NICO Phase II clinical trial - focus on an emerging immunotherapy strategy for the adjuvant treatment of locally-advanced oral cancers.

Outcomes remain poor for patients presenting with locally-advanced oral cancers and it remains imperative to re-evaluate adjuvant therapies to provide improved outcomes, ideally without compromising on long-term quality of life. We present current available evidence that supports the use of immune checkpoint inhibitors (ICI) in squamous cell carcinoma (SCC) of the head and neck and discuss trials examining the integration of ICI into the locoregional management of such lesions that are resectable. We focus particularly on the Neoadjuvant and adjuvant nivolumab as Immune Checkpoint inhibition in Oral cavity cancer (NICO) trial which is investigating the integration of neoadjuvant and adjuvant ICI into the treatment of resectable locally-advanced oral cavity cancers.

Adjuvant management of locally advanced oral squamous cell carcinoma - real-world challenges and opportunities.

Patients with locally advanced oral squamous cell cancer (LAOSCC) are treated with adjuvant radiotherapy (RT) or chemoradiotherapy (CRT) following surgical ablation. This depends on the pathological risk factors and aims to reduce the risk of local recurrence and improve survival. Delivery of these aggressive treatments is, however, challenging particularly following major surgery. To inform the adaptations necessary to deliver gold-standard therapy, we aimed to describe real-world delivery of multimodality treatment in LAOSCC, in a UK population with high levels of disease incidence and low socioeconomic status. Patients with LAOSCC (T1-4 N1-3/T3-4 N0) who were treated between October 2014 and October 2016 and had a minimum follow up of 24 months were included. They were identified using the Somerset Cancer Register and data were collected through retrospective case note review. Approval was obtained from the audit departments at the relevant NHS institutions, and data were analysed using IBM SPSS Statistics for Windows version 24 (IBM Corp). The analysis included 129 patients with 82% having an initial performance status (PS) of 0-1. The most frequent change in PS was a one point drop (46%). Twenty of the 93 eligible patients (22%) underwent adjuvant CRT. A total of 37 (40%) began adjuvant CRT/RT within 42 days, and 79 (85%) within 56 days. A delay in initiating adjuvant therapy was associated with higher rates of complications and a longer postoperative hospital stay. Concordance between imaging and pathological nodal staging was poor (cK 0.223). PS frequently declines after complex surgical procedures and long postoperative recovery periods, leading to difficulties providing adjuvant treatments within the national guidance of 42 days. Frequent deviation from planned adjuvant therapies highlights the need for improved treatment strategies.

Altered Nuclear Expression of the Deubiquitylase BAP1 Cannot be Used as a Prognostic Marker for Canine Melanoma.

BRCA1-associated protein-1 (BAP1) is a nuclear localized deubiquitylating enzyme that belongs to the ubiquitin c-terminal hydrolase subfamily. The encoded protein is highly homologous between man and dogs, suggesting a functional significance preserved by evolution. BAP1 has multiple properties, including tumour suppressor activity. Loss of BAP1 function is implicated in the oncogenesis of several types of cancers including uveal, mucosal and some cutaneous melanomas in humans, as well as in mesothelioma. In this study we investigate the significance of BAP1 in canine melanoma. Nuclear BAP1 protein was detected in five canine oral melanoma cell lines using an antibody commonly used for analysis of human tissues. BAP1 loss of function mutations often lead to loss of nuclear BAP1 (nBAP1) expression in humans; this is associated with a poorer prognosis in uveal and mucosal melanoma. Therefore, as a prelude to a study evaluating the prognostic significance of nBAP1 expression in dogs, immunohistochemistry (IHC) was used to assess cases of canine melanoma for nBAP1 expression. In 89 cases where tumour cells were identified by melan-A labelling, 100% of tumour cells were positive for nBAP1 expression, including eight uveal tract and 29 oral mucosal melanomas. This finding indicates that BAP1 IHC cannot be used as a prognostic marker in canine uveal and mucosal melanoma. Moreover, this observation suggests that either BAP1 has a different functional significance in canine melanoma or that loss of BAP1 function is achieved by a different route. This is a novel finding that warrants further investigation to determine the comparative biological relevance.

Modulating the DNA Damage Response to Improve Treatment Response in Cervical Cancer.

Cervical cancer is the fourth most common cause of cancer-related death in women worldwide and new therapeutic approaches are needed to improve clinical outcomes for this group of patients. Current treatment protocols for locally advanced and metastatic disease consist of ionising radiation and chemotherapy. Chemoradiation induces cytotoxic levels of DNA double-strand breaks, which activates programmed cell death via the DNA damage response (DDR). Cervical cancers are unique given an almost exclusive association with human papillomavirus (HPV) infection; a potent manipulator of the DDR, with the potential to alter tumour sensitivity to DNA-damaging agents and influence treatment response. This review highlights the wide range of therapeutic strategies in development that have the potential to modulate DDR and sensitise cervical tumours to DNA-damaging agents in the context of HPV oncogenesis.

The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells.

The phosphatidylinositol-3-kinase (PI3K) pathway is commonly hyperactivated in cancer. One mechanism by which this occurs is by silencing of the phosphatase and tensin homolog (PTEN), a tumor suppressor and major antagonist of the pathway, through genetic, epigenetic or posttranscriptional mechanisms. Here, we used an unbiased siRNA screen in non-small-cell lung cancer cells to identify deubiquitylases (DUBs) that have an impact on PI3K signaling by regulating the abundance of PTEN. We found that PTEN expression was induced by depleting any of three members of the Josephin family DUBs: ataxin 3 (ATXN3), ataxin 3-like (ATXN3L) and Josephin domain containing 1 (JOSD1). However, this effect is not mediated through altered PTEN protein stability. Instead, depletion of each DUB increases expression of both the PTEN transcript and its competing endogenous RNA, PTENP1. In ATXN3-depleted cells, under conditions of transcriptional inhibition, PTEN and PTENP1 mRNAs rapidly decay, suggesting that ATXN3 acts primarily by repressing their transcription. Importantly, the PTEN induction observed in response to ATXN3 siRNA is sufficient to downregulate Akt phosphorylation and hence PI3K signaling. Histone deacetylase inhibitors (HDACi) have been suggested as potential mediators of PTEN transcriptional reactivation in non-small-cell lung cancer. Although PTEN exhibits a very limited response to the broad-spectrum HDACi Vorinostat (SAHA) in A549 cells, we find that combination with ATXN3 depletion enhances PTEN induction in an additive manner. Similarly, these interventions additively decrease cell viability. Thus, ATXN3 provides an autonomous, complementary therapeutic target in cancers with epigenetic downregulation of PTEN.