Targeting CD46 Enhances Anti-Tumoral Activity of Adenovirus Type 5 for Bladder Cancer

Abstract

CD46 is generally overexpressed in many human cancers, representing a prime target for CD46-binding adenoviruses (Ads). This could help to overcome low anti-tumoral activity by coxsackie-adenoviral receptor (CAR)-targeting cancer gene therapy viruses. However, because of scarce side-by-side information about CAR and CD46 expression levels in cancer cells, mixed observations of cancer therapeutic efficacy have been observed. This study evaluated Ad-mediated therapeutic efficacy using either CAR-targeting Ad5 or CD46-targeting Ad5/35 fiber chimera in bladder cancer cell lines. Compared with normal urothelia, bladder cancer tissue generally overexpressed both CAR and CD46. While CAR expression was not correlated with disease progression, CD46 expression was inversely correlated with tumor grade, stage, and risk grade. In bladder cancer cell lines, expression levels of CD46 and CAR were highly correlated with Ad5/35- and Ad5-mediated gene transduction and cytotoxicity, respectively. In a human EJ bladder cancer xenograft mouse model, with either overexpressed or suppressed CD46 expression levels, Ad5/35-tk followed by ganciclovir (GCV) treatment significantly affected tumor growth, whereas Ad5-tk/GCV had only minimal effects. Overall, our findings suggest that bladder cancer cells overexpress both CAR and CD46, and that adenoviral cancer gene therapy targeting CD46 represents a more suitable therapy option than a CAR-targeting therapy, especially in patients with low risk bladder cancers.

CD46 and Oncologic Interactions: Friendly Fire against Cancer

“…Alternatively, some species B adenoviruses target CD46, thus presenting an improved approach to increase the effectiveness of cancer targeting. As an example, comparisons between CD46 and CAR-targeted adenoviral therapy have demonstrated superior outcomes with CD46 targeting in bladder cancer [69] and ovarian cancer [70], despite comparable receptor expression by the tumor cells. Other oncolytic strategies utilize measles virus that also targets CD46.…”

Adenovirus Receptor Expression in Cancer and Its Multifaceted Role in Oncolytic Adenovirus Therapy

“…CD46 expression is low or moderate in most normal tissues, but upregulated in many types of cancer [ 42 , 43 ]. One reason for the upregulation might be that CD46 can protect cancer cells from being killed by the complement system [ 44 ].…”

“…One reason for the upregulation might be that CD46 can protect cancer cells from being killed by the complement system [ 44 ]. Upregulation of CD46 for instance, is detected in primary and metastatic prostate cancer [ 43 ], as well as in bladder cancer [ 42 ]. In the latter, CD46 expression negatively correlated with the stage of the cancer.…”

<p>Virus–Receptor Interactions: Structural Insights For Oncolytic Virus Development</p>

“…113 CD46 structure is comprised of a C-terminal domain, a transmembrane domain, a short region with unknown function and four modules of short consensus repeats (SCR) 1-4 at the N terminus. 143,114 The crystal structure of dimeric H-CD46 identifies interactions between MV-H and SCR1, SCR1-SCR2 interface and SCR2 of CD46 ( Figure 2G). CD46 SCR1-2 is pivotal to capsid binding in adenoviruses, 115 discussed later in this review.…”

“…141 The majority of subtype B HAdVs and some of subtype D (AdV37) have been shown to exploit CD46, a type I transmembrane protein overexpressed in tumors, as the attachment receptor. 142,143 Crystallographic studies showed that AdV11 trimeric fibers form a compact knob that interacts with the SCR1-2 regions of three CD46 molecules ( Figure 3C). 115 Complementary or not to CD46, sialic acid has been shown to interact with the top region of AdV37 knob trimer.…”