Biomarkers for anti‑vascular endothelial growth factor drugs

Kuriyama,Sho; Kuriyama,Sho; Yamada,Takeshi; Yamada,Takeshi; Matsuda,Akihisa; Matsuda,Akihisa; Takahashi,Goro; Takahashi,Goro; Iwai,Takuma; Iwai,Takuma; Takeda,Kohki; Takeda,Kohki; Ueda,Koji; Ueda,Koji; Miyasaka,Toshimitsu; Miyasaka,Toshimitsu; Yokoyama,Yasuyuki; Yokoyama,Yasuyuki; Shinji,Seiichi; Shinji,Seiichi; Sonoda,Hiromichi; Sonoda,Hiromichi; Ohta,Ryo; Ohta,Ryo; Yonaga,Kazuhide; Yonaga,Kazuhide; Kanaka,Shintaro; Kanaka,Shintaro; Yoshida,Hiroshi; Yoshida,Hiroshi

doi:10.3892/ol.2022.13583

Biomarkers for anti‑vascular endothelial growth factor drugs

Authors:
- Sho Kuriyama
- Takeshi Yamada
- Akihisa Matsuda
- Goro Takahashi
- Takuma Iwai
- Kohki Takeda
- Koji Ueda
- Toshimitsu Miyasaka
- Yasuyuki Yokoyama
- Seiichi Shinji
- Hiromichi Sonoda
- Ryo Ohta
- Kazuhide Yonaga
- Shintaro Kanaka
- Hiroshi Yoshida
View Affiliations

Affiliations: Department of Gastrointestinal and Hepato‑Biliary‑Pancreatic Surgery, Nippon Medical School, Tokyo 113‑8603, Japan, Department of Digestive Surgery, Nippon Medical School Musashikosugi Hospital, Kawasaki, Kanagawa 211‑8533, Japan
Published online on: November 7, 2022 https://doi.org/10.3892/ol.2022.13583
Article Number: 463
Copyright: © Kuriyama et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Angiogenesis is regulated by interactions between vascular endothelial growth factors (VEGFs) and VEGF receptors. VEGF‑A, VEGF‑D, placental growth factor (PlGF) and plasminogen activator inhibitor‑1 (PAI‑1) have tumor angiogenic activity. VEGF‑A and PAI‑1 levels in the blood may impact the activity of bevacizumab, and VEGF‑D levels may similarly diminish the efficacy of ramucirumab. However, the dynamics of these angiogenic biomarkers for anti‑VEGF therapy have not been well established; therefore, they were evaluated in this retrospective study, which included two cohorts. Cohort 1 included patients who were treated with cytotoxic agents and bevacizumab as first‑line chemotherapy, and Cohort 2 comprised patients who were treated with cytotoxic agents and anti‑VEGF drugs (bevacizumab, ramucirumab or aflibercept) as second‑line chemotherapy. VEGF‑A, VEGF‑D, PlGF and PAI‑1 levels were measured before starting chemotherapy and were re‑assessed every 1‑2 months until disease progression. Bevacizumab had reduced benefit as a first‑line chemotherapeutant in patients with very low or very high levels of VEGF‑A. Bevacizumab increased VEGF‑A and PlGF levels, but not VEGF‑D or PAI‑1. Anti‑VEGF drugs offered the greatest benefit to patients with high PAI‑1 before first‑ and second‑line chemotherapy. PAI‑1 levels were not affected by anti‑VEGF drugs. Since ramucirumab increased VEGF‑D, it offered less benefit to patients with high VEGF‑D in second‑line chemotherapy. Conversely, aflibercept offered greater benefits to patients with high VEGF‑D, without increasing VEGF‑D. These biomarkers may be useful for the prediction of drug efficacy and may predict resistance to anti‑VEGF drugs.

View Figures

View References

1	Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, et al: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncol. 15:1065–1075. 2014. View Article : Google Scholar : PubMed/NCBI
2	Lenz HJ, Ou FS, Venook AP, Hochster HS, Niedzwiecki D, Goldberg RM, Mayer RJ, Bertagnolli MM, Blanke CD, Zemla T, et al: Impact of consensus molecular subtype on survival in patients with metastatic colorectal cancer: Results From CALGB/SWOG 80405 (Alliance). J Clin Oncol. 37:1876–1885. 2019. View Article : Google Scholar : PubMed/NCBI
3	Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS and Go WY: PEAK: A randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol. 32:2240–2247. 2014. View Article : Google Scholar : PubMed/NCBI
4	Saltz LB, Clarke S, Díaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, et al: Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: A randomized phase III study. J Clin Oncol. 26:2013–2019. 2008. View Article : Google Scholar : PubMed/NCBI
5	Sobrero A, Lenz HJ, Eng C, Scheithauer W, Middleton G, Chen W, Esser R, Nippgen J and Burris H: Extended RAS analysis of the phase III EPIC trial: Irinotecan + Cetuximab versus irinotecan as second-line treatment for patients with metastatic colorectal cancer. Oncologist. 26:e261–e269. 2021. View Article : Google Scholar : PubMed/NCBI
6	Bennouna J, Sastre J, Arnold D, Österlund P, Greil R, Van Cutsem E, von Moos R, Viéitez JM, Bouché O, Borg C, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol. 14:29–37. 2013. View Article : Google Scholar : PubMed/NCBI
7	Tabernero J, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Van Cutsem E, Grothey A, et al: Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): A randomised, double-blind, multicentre, phase 3 study. Lancet Oncol. 16:499–508. 2015. View Article : Google Scholar : PubMed/NCBI
8	Tabernero J, Van Cutsem E, Lakomý R, Prausová J, Ruff P, van Hazel GA, Moiseyenko VM, Ferry DR, McKendrick JJ, Soussan-Lazard K, et al: Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: Prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 50:320–331. 2014. View Article : Google Scholar : PubMed/NCBI
9	Neufeld G, Cohen T, Gengrinovitch S and Poltorak Z: Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13:9–22. 1999. View Article : Google Scholar : PubMed/NCBI
10	Ferrara N: Molecular and biological properties of vascular endothelial growth factor. J Mol Med (Berl). 77:527–543. 1999. View Article : Google Scholar : PubMed/NCBI
11	Carmeliet P and Jain RK: Angiogenesis in cancer and other diseases. Nature. 407:249–257. 2000. View Article : Google Scholar : PubMed/NCBI
12	Leung DW, Cachianes G, Kuang WJ, Goeddel DV and Ferrara N: Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 246:1306–1309. 1989. View Article : Google Scholar : PubMed/NCBI
13	Inoue M, Hager JH, Ferrara N, Gerber HP and Hanahan D: VEGF-A has a critical, nonredundant role in angiogenic switching and pancreatic beta cell carcinogenesis. Cancer Cell. 1:193–202. 2002. View Article : Google Scholar : PubMed/NCBI
14	de Vries C, Escobedo JA, Ueno H, Houck K, Ferrara N and Williams LT: The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 255:989–991. 1992. View Article : Google Scholar : PubMed/NCBI
15	Placencio VR and DeClerck YA: Plasminogen activator inhibitor-1 in cancer: Rationale and insight for future therapeutic testing. Cancer Res. 75:2969–2974. 2015. View Article : Google Scholar : PubMed/NCBI
16	Binder BR and Mihaly J: The plasminogen activator inhibitor ‘paradox’ in cancer. Immunol Lett. 118:116–124. 2008. View Article : Google Scholar : PubMed/NCBI
17	Nielsen HJ, Christensen IJ, Sørensen S, Moesgaard F and Brünner N: Preoperative plasma plasminogen activator inhibitor type-1 and serum C-reactive protein levels in patients with colorectal cancer. The RANX05 colorectal cancer study group. Ann Surg Oncol. 7:617–623. 2000. View Article : Google Scholar : PubMed/NCBI
18	Van Cutsem E, Paccard C, Chiron M and Tabernero J: Impact of prior bevacizumab treatment on VEGF-A and PlGF levels and outcome following second-line aflibercept treatment: Biomarker Post Hoc analysis of the VELOUR trial. Clin Cancer Res. 26:717–725. 2020. View Article : Google Scholar : PubMed/NCBI
19	Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L, Winkler M and Ferrara N: Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 57:4593–4599. 1997.PubMed/NCBI
20	Suzuki T, Shinozaki E, Osumi H, Nakayama I, Ota Y, Ichimura T, Ogura M, Wakatsuki T, Ooki A, Takahari D, et al: Second-line FOLFIRI plus ramucirumab with or without prior bevacizumab for patients with metastatic colorectal cancer. Cancer Chemother Pharmacol. 84:307–313. 2019. View Article : Google Scholar : PubMed/NCBI
21	Niki M, Yokoi T, Kurata T and Nomura S: New prognostic biomarkers and therapeutic effect of bevacizumab for patients with non-small-cell lung cancer. Lung Cancer (Auckl). 8:91–99. 2017.PubMed/NCBI
22	Liu Y, Starr MD, Brady JC, Rushing C, Pang H, Adams B, Alvarez D, Theuer CP, Hurwitz HI and Nixon AB: Modulation of circulating protein biomarkers in cancer patients receiving bevacizumab and the anti-endoglin antibody, TRC105. Mol Cancer Ther. 17:2248–2256. 2018. View Article : Google Scholar : PubMed/NCBI
23	Bal O, Ekinci AS, Dogan M, Atay C, Demirci A, Oksuzoglu B and Kilic S: The prognostic and predictive significance of plasma type 1 plasminogen activator inhibitor and endoglin in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy. J Cancer Res Ther. 15:48–53. 2019.PubMed/NCBI
24	Bajou K, Noël A, Gerard RD, Masson V, Brunner N, Holst-Hansen C, Skobe M, Fusenig NE, Carmeliet P, Collen D and Foidart JM: Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med. 4:923–928. 1998. View Article : Google Scholar : PubMed/NCBI
25	Bajou K, Maillard C, Jost M, Lijnen RH, Gils A, Declerck P, Carmeliet P, Foidart JM and Noel A: Host-derived plasminogen activator inhibitor-1 (PAI-1) concentration is critical for in vivo tumoral angiogenesis and growth. Oncogene. 23:6986–6990. 2004. View Article : Google Scholar : PubMed/NCBI
26	Takayama Y, Hattori N, Hamada H, Masuda T, Omori K, Akita S, Iwamoto H, Fujitaka K and Kohno N: Inhibition of PAI-1 limits tumor angiogenesis regardless of angiogenic stimuli in malignant pleural mesothelioma. Cancer Res. 76:3285–3294. 2016. View Article : Google Scholar : PubMed/NCBI
27	Naitoh H, Eguchi Y, Ueyama H, Kodama M and Hattori T: Localization of urokinase-type plasminogen activator, plasminogen activator inhibitor-1, 2 and plasminogen in colon cancer. Jpn J Cancer Res. 86:48–56. 1995. View Article : Google Scholar : PubMed/NCBI
28	Tabernero J, Hozak RR, Yoshino T, Cohn AL, Obermannova R, Bodoky G, Garcia-Carbonero R, Ciuleanu TE, Portnoy DC, Prausová J, et al: Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study. Ann Oncol. 29:602–609. 2018. View Article : Google Scholar : PubMed/NCBI