutic strategies. Semin Cancer Biol. 2020;60:238–248.PubMed
46.
Mohammad GH, Vassileva V, Acedo P, Olde Damink SWM, Malago M, Dhar DK, et al. Targeting pyruvate kinase M2 and lactate dehydrogenase A is an effective combination strategy for the treatment of pancreatic cancer. Cancers (Basel). 2019;11:E1372.
47.
Pisarsky L, Bill R, Fagiani E, Dimeloe S, Goosen RW, Hagmann J, et al. Targeting metabolic symbiosis to overcome resistance to 33 anti-angiogenic therapy. Cell Rep. 2016;15:1161–74.PubMedPubMedCentral
48.
Renner K, Bruss C, Schnell A, Koehl G, Becker HM, Fante M, et al. Restricting glycolysis preserves T cell effector functions and augments checkpoint therapy. Cell Rep. 2019;29(135–150):e9.
49.
Wong GS, Zhou J, Liu JB, Wu Z, Xu X, Li T, et al. Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med. 2018;24:968–77.PubMedPubMedCentral
50.
Liu Y, Zhang Z, Wang J, Chen C, Tang X, Zhu J, et al. Metabolic reprogramming results in abnormal glycolysis in gastric cancer: a review. Onco Targets Ther. 2019;12:1195–204.PubMedPubMedCentral
51.
Van Cutsem E, Muro K, Cunningham D, Bodoky G, Sobrero A, Cascinu S, et al. RAINBOW Investigators Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study. Eur J Cancer. 2020;127:150–7.PubMed
Metadata
Title
Glycolytic competence in gastric adenocarcinomas negatively impacts survival outcomes of patients treated with salvage paclitaxel-ramucirumab
Authors
Annamaria Ruzzo
Francesco Graziano
Irene Bagaloni
Maria Di Bartolomeo
Michele Prisciandaro
Giuseppe Aprile
Elena Ongaro
Bruno Vincenzi
Giuseppe Perrone
Daniele Santini
Lorenzo Fornaro
Caterina Vivaldi
Gianluca Tomasello
Fotios Loupakis
Sara Lonardi
Matteo Fassan
Michele Valmasoni
Donatella Sarti
Paola Lorenzini
Vincenzo Catalano
Renato Bisonni
Michela Del Prete
Guido Collina
Mauro Magnani
Publication date
01-11-2020
Publisher
Springer Singapore
Keyword
Ramucirumab
Published in
Gastric Cancer / Issue 6/2020
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-020-01078-0

Other articles of this Issue 6/2020

Gastric Cancer 6/2020 Go to the issue

Original Article

Endoscopic three-categorical diagnosis of Helicobacter pylori infection using linked color imaging and deep learning: a single-center prospective study (with video)

Original Article

Resistance to FGFR1-targeted therapy leads to autophagy via TAK1/AMPK activation in gastric cancer

Original Article

Clinical outcomes of laparoscopic and endoscopic cooperative surgery for submucosal tumors on the esophagogastric junction: a retrospective single-center analysis

Original Article

Jab1 promotes gastric cancer tumorigenesis via non-ubiquitin proteasomal degradation of p14ARF

Original Article

Development and validation of a deep learning system for ascites cytopathology interpretation

Review Article

Epstein–Barr virus-associated gastric cancer: disease that requires special approach

ACC 2024 Congress Coverage

Cardiology Video

Highlights from the ACC 2024 Congress

Watch now

Watch official videos from the ACC congress summarizing key highlights from the last year in heart failure, cardiomyopathies, valvular disease, pulmonary vascular disease, and pediatric cardiology.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits