Role of DNA methylation and epigenetic silencing of HAND2 in endometrial cancer development

Background: Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development. Methods and Findings: Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression. Conclusions: HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies.publishedVersio

Role of DNA Methylation and Epigenetic Silencing of HAND2 in Endometrial Cancer Development

Peer reviewe

Biomarkers in Advanced Colorectal Cancer: Challenges in Translating Clinical Research into Practice

The growing number of therapeutic agents and known molecular targets in oncology makes the study and clinical use of biomarkers imperative for improving response and survival, reducing toxicity and ensuring economic sustainability. Colorectal cancer, among others, is at the forefront of development of predictive and prognostic biomarkers; however, the difficulty lies in translating potential biomarkers garnered from retrospective analyses in small numbers of patients to generalizable and affordable biomarkers used worldwide. This review outlines the progress made in prognostic and predictive biomarkers in advanced colorectal cancer (ACRC) from the early use of carcinoembryonic antigen (CEA) to the KRAS mutation and beyond. Future challenges are to incorporate standardized and validated methods preferentially during early phases of drug development linked with sophisticated biostatistical support. New trial designs focusing on biomarkers will be essential not only for better understanding of mechanisms of action, but also to make confident ‘go or no-go’ decisions

Novel Treatments for Metastatic Cutaneous Melanoma and the Management of Emergent Toxicities

Abstract: The last 12 months have seen the beginning of a new era in the treatment options available for patients with metastatic cutaneous melanoma, a disease previously characterised by its poor prognosis and limited treatment options. Two mechanistically diverse agents have now demonstrated an overall survival benefit in different patient subgroups and further clinical trials are ongoing with emerging single agents and novel combinations. The first agent to demonstrate an overall survival benefit was the CTLA-4 antibody, ipilimumab, illustrating the importance of the immune system and immunomodulation in melanoma tumorigenesis. The second group of agents to show a survival benefit were the selective BRAF inhibitors, vemurafenib and GSK2118436, in patients who are BRAF V600 mutation positive. In addition, in the same BRAF mutant patient population, MEK inhibitors also show promising results and are currently under investigation in later stage trials. Although ipilimumab, BRAF and MEK inhibitors are just passing through the clinical trials arena, their use will rapidly become more widespread. Along with their significant clinical benefits, there are also unique adverse events related to these agents. Although the majority are mild and can be managed with supportive treatment, some toxicities require special management strategies. We outline up-to-date clinical development and management guidelines for ipilimumab, as well as the BRAF and MEK inhibitors. Keywords: BRAF-inhibitor, MEK-inhibitor, ipilimumab, cutaneous melanoma, ocular toxicity, squamous cell carcinoma, fever, diarrhea, skin rash, immune related adverse event

New molecular and immunotherapeutic approaches in biliary cancer

Biliary tract carcinoma is a collective term for a group of rare gastrointestinal cancers. This overview outlines the key pathways and specialised therapeutics in biliary cancer and the emerging role of immunotherapy by highlighting the rationale and selected examples of studies in each area

Patients' perceptions of research biopsies in Phase I Oncology Trials

Objective: Research biopsies are increasingly incorporated into phase I oncology trials resulting in ethical and logistical challenges for patients and clinicians. Patients' understanding and willingness to undergo these biopsies are crucial. Methods: Over 12 months, we administered a questionnaire comprising three sections: demographics and previous cancer therapy, understanding of phase I trials and personalized medicine, and understanding of biopsies and associated risks. Results: Out of 56 patients approached, 47 patients completed the questionnaire. Overall, the patients were well informed about the concepts of personalized medicine and 89% (n = 42) were aware that early phase clinical trials aim to define a dose and explore side effects of new drugs. Interestingly, 76% (n = 36) expected early phase trials to improve symptoms, quality of life and survival. Offering hope and feeling in control of their treatment were important components for 80% (n = 38) and 57% (n = 27), respectively. The majority of this highly selective patient cohort understood the concept of research biopsies, with 59% (n = 28) willing to have a fresh research biopsy for trial participation. Although 72% (n = 34) felt that research biopsies should be optional, only 19% (n = 9) would not participate in a clinical trial with mandatory biopsies. Compared to diagnostic biopsies, the patients were less likely to accept associated risks with research biopsies. Conclusion: As research biopsies are crucial to many components of the drug development process, our study provides evidence for patients' overall willingness to undergo research biopsies for trial purposes. A consent process tailored to the biopsy site may help patients weigh up the associated risks versus benefits

Erratum to:Development and Evaluation of a New Technological Way of Engaging Patients and Enhancing Understanding of Drug Tolerability in Early Clinical Development: PROACT

INTRODUCTION: During early clinical testing of a new medication, it is critical to understand and characterise patient tolerability. However, in early clinical studies, it is difficult for patients to contribute directly to the sponsors’ understanding of a new compound. Patient reported opinions about clinical tolerability (PROACT) provides a new, simple and innovative way in which patients can collaborate using an application downloaded to a mobile computer or smartphone. METHODS: PROACT was designed with special consideration given to patient confidentiality, patient engagement and data security. A pilot study was conducted to investigate patient uptake of PROACT and to characterize clinical trial information it captured. Patients recruited to Phase I oncology trials at a UK center were eligible to participate but were required to have a tablet computer or smartphone. Patients used PROACT to upload audio/video messages that became available instantly to their clinical team, who were able to reply to the patient within PROACT. The patient’s message was also analyzed, personally-identifiable information removed and anonymized information then made available to the sponsor in an analytics module for decision-making. In parallel, a patient focus group was engaged to provide feedback on communication needs during early clinical trials and the PROACT concept. RESULTS: Of the 16 patients informed of PROACT, 8 had a smart device and consented to take part. Use of PROACT varied and all messages volunteered were relevant and informative for drug development. Topics disclosed included tolerability impacts, study design, and drug formulation. Alignment with the clinical study data provided a richer understanding of tolerability and treatment consequences. This information was available to be shared among the clinical team and the sponsor, to improve patient support and experience. Patient forum feedback endorsed the concept and provided further information to enhance the application. CONCLUSION: Overall, PROACT achieved proof of concept in this small pilot study and delivered a secure end-to-end system that protected patient privacy and provided preliminary insight into patient experiences beyond the usual clinical trial data set. The use of mobile devices to interact actively with participants in clinical trials may be a new way of engaging and empowering patients. Further validation of this technology in larger patient cohorts is ongoing. FUNDING: AstraZeneca

A first-in-human, phase 1, dose-escalation study of ABBV-176, an antibody-drug conjugate targeting the prolactin receptor, in patients with advanced solid tumors

ABBV-176 is an antibody-drug conjugate composed of the humanized antibody h16f (PR-1594804) conjugated to a highly potent, cytotoxic cross-linking pyrrolobenzodiazepine dimer (PBD; SGD-1882) targeting the prolactin receptor (PRLR), which is overexpressed in several solid tumor types. This phase 1, dose-escalation study (NCT03145909) evaluated the safety, pharmacokinetics, and preliminary activity of ABBV-176 in patients with advanced solid tumors likely to exhibit elevated levels of PRLR. Patients received ABBV-176 once every 3\ua0weeks. Dose escalation was by an exposure-adjusted, continual reassessment method. Dose-limiting toxicities (DLTs) were assessed from the first day of dosing until the next dose of ABBV-176 to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Nineteen patients received ABBV-176 at doses from 2.7–109.35\ua0μg/kg. Patients enrolled had colorectal cancer (n = 11), breast cancer (n = 6), or adrenocortical carcinoma (n = 2). DLTs occurred in 4 patients and included thrombocytopenia (n = 2; both at 99.9-μg/kg dose level), neutropenia (n = 2; 78.3-μg/kg and 99.9-μg/kg dose levels), and pancytopenia (n = 1; 109.35-μg/kg dose level). The most common treatment-emergent adverse events related to ABBV-176 were thrombocytopenia, neutropenia, increased aspartate aminotransferase, nausea, fatigue, and pleural effusions. Effusions and edema were common, and timing of onset suggested possible cumulative ABBV-176 toxicity. Tumor expression of PRLR varied among patients enrolled and analyzed. No patient had an objective response. MTD was not formally determined, as identification of a tolerable dose was confounded by late-onset toxicities. ABBV-176 was associated with significant toxicity in this phase 1, dose-escalation study. Although cytopenias were often dose limiting, effusions and edema were also common and had late onset that suggested cumulative toxicity. No responses were observed, although data were available from a small number of patients with variable tumor PRLR expression. This study was terminated after the dosing of 19 patients