GM101 in Combination with Histone Deacetylase Inhibitor Enhances Anti-Tumor Effects in Desmoplastic Microenvironment.

Han-Gyu Chang,Joung-Woo Choi,Chae-Ok Yun,Yong-Hyeon Choi,Jinwoo Hong,A-Rum Yoon

doi:10.3390/cells10112811

Han-Gyu Chang, Joung-Woo Choi + Show 4 more

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https://doi.org/10.3390/cells10112811

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Journal: Cells	Publication Date: Oct 20, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: Hanyang University, Anyang University

Abstract

Oncolytic adenoviruses (oAds) have been evaluated in numerous clinical trials due to their promising attributes as cancer therapeutics. However, the therapeutic efficacy of oAds was limited due to variable coxsackie and adenovirus receptor (CAR) expression levels and the dense extracellular matrix (ECM) of heterogenic clinical tumors. To overcome these limitations, our present report investigated the therapeutic efficacy of combining GM101, an oAd with excellent tumor ECM degrading properties, and histone deacetylase inhibitor (HDACi). Four different HDACi (suberohydroxamic acid (SBHA), MS-275, trichostatin A (TSA), and valproic acid) candidates in combination with replication-incompetent and GFP-expressing Ad (dAd/GFP) revealed that SBHA and MS-275 exerted more potent enhancement in Ad transduction efficacy than TSA or valproic acid. Further characterization revealed that SBHA and MS-275 effectively upregulated CAR expression in cancer cells, improved the binding of Ad with cancer cell membranes, and led to dynamin 2- and clathrin-mediated endocytosis of Ad. The combination of GM101 with HDACi induced superior cancer cell killing effects compared to any of the monotherapies, without any additional cytotoxicity in normal cell lines. Further, GM101+SBHA and GM101+MS-275 induced more potent antitumor efficacy than any monotherapy in U343 xenograft tumor model. Potent antitumor efficacy was achieved via the combination of GM101 with HDACi, inducing necrotic and apoptotic cancer cell death, inhibiting cancer cell proliferation, degrading ECM in tumor tissue, and thus exerting the highest level of virus dispersion and accumulation. Collectively, these data demonstrate that the combination of GM101 and HDACi can enhance intratumoral dispersion and accumulation of oAd through multifaced mechanisms, making it a promising strategy to address the challenges toward successful clinical development of oAd.

Highlights

In eukaryotic cells, histone acetyltransferase and histone deacetylase (HDAC) play a crucial role in the regulation of DNA transcription and gene expression through the addition and removal of acetyl groups on the lysine residues of histones [1]
As there are numerous histone deacetylase inhibitor (HDACi) in development for cancer therapy, we first investigated which of the HDACi (SBHA, MS-275, TSA, or valproic acid) could enhance the Ad-mediated transgene expression in human cancer cells (U343 and A549)
The present report investigated the combination of extracellular matrix (ECM)-degrading Oncolytic adenoviruses (oAds) (GM101) with HDACi to maximize the intratumoral distribution of virus through upregulation of coxsackie and adenovirus receptor (CAR), and synergistic degradation of ECM and induction of apoptosis

Summary

Introduction

Histone acetyltransferase and histone deacetylase (HDAC) play a crucial role in the regulation of DNA transcription and gene expression through the addition and removal of acetyl groups on the lysine residues of histones [1]. The HDAC-mediated gene regulation process is dysregulated and promotes oncogenic phenotype of cancer cells, the inhibition of HDAC with chemical inhibitors (HDACi) is under active preclinical and clinical investigation with several products, such as vorinostat (suberanilohydroxamic acid) and panobinostat (hydroxamic acid), approved by the US Food and Drug Administration [2,3,4,5]. HDACi treatment has been shown to reactivate tumor suppressor genes or death signaling pathways [6] and induce apoptosis of cancer cells [7], resulting in antitumor efficacy. Oncolytic adenoviruses (oAds) are under clinical evaluation across multiple clinical trials to treat various types of cancer [8,9,10]. OAds induce highly preferential killing of cancer cells through cancer-specific replication of the virus and exponential amplification of therapeutic transgene expression, resulting in antitumor effects [11]. OAd has minimal insertional mutagenesis risks and a well-documented safety record across multiple clinical trials being conducted from the 1990s [12].

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