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

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.

Dipeptidyl peptidase 4 inhibitors as novel agents in improving survival in diabetic patients with colorectal cancer and lung cancer: A Surveillance Epidemiology and Endpoint Research Medicare study

“…Our study included two groups of cancers, CRC and lung cancers, which have a different clinical course. We included the same group of cancers as we included in our initial retrospective study . With a larger sample size, our present study showed statistically significant HR in the combined cohort of CRC and lung cancer patients.…”

“…Due to these in‐vivo studies showing that DPP4/CD26 inhibition can either deter or facilitate tumor progression, we previously conducted a multi‐institutional retrospective study involving patients with advanced airway and colorectal cancers (CRCs) who were being treated for diabetes with DPP4 inhibitors. Our study, which to our knowledge was the first study evaluating the role of DPP4 inhibition on cancers in human subjects, found statistically significant benefit in progression‐free survival and a positive trend in overall survival (OS); however, this benefit in OS did not reach the level of statistical significance, likely due to the relatively small number of subjects included in the study . As a follow‐up and to further clarify the role of DPP4 inhibitors in human malignancies, we conducted a national database study in CRC and lung cancer.…”

“…Our study, which to our knowledge was the first study evaluating the role of DPP4 inhibition on cancers in human subjects, found statistically significant benefit in progressionfree survival and a positive trend in overall survival (OS); however, this benefit in OS did not reach the level of statistical significance, likely due to the relatively small number of subjects included in the study. 12 As a follow-up and to further clarify the role of DPP4 inhibitors in human malignancies, we conducted a national database study in CRC and lung cancer.…”

The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease

“…Interestingly, DPP-4 can act either as a tumor activator or suppressor depending on paracrine signals, the microenvironment, and molecular interactions [42,43]. The pharmacological inhibition of DPP-4 in lung cancer patients showed improved overall survival, which was attributed to the effect of DPP-4 inhibition on tumor immunoregulation [44,45]. Information on the role of DPP-4/CD26 in tumor biology can be inferred from either transgenic animals that lack DPP-4 or its pharmacological inhibition.…”

“…Metastasis and tumor invasion are dependent upon matrix degradation, which allows cell mobility and tissue penetration. DPP-4/CD26 has been shown to have a pivotal role in both tumor cell metastasis and invasion [45,50]. There are a variety of suggested mechanisms for DPP-4 to impinge on cancer metastasis.…”