HDAC Inhibitors Enhance Efficacy of the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T in Pancreatic and Triple-Negative Breast Cancer Models

Rodríguez, María Del Carmen Rodríguez; García-Rodríguez, Inés; Nattress, Callum; Qureshi, Ahad; Halldén, Gunnel

doi:10.3390/v14051006

Cited by 7 publications

(4 citation statements)

References 48 publications

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“… 23 , 24 , 25 HDAC inhibition assists multiple processes of oncolytic virotherapy, such as enhancing virus entry, replication, propagation, and spread; decreasing antivirus response; promoting apoptosis; and induction of tumor antigen expression. 27 , 28 Among several HDAC inhibitors, TSA, the pan‐HDAC inhibitor, targets class I (HDAC1, HDAC2, HDAC3, and HDAC8) and class II (HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, and HDAC10) HDACs and is frequently combined with several OVs, such as adenovirus, 32 , 33 , 34 , 35 , 36 bovine herpesvirus type 1, 37 and herpes simplex virus. 38 , 39 , 40 It is also the most potent enhancer of VV replication and spread among other HDAC inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor boosts anticancer potential of fusogenic oncolytic vaccinia virus by enhancing cell–cell fusion

Nakatake,

Kurosaki,

Nakamura

2023

Cancer Science

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Oncolytic viruses have two anticancer functions: direct oncolysis and elicitation of antitumor immunity. We previously developed a novel fusogenic oncolytic vaccinia virus (FUVAC) from a non‐fusogenic vaccinia virus (VV) and, by remodeling the tumor immune microenvironment, we demonstrated that FUVAC induced stronger oncolysis and antitumor immune responses compared with non‐fusogenic VV. These functions depend strongly on cell–cell fusion induction. However, FUVAC tends to have decreased fusion activity in cells with low virus replication efficacy. Therefore, another combination strategy was required to increase cell–cell fusion in these cells. Histone deacetylase (HDAC) inhibitors suppress the host virus defense response and promote viral replication. Therefore, in this study, we selected an HDAC inhibitor, trichostatin A (TSA), as the combination agent for FUVAC to enhance its fusion‐based antitumor potential. TSA was added prior to FUVAC treatment of murine tumor B16‐F10 and CT26 cells. TSA increased the replication of both FUVAC and parental non‐fusogenic VV. Moreover, TSA enhanced cell–cell fusion and FUVAC cytotoxicity in these tumor cells in a dose‐dependent manner. Transcriptome analysis revealed that TSA‐treated tumors showed altered expression of cellular component‐related genes, which may affect fusion tolerance. In a bilateral tumor‐bearing mouse model, combination treatment of TSA and FUVAC significantly prolonged mouse survival compared with either treatment alone or in combination with non‐fusogenic VV. Our findings demonstrate that TSA is a potent enhancer of cell–cell fusion efficacy of FUVAC.

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Section: Discussionmentioning

confidence: 99%

Histone deacetylase inhibitor boosts anticancer potential of fusogenic oncolytic vaccinia virus by enhancing cell–cell fusion

Nakatake,

Kurosaki,

Nakamura

2023

Cancer Science

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“…Since αvβ6-integrin is expressed only in solid tumours, including TNBC cell lines and tumours, and not in healthy tissues (Whilding et al, 2017), we suggest that Ad5-3Δ-A20T has potential for translation into the clinic for treatment of TNBC. We recently demonstrated that the replication and anti-tumour efficacy of OAds including Ad5-3Δ-A20T can be augmented when combined with novel therapeutics such as histone deacetylase inhibitors (HDACis) (Rodríguez et al, 2022).…”

Section: Discussion and Concluding Remarksmentioning

confidence: 99%

Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses

Green-Tripp

Nattress²,

Halldén³

2022

Front. Mol. Biosci.

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Breast cancer (BC) is the most common cancer globally, accounting for 685,000 deaths in 2020. Triple-negative breast cancers (TNBC) lack oestrogen (ER) and progesterone (PR) hormone receptor expression and HER2 overexpression. TNBC represent 10–15% of all BC with high incidence in women under 50-years old that have BRCA mutations, and have a dismal prognosis. African American and Hispanic women are at higher risk partly due to the common occurrence of BRCA mutations. The standard treatment for TNBC includes surgery, radiotherapy, and chemotherapy although, resistance to all standard-of-care therapies eventually develops. It is crucial to identify and develop more efficacious therapeutics with different mechanisms of action to improve on survival in these women. Recent findings with oncolytic adenoviruses (OAds) may generate a new strategy to improve on the outcomes for women afflicted by TNBC and other types of BC. OAds are genetically engineered to selectively lyse, eliminate and recruit the host antitumour immune responses, leaving normal cells unharmed. The most common modifications are deletions in the early gene products including the E1B55 KDa protein, specific regions of the E1A protein, or insertion of tumour-specific promoters. Clinical trials using OAds for various adenocarcinomas have not yet been sufficiently evaluated in BC patients. Preclinical studies demonstrated efficacy in BC cell lines, including TNBC cells, with promising novel adenoviral mutants. Here we review the results reported for the most promising OAds in preclinical studies and clinical trials administered alone and in combination with current standard of care or with novel therapeutics. Combinations of OAds with small molecule drugs targeting the epidermal growth factor receptor (EGFR), androgen receptor (AR), and DNA damage repair by the novel PARP inhibitors are currently under investigation with reported enhanced efficacy. The combination of the PARP-inhibitor Olaparib with OAds showed an impressive anti-tumour effect. The most promising findings to date are with OAds in combination with antibodies towards the immune checkpoints or expression of cytokines from the viral backbone. Although safety and efficacy have been demonstrated in numerous clinical trials and preclinical studies with cancer-selective OAds, further developments are needed to eliminate metastatic lesions, increase immune activation and intratumoural viral spread. We discuss shortcomings of the OAds and potential solutions for improving on patient outcomes.

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“…Furthermore, a recombinant ADV expressing granulocyte-macrophage colony-stimulating factor (GMCSF) in combination with immune checkpoint inhibitors (ICIs) was able to control tumor growth in vivo and promote increased survival compared to control-treated animals [ 121 ]. Pairing histone deacetylase inhibitors (HDACis) with a recombinant ADV expressing an αvβ6-integrin-binding peptide from foot and mouth disease virus demonstrated effective tumor reduction and increased viral replication in a SUM159 xenograft mouse model [ 122 ].…”

Section: Preclinical Ovs For Tnbcmentioning

confidence: 99%

Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses

Monaco

Idris

Essani

2023

Cancers

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Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. TNBC diagnoses account for approximately one-fifth of all breast cancer cases globally. The lack of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER-2, CD340) results in a lack of available molecular-based therapeutics. This increases the difficulty of treatment and leaves more traditional as well as toxic therapies as the only available standards of care in many cases. Recurrence is an additional serious problem, contributing substantially to its higher mortality rate as compared to other breast cancers. Tumor heterogeneity also poses a large obstacle to treatment approaches. No driver of tumor development has been identified for TNBC, and large variations in mutational burden between tumors have been described previously. Here, we describe the biology of six different subtypes of TNBC, based on differential gene expression. Subtype differences can have a large impact on metastatic potential and resistance to treatment. Emerging antibody-based therapeutics, such as immune checkpoint inhibitors, have available targets for small subsets of TNBC patients, leading to partial responses and relatively low overall efficacy. Immuno-oncolytic viruses (OVs) have recently become significant in the pursuit of effective treatments for TNBC. OVs generally share the ability to ignore the heterogeneous nature of TNBC cells and allow infection throughout a treated tumor. Recent genetic engineering has allowed for the enhancement of efficacy against certain tumor types while avoiding the most common side effects in non-cancerous tissues. In this review, TNBC is described in order to address the challenges it presents to potential treatments. The OVs currently described preclinically and in various stages of clinical trials are also summarized, as are their strategies to enhance therapeutic potential.

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HDAC Inhibitors Enhance Efficacy of the Oncolytic Adenoviruses Ad∆∆ and Ad-3∆-A20T in Pancreatic and Triple-Negative Breast Cancer Models

Cited by 7 publications

References 48 publications

Histone deacetylase inhibitor boosts anticancer potential of fusogenic oncolytic vaccinia virus by enhancing cell–cell fusion

Histone deacetylase inhibitor boosts anticancer potential of fusogenic oncolytic vaccinia virus by enhancing cell–cell fusion

Targeting Triple Negative Breast Cancer With Oncolytic Adenoviruses

Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses

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