A multi‑center retrospective analysis of the effect of DPP4 inhibitors on progression‑free survival in advanced airway and colorectal cancers

Ali,Azka; Fuentes,Alejandra; Skelton Iv,William  Paul; Wang,Yu; McGorray,Susan; Shah,Chintan; Bishnoi,Rohit; Dang,Long  H.; Dang,Nam  H.

doi:10.3892/mco.2018.1766

A multi‑center retrospective analysis of the effect of DPP4 inhibitors on progression‑free survival in advanced airway and colorectal cancers

Authors:
- Azka Ali
- Alejandra Fuentes
- William Paul Skelton Iv
- Yu Wang
- Susan McGorray
- Chintan Shah
- Rohit Bishnoi
- Long H. Dang
- Nam H. Dang
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Affiliations: Department of Medicine, University of Florida, Gainesville, FL 32608, USA, Department of Medicine, Section of Hematology and Oncology, Louisiana State University, New Orleans, LA 70112, USA, Department of Biostatistics, University of Florida, Gainesville, FL 32608, USA, Department of Medicine, Division of Hematology and Oncology, University of Florida, Gainesville, FL 32608, USA
Published online on: November 13, 2018 https://doi.org/10.3892/mco.2018.1766
Pages: 118-124

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Abstract

Cluster of differentiation 26 (CD26), also known as dipeptidyl peptidase IV (DPP4), is a cell surface protein with exopeptidase activity and is expressed by most cell types. CD26/DPP4 is a multifunctional molecule with diverse biological effects, including regulatory effects on tumor growth, invasion and metastasis, and is a potential novel therapeutic target for selected cancers. In this study, we retrospectively analyzed diabetic patients with concurrent advanced airway or colorectal cancer to examine the effect of DPP4‑inhibitors on progression‑free survival (PFS). We performed a multi‑center retrospective review of patients with advanced colorectal or airway (lung, head and neck) cancer and a concurrent diagnosis of diabetes. The control group included patients on metformin and a sulfonylurea, and the study group included patients on metformin and a DPP4 inhibitor. Ninety‑six patients were eligible for the study. The cancers progressed in 23.7% of patients treated with DPP4 inhibitors compared to 50.9% of patients in the control group with an odds ratio of 0.303 [95% confidence interval (CI): 0.106‑0.809] and P=0.010. There was a statistically significant improvement in PFS in the study group as compared to the control group, hazard ratio=0.42 (95% CI: 0.21‑0.84) and P=0.014. There was a trend toward improvement in overall survival, although this effect was not statistically significant (P=0.11). Exposure to DPP4 inhibitors in the study group led to higher PFS in patients with advanced colorectal and airway cancers. Additional investigations with larger patient cohorts are needed to validate the relationship between DPP4 inhibition and the clinical outcome of selected malignancies.

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1	Havre PA, Abe M, Urasaki Y, Ohnuma K, Morimoto C and Dang NH: The role of CD26/dipeptidyl peptidase IV in cancer. Front Biosci. 13:1634–1645. 2008. View Article : Google Scholar : PubMed/NCBI
2	Pro B and Dang NH: CD26/dipeptidyl peptidase IV and its role in cancer. Histol Histopathol. 19:1345–1351. 2004.PubMed/NCBI
3	Beckenkamp A, Davies S, Willig JB and Buffon A: DPPIV/CD26: A tumor suppressor or a marker of malignancy? Tumour Biol. 37:7059–7073. 2016. View Article : Google Scholar : PubMed/NCBI
4	Javidroozi M, Zucker S and Chen WT: Plasma seprase and DPP4 levels as markers of disease and prognosis in cancer. Dis Markers. 32:309–320. 2012. View Article : Google Scholar : PubMed/NCBI
5	Angevin E, Isambert N, Trillet-Lenoir V, You B, Alexandre J, Zalcman G, Vielh P, Farace F, Valleix F, Podoll T, et al: First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers. Br J Cancer. 116:1126–1134. 2017. View Article : Google Scholar : PubMed/NCBI
6	Ho L, Aytac U, Stephens LC, Ohnuma K, Mills GB, McKee KS, Neumann C, LaPushin R, Cabanillas F, Abbruzzese JL, et al: In vitro and in vivo antitumor effect of the anti-CD26 monoclonal antibody 1F7 on human CD30+ anaplastic large cell T-cell lymphoma Karpas 299. Clin Cancer Res. 7:2031–2040. 2001.PubMed/NCBI
7	Femia AP, Raimondi L, Maglieri G, Lodovici M, Mannucci E and Caderni G: Long-term treatment with Sitagliptin, a dipeptidyl peptidase-4 inhibitor, reduces colon carcinogenesis and reactive oxygen species in 1,2-dimethylhydrazine-induced rats. Int J Cancer. 133:2498–2503. 2013. View Article : Google Scholar : PubMed/NCBI
8	Tang Z, Li J, Shen Q, Feng J, Liu H, Wang W, Xu L, Shi G, Ye X, Ge M, et al: Contribution of upregulated dipeptidyl peptidase 9 (DPP9) in promoting tumoregenicity, metastasis and the prediction of poor prognosis in non-small cell lung cancer (NSCLC). Int J Cancer. 140:1620–1632. 2017. View Article : Google Scholar : PubMed/NCBI
9	Gonzalez-Gronow M, Grenett HE, Weber MR, Gawdi G and Pizzo SV: Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells. Biochem J. 355:397–407. 2001. View Article : Google Scholar : PubMed/NCBI
10	Havre PA, Dang LH, Ohnuma K, Iwata S, Morimoto C and Dang NH: CD26 expression on T-anaplastic large cell lymphoma (ALCL) line Karpas 299 is associated with increased expression of versican and MT1-MMP and enhanced adhesion. BMC Cancer. 13:5172013. View Article : Google Scholar : PubMed/NCBI
11	Ghersi G, Zhao Q, Salamone M, Yeh Y, Zucker S and Chen WT: The protease complex consisting of dipeptidyl peptidase IV and seprase plays a role in the migration and invasion of human endothelial cells in collagenous matrices. Cancer Res. 66:4652–4661. 2006. View Article : Google Scholar : PubMed/NCBI
12	Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, Gopinathan A, Tuveson DA and Fearon DT: Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science. 330:827–830. 2010. View Article : Google Scholar : PubMed/NCBI
13	Liao Y, Ni Y, He R, Liu W and Du J: Clinical implications of fibroblast activation protein-α in non-small cell lung cancer after curative resection: A new predictor for prognosis. J Cancer Res Clin Oncol. 139:1523–1528. 2013. View Article : Google Scholar : PubMed/NCBI
14	Dang NH, Torimoto Y, Schlossman SF and Morimoto C: Human CD4 helper T cell activation: Functional involvement of two distinct collagen receptors, 1F7 and VLA integrin family. J Exp Med. 172:649–652. 1990. View Article : Google Scholar : PubMed/NCBI
15	Dang DT, Chun SY, Burkitt K, Abe M, Chen S, Havre P, Mabjeesh NJ, Heath EI, Vogelzang NJ, Cruz-Correa M, et al: Hypoxia-inducible factor-1 target genes as indicators of tumor vessel response to vascular endothelial growth factor inhibition. Cancer Res. 68:1872–1880. 2008. View Article : Google Scholar : PubMed/NCBI
16	Ohnuma K, Hatano R and Morimoto C: DPP4 in anti-tumor immunity: Going beyond the enzyme. Nat Immunol. 16:791–792. 2015. View Article : Google Scholar : PubMed/NCBI
17	Janssens R, Mortier A, Boff D, Ruytinx P, Gouwy M, Vantilt B, Larsen O, Daugvilaite V, Rosenkilde MM, Parmentier M, et al: Truncation of CXCL12 by CD26 reduces its CXC chemokine receptor 4- and atypical chemokine receptor 3-dependent activity on endothelial cells and lymphocytes. Biochem Pharmacol. 132:92–101. 2017. View Article : Google Scholar : PubMed/NCBI
18	da Silva Barreira R, Laird ME, Yatim N, Fiette L, Ingersoll MA and Albert ML: Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat Immunol. 16:850–858. 2015. View Article : Google Scholar : PubMed/NCBI
19	Beckenkamp A, Willig JB, Santana DB, Nascimento J, Paccez JD, Zerbini LF, Bruno AN, Pilger DA, Wink MR and Buffon A: Differential expression and enzymatic activity of DPPIV/CD26 affects migration ability of cervical carcinoma cells. PLoS One. 10:e01343052015. View Article : Google Scholar : PubMed/NCBI
20	Jang JH, Baerts L, Waumans Y, De Meester I, Yamada Y, Limani P, Gil-Bazo I, Weder W and Jungraithmayr W: Suppression of lung metastases by the CD26/DPP4 inhibitor Vildagliptin in mice. Clin Exp Metastasis. 32:677–687. 2015. View Article : Google Scholar : PubMed/NCBI
21	Lam CS, Cheung AH, Wong SK, Wan TM, Ng L, Chow AK, Cheng NS, Pak RC, Li HS, Man JH, et al: Prognostic significance of CD26 in patients with colorectal cancer. PLoS One. 9:e985822014. View Article : Google Scholar : PubMed/NCBI