Possible new therapeutic agents for malignant pleural mesothelioma: anti-CD26 monoclonal antibody and naftopidil

KEYWORDS:

• Mesothelioma
• β-blockers
• naftopidil
• CD26
• dipeptidyl peptidase IV
• anti-CD26 monoclonal antibody
• amatuximab
• nintedanib

1. Introduction

Malignant pleural mesothelioma (MPM) is a locally aggressive tumor that is causally linked to asbestos exposure. MPM often develops after a long latency period of around 40 years, and its incidence is expected to continue to increase worldwide over the next 20 years. Asbestos is still being used in developing countries where little is known about the epidemic of asbestos-related diseases, including mesothelioma.

The prognoses of patients with MPM are poor, with a median overall survival (OS) of about 10 months for untreated patients and a 5-year survival rate of <5%. Almost all of the available therapies have little effect on outcomes. Multimodality treatment, including curative intent surgery, chemotherapy, and radiotherapy, offers some benefits to highly selected patients. However, most patients with resectable MPM receive only modest benefit from intensive treatment.

The only standard first-line chemotherapy with proven evidence of efficacy is the pemetrexed (PEM) and cisplatin (CDDP) combination, which was established as a treatment for advanced MPM based on the results of a phase III randomized study [1]. This standard treatment provides nearly 3 months of survival benefit, with an OS of 12.1 months and a median progression-free survival (PFS) of 5.7 months. For >10 years, no standard chemotherapy proved to be superior to the PEM/CDDP combination treatment.

More recently, preclinical studies clearly demonstrated that vascular endothelial growth factor (VEGF) is a key trigger of tumor angiogenesis in MPM, and therefore VEGF-targeting therapy may improve treatment outcomes. Although a randomized phase II trial combining CDDP/gemcitabine ± bevacizumab (BEV) showed no significant benefit for PFS, addition of BEV to the standard PEM/CDDP combination significantly improved OS and PFS in patients with MPM (the Mesothelioma Avastin Cisplatin Pemetrexed Study [MAPS] trial) [2].

Recently, the novel VEGF-independent angiogenic factors progranulin and granulin-like protein were found in mesothelioma cell lines [3]. Nintedanib is a tyrosine kinase inhibitor that targets three angiogenesis-related transmembrane receptors. The results of a randomized study that compared nintedanib plus PEM/CDDP with placebo plus PEM/CDDP for the treatment of patients with unresectable MPM are eagerly awaited.

In addition to angiogenesis inhibitors, mesothelin is an attractive target in the treatment of mesothelioma [4]. A single-arm phase II study of amatuximab (a chimeric anti-mesothelin antibody) in combination with PEM/CDDP showed a median OS of 14.8 months, and 91% of patients achieved a partial response or stable disease (SD) [5]. Amatuximab and anetumab ravtansine (an antibody-drug conjugate consisting of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor) are currently being tested in randomized trials.

Emerging immunotherapy that targets the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1/programmed cell death ligand-1 (PD-L1) has changed the cancer therapeutic strategy. However, the CTLA-4 inhibitor tremelimumab administered as a single agent has failed to improve patient survival in the second- and third-line settings. Preliminary results of 25 pretreated PD-L1-positive mesotheliomas treated with pembrolizumab showed an encouraging response rate of 28% and a high disease control rate of 76%, including durable response rates and a PFS rate at 6 months of 49% [6].

The promising treatment success observed in some malignancies in response to immune checkpoint inhibitors has spurred global clinical evaluations of these agents for the treatment of mesothelioma. Most clinical trials are still ongoing, and the results are eagerly awaited. Understanding the molecular pathways that induce carcinogenesis and tumor growth has led to the development of novel and targeted agents in the treatment of mesothelioma. Possible agents other than immune checkpoint inhibitors have been identified and are being developed for new approaches to the treatment of MPM.

2. Humanized anti-CD26 monoclonal antibody (YS110) for the treatment of mesothelioma

Cluster of differentiation 26 (CD26) is a 110-kDa multifunctional transmembrane glycoprotein with dipeptidyl peptidase IV (DPPIV) activity in the extracellular domain [7]. Recently, CD26/DPPIV inhibitors have been widely used in the treatment of type 2 diabetes. Vascular inflammation is a key feature of diabetic micro- and macrovascular complications. It has been clearly demonstrated that expression of CD26 in human microvascular endothelial cells is suppressed by proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-1β, and that pharmacological inhibition of enzymatic activity of CD26/DPPIV is directly associated with endothelial proliferation and migration and neovascularization in the inflammatory setting [8]. Experimental findings and preliminary clinical data suggest that the inhibitors can ameliorate diabetic microangiopathy.

CD26 is expressed on the surface of various human cells and inactivates some bioactive peptides. It is the cellular binding protein for adenosine deaminase. CD26 is also known to interact with extracellular matrix (ECM) [9]. In addition, CD26 has been demonstrated to be involved in tumorigenesis. It is expressed in various tumors, including lung adenocarcinoma, prostate cancer, renal cell carcinoma, colorectal cancer, hepatocellular carcinoma, and gastrointestinal stromal tumors. Pharmacological inhibition of DPPIV activity with sitagliptin and vildagliptin showed anticancer properties in in vitro models [10] through the preservation of biologically active C-X-C motif chemokine ligand 10 in the tumor microenvironment [11]. CD26 is preferentially overexpressed in MPM cells but not in normal mesothelial cells, the expression level of which correlates with good clinical outcomes and therapeutic responses [12]. Most epithelioid (80%) and epithelioid components of biphasic mesothelioma (95%) express CD26 on the cell membrane, whereas the sarcomatoid subtype shows a lack of CD26 surface expression [12].

In vivo experimental xenograft models involving human MPM cells demonstrated that humanized anti-CD26 monoclonal antibody (YS110) treatment drastically inhibited tumor growth in tumor-bearing mice and reduced the formation of metastases, resulting in enhanced survival [13]. The active anti-mesothelioma agent PEM rapidly induces CD26 expression on the cell surface and inhibits in vivo tumor growth synergistically with YS110 [14]. The mechanisms of YS110 antitumor action for CD26-positive mesotheliomas are the following: (a) cell lysis of MPM cells via antibody-dependent cell-mediated cytotoxicity in addition to its direct antitumor effect via cyclin-dependent kinase (CDK) inhibitor p27^kip1 upregulation and disruption of binding to ECM [13]; (b) G1/S cell cycle arrest and G2/M cell cycle delay by upregulating CDK inhibitor p27^kip1 and p21^cip/waf1 via multiple signaling pathways [13–15]; and (c) induction of nuclear translocation of cell-surface CD26 molecules by internalization of the CD26–YS110 complexes to inhibit proliferation of MPM cells via suppression of POLR2A gene expression [16]. The reduction of distant metastases by YS110 treatment in experimental models may be explained by CD26’s function as a binding protein to distinct ECM proteins [13].

These data strongly suggest that YS110 may have potential clinical use as a novel cancer therapeutic agent for CD26-positive malignant mesothelioma. The first human phase I trial of YS110 was conducted for 33 pretreated patients, including 22 patients with MPM and 11 patients with other CD26-positive solid tumors [17]. No objective response was obtained but SD was achieved in 13 of the 26 evaluable patients, with a median PFS of 32 weeks (range, 12–57 weeks). This first human phase I clinical trial demonstrated that YS110 exhibited a favorable safety profile and had signs of clinical activity in heavily pretreated CD26-positive MPM patients who previously showed disease progression while receiving conventional standard chemotherapies [17]. These promising preliminary results led to the launching of a phase II study of YS110 for the treatment of advanced/refractory CD26-expressing MPM.

3. Naftopidil and naftopidil analogue (HUHS1015) for the treatment of mesothelioma

β-Blockers are widely used in the treatment of cardiovascular diseases such as hypertension, coronary artery disease, and arrhythmia. β-Catecholamines can upregulate VEGF expression and induce tumor angiogenesis, which promotes the proliferation and invasiveness of cancer cell lines [18]. Several epidemiological studies have revealed that β-blockers have an antitumor activity, which reduces metastasis, tumor recurrence, and cancer-specific mortality in patients with breast cancer and increases survival time in patients with non-small-cell lung cancer [19,20].

It is intriguing that α₁-adrenoceptor antagonists such as prazosin, doxazosin, and terazosin have shown potential to inhibit cell growth by arresting the cell cycle or inducing apoptosis through several different mechanisms, including mitochondria-mediated activation of caspase-3/caspase-9 and c-Jun N-terminal kinase 1/2, recruitment of Fas-associated death domain and the ensuing activation of caspase-8, activation of transforming growth factor-β1 followed by induction of IκBα, and the antagonistic effect of B-cell lymphoma 2. In addition, α₁-adrenoceptor antagonists exhibit antiangiogenic effects, resulting in suppression of cell growth in human prostate and bladder cancers.

Naftopidil, an antagonist of the α₁-adrenoceptor that has higher selectivity for α_1A and α_1D receptors, has been clinically used in the treatment of hypertension and benign prostate hyperplasia. Recently, it was shown that naftopidil exerts an antitumor action on prostate cancer cells and renal cell carcinoma by arresting cells in the G₁ phase of the cell cycle. In addition, the prostate cancer incidence was significantly lower in men who received naftopidil for ≥3 months than in those who received tamsulosin [21,22].

Mesothelioma is classically divided into three histological subtypes: epithelioid, biphasic, and sarcomatoid. In general, sarcomatoid mesothelioma is highly chemoresistant. Naftopidil induces apoptosis in human malignant mesothelioma cell lines, including sarcomatoid cells NCI-H28 and NCI-H2052, epithelioid cells NCI-H2452, and biphasic cells MSTO-211H by activating caspase-8 and the effector caspase-3, regardless of α₁-adrenoceptor blocking [23]. A similar effect was obtained with prazosin, another α₁-adrenoceptor blocker [23]. Naftopidil has been shown to attenuate neovascularization in an in vivo Matrigel plug assay. Moreover, studies in mouse xenograft models have shown a significant microvessel density reduction in naftopidil-treated excised human renal cell carcinoma [22]. Naftopidil induces apoptosis of mesothelioma cells by upregulating the expression of TNF-α and stimulating the secretion of FasL, a ligand for the death receptor Fas, both of which activate caspase-8 and the effector caspase-3, which lead to the suppression of mesothelioma cell proliferation in vivo [24].

The newly synthesized naftopidil analogue HUHS1015 induces apoptosis in various cancer cell lines, including mesothelioma, lung cancer, hepatocellular carcinoma, gastric cancer, and bladder cancer [25]. HUHS1015 induced mitochondrial apoptosis and suppressed tumor growth in mice inoculated with mesothelioma cells [26]. These preliminary encouraging results suggest that naftopidil and its analogue HUHS1015 can be developed as effective anticancer drugs for the treatment of MPM.

The prognosis of patients with MPM is poor and only modestly affected by conventional treatment. New effective agents should be introduced into clinical practice to improve treatment benefit. The CD26-targeting monoclonal antibody YS110 and the α1-adrenoceptor antagonist naftopidil and its analogue have been identified to have anti-mesothelioma activity and are expected to be evaluated soon for clinical use in mesothelioma.

Declaration of interest

T. Nakano has served as a consultant for Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.