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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.

ABSTRACT: The prognosis for triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) is dismal. TNBC and PDAC are highly aggressive cancers with few treatment options and a potential for rapid resistance to standard-of-care chemotherapeutics. Oncolytic adenoviruses (OAds) represent a promising tumour-selective strategy that can overcome treatment resistance and eliminate cancer cells by lysis and host immune activation. We demonstrate that histone deacetylase inhibitors (HDACi) potently enhanced the cancer-cell killing of our OAds, Ad∆∆ and Ad-3∆-A20T in TNBC and PDAC preclinical models. In the TNBC cell lines MDA-MB-436, SUM159 and CAL51, cell killing, viral uptake and replication were increased when treated with sublethal doses of the Class-I-selective HDACis Scriptaid, Romidepsin and MS-275. The pan-HDACi, TSA efficiently improved OAd efficacy, both in vitro and in SUM159 xenograft models in vivo. Cell killing and Ad∆∆ replication was also significantly increased in five PDAC cell lines when pre-treated with TSA. Efficacy was dependent on treatment time and dose, and on the specific genetic alterations in each cell line. Expression of the cancer specific αvß6-integrin supported higher viral uptake of the integrin-retargeted Ad-3∆-A20T in combination with Scriptaid. In conclusion, we demonstrate that inhibition of specific HDACs is a potential means to enhance OAd activity, supporting clinical translation.

SUBMITTER: Rodriguez MDCR

PROVIDER: S-EPMC9143155 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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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.

Rodríguez María Del Carmen Rodríguez MDCR Rodríguez Inés García IG Nattress Callum C Qureshi Ahad A Halldén Gunnel G

Viruses 20220509 5

The prognosis for triple-negative breast cancer (TNBC) and pancreatic ductal adenocarcinoma (PDAC) is dismal. TNBC and PDAC are highly aggressive cancers with few treatment options and a potential for rapid resistance to standard-of-care chemotherapeutics. Oncolytic adenoviruses (OAds) represent a promising tumour-selective strategy that can overcome treatment resistance and eliminate cancer cells by lysis and host immune activation. We demonstrate that histone deacetylase inhibitors (HDACi) pot ...[more]

PMID: 35632748

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Project description: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.

Dataset Information

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

Publications

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

Similar Datasets

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