STAT3 Signaling in Breast Cancer: Multicellular Actions and Therapeutic Potential

Interleukin (IL)-6 family cytokines, such as IL-6 and IL-11, are defined by the shared use of the gp130 receptor for the downstream activation of STAT3 signaling and the activation of genes which contribute to the “hallmarks of cancer”, including proliferation, survival, invasion and metastasis. Increased expression of these cytokines, or the ligand-specific receptors IL-6R and IL-11RA, in breast tumors positively correlate to disease progression and poorer patient outcome. In this review, we examine evidence from pre-clinical studies that correlate enhanced IL-6 and IL-11 mediated gp130/STAT3 signaling to the progression of breast cancer. Key processes by which the IL-6 family cytokines contribute to the heterogeneous nature of breast cancer, immune evasion and metastatic potential, are discussed. We examine the latest research into the therapeutic targeting of IL-6 family cytokines that inhibit STAT3 transcriptional activity as a potential breast cancer treatment, including current clinical trials. The importance of the IL-6 family of cytokines in cellular processes that promote the development and progression of breast cancer warrants further understanding of the molecular basis for its actions to help guide the development of future therapeutic targets.

LncRNAs and the Angiogenic Switch in Cancer: Clinical Significance and Therapeutic Opportunities

Angiogenesis is one of the hallmarks of cancer, and the establishment of new blood vessels is vital to allow for a tumour to grow beyond 1–2 mm in size. The angiogenic switch is the term given to the point where the number or activity of the pro-angiogenic factors exceeds that of the anti-angiogenic factors, resulting in the angiogenic process proceeding, giving rise to new blood vessels accompanied by increased tumour growth, metastasis, and potential drug resistance. Long noncoding ribonucleic acids (lncRNAs) have been found to play a role in the angiogenic switch by regulating gene expression, transcription, translation, and post translation modification. In this regard they play both anti-angiogenic and pro-angiogenic roles. The expression levels of the pro-angiogenic lncRNAs have been found to correlate with patient survival. These lncRNAs are also potential drug targets for the development of therapies that will inhibit or modify tumour angiogenesis. Here we review the roles of lncRNAs in regulating the angiogenic switch. We cover specific examples of both pro and anti-angiogenic lncRNAs and discuss their potential use as both prognostic biomarkers and targets for the development of future therapies.

Tackling the Behavior of Cancer Cells: Molecular Bases for Repurposing Antipsychotic Drugs in the Treatment of Glioblastoma

Glioblastoma (GBM) is associated with a very dismal prognosis, and current therapeutic options still retain an overall unsatisfactorily efficacy in clinical practice. Therefore, novel therapeutic approaches and effective medications are highly needed. Since the development of new drugs is an extremely long, complex and expensive process, researchers and clinicians are increasingly considering drug repositioning/repurposing as a valid alternative to the standard research process. Drug repurposing is also under active investigation in GBM therapy, since a wide range of noncancer and cancer therapeutics have been proposed or investigated in clinical trials. Among these, a remarkable role is played by the antipsychotic drugs, thanks to some still partially unexplored, interesting features of these agents. Indeed, antipsychotic drugs have been described to interfere at variable incisiveness with most hallmarks of cancer. In this review, we analyze the effects of antipsychotics in oncology and how these drugs can interfere with the hallmarks of cancer in GBM. Overall, according to available evidence, mostly at the preclinical level, it is possible to speculate that repurposing of antipsychotics in GBM therapy might contribute to providing potentially effective and inexpensive therapies for patients with this disease.

Hydrophilic magnetic covalent triazine frameworks fishing for differential N-glycopeptides in breast cancer plasma membrane

The alterations in plasma membrane glycoproteins (PMGs) have been identified as the hallmarks of cancer. The comparison and identification of differential PMGs is significant for finding new markers and understanding...

The Intriguing Thyroid Hormones–Lung Cancer Association as Exemplification of the Thyroid Hormones–Cancer Association: Three Decades of Evolving Research

Exemplifying the long-pursued thyroid hormones (TH)–cancer association, the TH–lung cancer association is a compelling, yet elusive, issue. The present narrative review provides background knowledge on the molecular aspects of TH actions, with focus on the contribution of TH to hallmarks of cancer. Then, it provides a comprehensive overview of data pertinent to the TH–lung cancer association garnered over the last three decades and identifies obstacles that need to be overcome to enable harnessing this association in the clinical setting. TH contribute to all hallmarks of cancer through integration of diverse actions, currently classified according to molecular background. Despite the increasingly recognized implication of TH in lung cancer, three pending queries need to be resolved to empower a tailored approach: (1) How to stratify patients with TH-sensitive lung tumors? (2) How is determined whether TH promote or inhibit lung cancer progression? (3) How to mimic the antitumor and/or abrogate the tumor-promoting TH actions in lung cancer? To address these queries, research should prioritize the elucidation of the crosstalk between TH signaling and oncogenic signaling implicated in lung cancer initiation and progression, and the development of efficient, safe, and feasible strategies leveraging this crosstalk in therapeutics.

P-OGC08 Translational Insights from the Dual ErbB Inhibition in Oesophago-gastric Cancer (DEBIOC) Clinical Trial - A Bioinformatic Analysis

Background Oesophageal Adenocarcinoma (OAC) incidence in the Western-world has increased markedly over 30 years. 5-year survival rates for patients remains below 20% with dismal response to neo-adjuvant or perioperative chemotherapy for operable tumours. The Dual ErbB Inhibition in Oesophago-gastric Cancer (DEBIOC) clinical trial assessed efficacy of combined oxaliplatin and capecitabine (Xelox) with dual ErbB inhibitor AZD8931 in providing additional benefit to operable patients compared to Xelox alone. We utilised a bioinformatic approach combing Almac Clara-T Transcriptional Discovery software with unsupervised machine learning methods to unveil translational clinical potential and biological insights from DEBIOC patient biopsy and resection specimens. Methods Using microarrays of DEBIOC patient specimens with documented clinical observations, we combined unsupervised machine learning techniques with state-of-the-art Almac Clara-T software to assess transcriptional changes between treatment types regarding the 10 hallmarks of cancer, characterised by representative gene-expression signatures and scores. These methods were employed to identify possible mechanisms of treatment resistance, evaluate changes in the tumour-microenvironment and determine clinically significant molecular subgroups in OAC. Differential expression and pathway analytics were used to describe signalling dissimilarities between clusters from unsupervised analysis and phenotypes respective to hallmarks of cancer, with alignment of sensitivities to single-gene drug targets for subgroups of interest. Results Unsupervised clustering analysis of biopsy specimens, resulted in the identification of two robust subgroups pre-treatment in OAC, determined to be significantly associated with the prediction of Mandard Score (Tumour Regression Grade 1-5) post-treatment (fishers exact p < 0.05). Differential expression analysis revealed distinguishing biology between subtypes and noted increased ErbB signalling in non-responding patients in addition to increased PI3K signalling, highlighting a potential mechanism of resistance to dual ErbB inhibition (nominal p-value <0.05, FDR p-value <0.2). Semi-supervised clustering revealed hallmark-specific-phenotypes associated with clinical observations including lymph node involvement, EGFR FISH classification, vascular invasion and progression events at BH adjusted p-values <0.05. Conclusions Our analysis has revealed translational insights into possible mechanisms of drug resistance as well as cancer hallmark-specific phenotypes significantly associated with clinico-pathological factors during the DEBIOC clinical trial. Continued analysis into resulting phenotypes and clusters combined with the alignment of single gene drug target sensitivities is anticipated to reveal novel molecular pathways driving phenotypic differences in an effort to further inform biological understanding and improve treatment response and survival outcomes in OAC patients.