Sialyl-Tn serves as a potential therapeutic target for ovarian cancer.
Companion diagnostic
Ovarian cancer
Sialyl-Tn
Targeted therapy
Journal
Journal of ovarian research
ISSN: 1757-2215
Titre abrégé: J Ovarian Res
Pays: England
ID NLM: 101474849
Informations de publication
Date de publication:
02 Apr 2024
02 Apr 2024
Historique:
received:
24
08
2023
accepted:
21
03
2024
medline:
3
4
2024
pubmed:
3
4
2024
entrez:
2
4
2024
Statut:
epublish
Résumé
Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer. We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples. Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis. Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.
Sections du résumé
BACKGROUND
BACKGROUND
Ovarian cancer remains the deadliest of the gynecologic cancers in the United States. There have been limited advances in treatment strategies that have seen marked increases in overall survival. Thus, it is essential to continue developing and validating new treatment strategies and markers to identify patients who would benefit from the new strategy. In this report, we sought to further validate applications for a novel humanized anti-Sialyl Tn antibody-drug conjugate (anti-STn-ADC) in ovarian cancer.
METHODS
METHODS
We aimed to further test a humanized anti-STn-ADC in sialyl-Tn (STn) positive and negative ovarian cancer cell line, patient-derived organoid (PDO), and patient-derived xenograft (PDX) models. Furthermore, we sought to determine whether serum STn levels would reflect STn positivity in the tumor samples enabling us to identify patients that an anti-STn-ADC strategy would best serve. We developed a custom ELISA with high specificity and sensitivity, that was used to assess whether circulating STn levels would correlate with stage, progression-free survival, overall survival, and its value in augmenting CA-125 as a diagnostic. Lastly, we assessed whether the serum levels reflected what was observed via immunohistochemical analysis in a subset of tumor samples.
RESULTS
RESULTS
Our in vitro experiments further define the specificity of the anti-STn-ADC. The ovarian cancer PDO, and PDX models provide additional support for an anti-STn-ADC-based strategy for targeting ovarian cancer. The custom serum ELISA was informative in potential triaging of patients with elevated levels of STn. However, it was not sensitive enough to add value to existing CA-125 levels for a diagnostic. While the ELISA identified non-serous ovarian tumors with low CA-125 levels, the sample numbers were too small to provide any confidence the STn ELISA would meaningfully add to CA-125 for diagnosis.
CONCLUSIONS
CONCLUSIONS
Our preclinical data support the concept that an anti-STn-ADC may be a viable option for treating patients with elevated STn levels. Moreover, our STn-based ELISA could complement IHC in identifying patients with whom an anti-STn-based strategy might be more effective.
Identifiants
pubmed: 38566237
doi: 10.1186/s13048-024-01397-1
pii: 10.1186/s13048-024-01397-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
71Subventions
Organisme : NCI NIH HHS
ID : HHSN261200700063C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200700063C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200700063C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200700063C
Pays : United States
Organisme : NCI NIH HHS
ID : HHSN261200700063C
Pays : United States
Organisme : NIH HHS
ID : NIH 1DP5OD029637
Pays : United States
Informations de copyright
© 2024. The Author(s).
Références
Torre LA, Trabert B, DeSantis CE, Miller KD, Samimi G, Runowicz CD, Gaudet MM, Jemal A, Siegel RL. Ovarian cancer statistics, 2018. CA Cancer J Clin. 2018;68(4):284–96.
pubmed: 29809280
pmcid: 6621554
doi: 10.3322/caac.21456
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33.
pubmed: 35020204
doi: 10.3322/caac.21708
Zhang Z, Wuhrer M, Holst S. Serum sialylation changes in cancer. Glycoconj J. 2018;35(2):139–60.
pubmed: 29680984
pmcid: 5916985
doi: 10.1007/s10719-018-9820-0
Eavarone DA, Al-Alem L, Lugovskoy A, Prendergast JM, Nazer RI, Stein JN, Dransfield DT, Behrens J, Rueda BR. Humanized anti-sialyl-tn antibodies for the treatment of ovarian carcinoma. PLoS ONE. 2018;13(7):e0201314.
pubmed: 30052649
pmcid: 6063429
doi: 10.1371/journal.pone.0201314
Starbuck K, Al-Alem L, Eavarone DA, Hernandez SF, Bellio C, Prendergast JM, Stein J, Dransfield DT, Zarrella B, Growdon WB, et al. Treatment of ovarian cancer by targeting the tumor stem cell-associated carbohydrate antigen, Sialyl-Thomsen-Nouveau. Oncotarget. 2018;9(33):23289–305.
pubmed: 29796189
pmcid: 5955411
doi: 10.18632/oncotarget.25289
Prendergast JM, Galvao da Silva AP, Eavarone DA, Ghaderi D, Zhang M, Brady D, Wicks J, DeSander J, Behrens J, Rueda BR. Novel anti-sialyl-tn monoclonal antibodies and antibody-drug conjugates demonstrate tumor specificity and anti-tumor activity. MAbs. 2017;9(4):615–27.
pubmed: 28281872
pmcid: 5419082
doi: 10.1080/19420862.2017.1290752
Julien S, Videira PA, Delannoy P. Sialyl-tn in cancer: (how) did we miss the target? Biomolecules 2012, 2(4):435–66.
Werther JL, Tatematsu M, Klein R, Kurihara M, Kumagai K, Llorens P, Guidugli Neto J, Bodian C, Pertsemlidis D, Yamachika T, et al. Sialosyl-Tn antigen as a marker of gastric cancer progression: an international study. Int J Cancer. 1996;69(3):193–9.
pubmed: 8682587
doi: 10.1002/(SICI)1097-0215(19960621)69:3<193::AID-IJC8>3.0.CO;2-V
Munkley J. The role of Sialyl-Tn in Cancer. Int J Mol Sci. 2016;17(3):275.
pubmed: 26927062
pmcid: 4813139
doi: 10.3390/ijms17030275
Ferreira JA, Videira PA, Lima L, Pereira S, Silva M, Carrascal M, Severino PF, Fernandes E, Almeida A, Costa C, et al. Overexpression of tumour-associated carbohydrate antigen sialyl-Tn in advanced bladder tumours. Mol Oncol. 2013;7(3):719–31.
pubmed: 23567325
pmcid: 5528473
doi: 10.1016/j.molonc.2013.03.001
Carvalho S, Abreu CM, Ferreira D, Lima L, Ferreira JA, Santos LL, Ribeiro R, Grenha V, Martinez-Fernandez M, Duenas M, et al. Phenotypic analysis of Urothelial Exfoliated cells in bladder Cancer via Microfluidic immunoassays: Sialyl-Tn as a Novel Biomarker in Liquid biopsies. Front Oncol. 2020;10:1774.
pubmed: 33042825
pmcid: 7526084
doi: 10.3389/fonc.2020.01774
Kobayashi H, Terao T, Kawashima Y. Serum sialyl tn as an independent predictor of poor prognosis in patients with epithelial ovarian cancer. J Clin Oncol. 1992;10(1):95–101.
pubmed: 1727929
doi: 10.1200/JCO.1992.10.1.95
Carrascal MA, Severino PF, Guadalupe Cabral M, Silva M, Ferreira JA, Calais F, Quinto H, Pen C, Ligeiro D, Santos LL, et al. Sialyl Tn-expressing bladder cancer cells induce a tolerogenic phenotype in innate and adaptive immune cells. Mol Oncol. 2014;8(3):753–65.
pubmed: 24656965
pmcid: 5528624
doi: 10.1016/j.molonc.2014.02.008
Al-Alem LF, Pandya UM, Baker AT, Bellio C, Zarrella BD, Clark J, DiGloria CM, Rueda BR. Ovarian cancer stem cells: what progress have we made? Int J Biochem Cell Biol. 2019;107:92–103.
pubmed: 30572025
doi: 10.1016/j.biocel.2018.12.010
Foster R, Buckanovich RJ, Rueda BR. Ovarian cancer stem cells: working towards the root of stemness. Cancer Lett. 2013;338(1):147–57.
pubmed: 23138176
doi: 10.1016/j.canlet.2012.10.023
Wang WY, Cao YX, Zhou X, Wei B, Zhan L, Sun SY. Stimulative role of ST6GALNAC1 in proliferation, migration and invasion of ovarian cancer stem cells via the akt signaling pathway. Cancer Cell Int. 2019;19:86.
pubmed: 30996686
pmcid: 6451308
doi: 10.1186/s12935-019-0780-7
Reddish MA, Jackson L, Koganty RR, Qiu D, Hong W, Longenecker BM. Specificities of anti-sialyl-tn and anti-tn monoclonal antibodies generated using novel clustered synthetic glycopeptide epitopes. Glycoconj J. 1997;14(5):549–60.
pubmed: 9298687
doi: 10.1023/A:1018576224062
Murad JP, Kozlowska AK, Lee HJ, Ramamurthy M, Chang WC, Yazaki P, Colcher D, Shively J, Cristea M, Forman SJ, et al. Effective targeting of TAG72(+) peritoneal ovarian tumors via Regional Delivery of CAR-Engineered T cells. Front Immunol. 2018;9:2268.
pubmed: 30510550
pmcid: 6254427
doi: 10.3389/fimmu.2018.02268
Loureiro LR, Carrascal MA, Barbas A, Ramalho JS, Novo C, Delannoy P, Videira PA. Challenges in antibody development against tn and Sialyl-Tn antigens. Biomolecules. 2015;5(3):1783–809.
pubmed: 26270678
pmcid: 4598775
doi: 10.3390/biom5031783
Hamilton TC, Young RC, McKoy WM, Grotzinger KR, Green JA, Chu EW, Whang-Peng J, Rogan AM, Green WR, Ozols RF. Characterization of a human ovarian carcinoma cell line (NIH:OVCAR-3) with androgen and estrogen receptors. Cancer Res. 1983;43(11):5379–89.
pubmed: 6604576
Provencher DM, Lounis H, Champoux L, Tetrault M, Manderson EN, Wang JC, Eydoux P, Savoie R, Tonin PN, Mes-Masson AM. Characterization of four novel epithelial ovarian cancer cell lines. Vitro Cell Dev Biol Anim. 2000;36(6):357–61.
doi: 10.1290/1071-2690(2000)036<0357:COFNEO>2.0.CO;2
Domcke S, Sinha R, Levine DA, Sander C, Schultz N. Evaluating cell lines as tumour models by comparison of genomic profiles. Nat Commun. 2013;4:2126.
pubmed: 23839242
doi: 10.1038/ncomms3126
Groeneweg JW, DiGloria CM, Yuan J, Richardson WS, Growdon WB, Sathyanarayanan S, Foster R, Rueda BR. Inhibition of notch signaling in combination with Paclitaxel reduces platinum-resistant ovarian tumor growth. Front Oncol. 2014;4:171.
pubmed: 25072022
pmcid: 4083224
doi: 10.3389/fonc.2014.00171
Curley MD, Therrien VA, Cummings CL, Sergent PA, Koulouris CR, Friel AM, Roberts DJ, Seiden MV, Scadden DT, Rueda BR, et al. CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells. 2009;27(12):2875–83.
pubmed: 19816957
doi: 10.1002/stem.236
McCann CK, Growdon WB, Kulkarni-Datar K, Curley MD, Friel AM, Proctor JL, Sheikh H, Deyneko I, Ferguson JA, Vathipadiekal V, et al. Inhibition of hedgehog signaling antagonizes serous ovarian cancer growth in a primary xenograft model. PLoS ONE. 2011;6(11):e28077.
pubmed: 22140510
pmcid: 3226669
doi: 10.1371/journal.pone.0028077
Groeneweg JW, Hernandez SF, Byron VF, DiGloria CM, Lopez H, Scialabba V, Kim M, Zhang L, Borger DR, Tambouret R, et al. Dual HER2 targeting impedes growth of HER2 gene-amplified uterine serous carcinoma xenografts. Clin Cancer Res. 2014;20(24):6517–28.
pubmed: 25294905
pmcid: 4268047
doi: 10.1158/1078-0432.CCR-14-1647
Hill SJ, Decker B, Roberts EA, Horowitz NS, Muto MG, Worley MJ Jr., Feltmate CM, Nucci MR, Swisher EM, Nguyen H, et al. Prediction of DNA repair inhibitor response in short-term patient-derived ovarian Cancer Organoids. Cancer Discov. 2018;8(11):1404–21.
pubmed: 30213835
pmcid: 6365285
doi: 10.1158/2159-8290.CD-18-0474
Hafner M, Niepel M, Chung M, Sorger PK. Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nat Methods. 2016;13(6):521–7.
pubmed: 27135972
pmcid: 4887336
doi: 10.1038/nmeth.3853
Team RC. R: A language and environment for statistical computing. 2020.
Team SD. Stan Modeling Language Users Guide and Reference Manual, 2.28. 2021.
Team SD. RStan: the R interface to Stan. R package version 2.21.2. 2020.
Skates SJ, Horick N, Yu Y, Xu FJ, Berchuck A, Havrilesky LJ, de Bruijn HW, van der Zee AG, Woolas RP, Jacobs IJ, et al. Preoperative sensitivity and specificity for early-stage ovarian cancer when combining cancer antigen CA-125II, CA 15 – 3, CA 72 – 4, and macrophage colony-stimulating factor using mixtures of multivariate normal distributions. J Clin Oncol. 2004;22(20):4059–66.
pubmed: 15381683
doi: 10.1200/JCO.2004.03.091
Kobayashi H, Terao T, Kawashima Y. Clinical evaluation of circulating serum sialyl tn antigen levels in patients with epithelial ovarian cancer. J Clin Oncol. 1991;9(6):983–7.
pubmed: 1851822
doi: 10.1200/JCO.1991.9.6.983
Kobayashi H, Terao T, Kawashima Y. [Serum sialyl tn antigen as a prognostic marker in patients with epithelial ovarian cancer]. Nihon Sanka Fujinka Gakkai Zasshi. 1992;44(1):14–20.
pubmed: 1541859
Doerr RJ, Abdel-Nabi H, Krag D, Mitchell E. Radiolabeled antibody imaging in the management of colorectal cancer. Results of a multicenter clinical study. Ann Surg. 1991;214(2):118–24.
pubmed: 1867518
pmcid: 1358510
doi: 10.1097/00000658-199108000-00005
Bohdiewicz PJ. Indium-111 satumomab pendetide: the first FDA-approved monoclonal antibody for tumor imaging. J Nucl Med Technol. 1998;26(3):155–63. quiz 170 – 151.
pubmed: 9755434
Bhatt P, Vhora I, Patil S, Amrutiya J, Bhattacharya C, Misra A, Mashru R. Role of antibodies in diagnosis and treatment of ovarian cancer: basic approach and clinical status. J Control Release. 2016;226:148–67.
pubmed: 26860284
doi: 10.1016/j.jconrel.2016.02.008
Colakovic S, Lukic V, Mitrovic L, Jelic S, Susnjar S, Marinkovic J. Prognostic value of CA125 kinetics and half-life in advanced ovarian cancer. Int J Biol Markers. 2000;15(2):147–52.
pubmed: 10883888
doi: 10.1177/172460080001500204
van der Burg ME, Lammes FB, van Putten WL, Stoter G. Ovarian cancer: the prognostic value of the serum half-life of CA125 during induction chemotherapy. Gynecol Oncol. 1988;30(3):307–12.
pubmed: 3164697
doi: 10.1016/0090-8258(88)90244-2
Giudice LC, Jacobs AJ, Bell CE, Lippmann L. Serum levels of CA-125 in patients with endometriosis. Gynecol Oncol. 1986;25(2):256–8.
pubmed: 3463522
doi: 10.1016/0090-8258(86)90107-1
Fedele L, Vercellini P, Arcaini L, da Dalt MG, Candiani GB. CA 125 in serum, peritoneal fluid, active lesions, and endometrium of patients with endometriosis. Am J Obstet Gynecol. 1988;158(1):166–70.
pubmed: 3422132
doi: 10.1016/0002-9378(88)90803-4
Jacobs I, Bast RC Jr. The CA 125 tumour-associated antigen: a review of the literature. Hum Reprod. 1989;4(1):1–12.
pubmed: 2651469
doi: 10.1093/oxfordjournals.humrep.a136832
Moloney MD, Thornton JG, Cooper EH. Serum CA 125 antigen levels and disease severity in patients with endometriosis. Obstet Gynecol. 1989;73(5 Pt 1):767–9.
pubmed: 2704505
Burghaus S, Drazic P, Wolfler M, Mechsner S, Zeppernick M, Meinhold-Heerlein I, Mueller MD, Rothmund R, Vigano P, Becker CM, et al. Multicenter evaluation of blood-based biomarkers for the detection of endometriosis and adenomyosis: a prospective non-interventional study. Int J Gynaecol Obstet. 2024;164(1):305–14.
pubmed: 37635683
doi: 10.1002/ijgo.15062
Bayoumy S, Hyytia H, Leivo J, Talha SM, Huhtinen K, Poutanen M, Hynninen J, Perheentupa A, Lamminmaki U, Gidwani K, et al. Glycovariant-based lateral flow immunoassay to detect ovarian cancer-associated serum CA125. Commun Biol. 2020;3(1):460.
pubmed: 32826955
pmcid: 7442799
doi: 10.1038/s42003-020-01191-x
Saldova R, Struwe WB, Wynne K, Elia G, Duffy MJ, Rudd PM. Exploring the glycosylation of serum CA125. Int J Mol Sci. 2013;14(8):15636–54.
pubmed: 23896595
pmcid: 3759877
doi: 10.3390/ijms140815636
Fu C, Zhao H, Wang Y, Cai H, Xiao Y, Zeng Y, Chen H. Tumor-associated antigens: tn antigen, sTn antigen, and T antigen. HLA. 2016;88(6):275–86.
pubmed: 27679419
doi: 10.1111/tan.12900
Marcos-Silva L, Narimatsu Y, Halim A, Campos D, Yang Z, Tarp MA, Pereira PJ, Mandel U, Bennett EP, Vakhrushev SY, et al. Characterization of binding epitopes of CA125 monoclonal antibodies. J Proteome Res. 2014;13(7):3349–59.
pubmed: 24850311
doi: 10.1021/pr500215g
Li Q, Kailemia MJ, Merleev AA, Xu G, Serie D, Danan LM, Haj FG, Maverakis E, Lebrilla CB. Site-specific glycosylation quantitation of 50 serum glycoproteins enhanced by Predictive Glycopeptidomics for Improved Disease Biomarker Discovery. Anal Chem. 2019;91(8):5433–45.
pubmed: 30882205
doi: 10.1021/acs.analchem.9b00776