Alexandra Drakaki

An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis

Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4α and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4α circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4α and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4α circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer.

Safety and Efficacy of Durvalumab (MEDI4736), an Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With Advanced Urothelial Bladder Cancer

PURPOSE To investigate the safety and efficacy of durvalumab, a human monoclonal antibody that binds programmed cell death ligand-1 (PD-L1), and the role of PD-L1 expression on clinical response in patients with advanced urothelial bladder cancer (UBC). METHODS A phase 1/2 multicenter, open-label study is being conducted in patients with inoperable or metastatic solid tumors. We report here the results from the UBC expansion cohort. Durvalumab (MEDI4736, 10 mg/kg every 2 weeks) was administered intravenously for up to 12 months. The primary end point was safety, and objective response rate (ORR, confirmed) was a key secondary end point. An exploratory analysis of pretreatment tumor biopsies led to defining PD-L1-positive as ≥ 25% of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1. RESULTS A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4% of whom received one or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months). The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-related grade 4 or 5 AEs. One treatment-related AE (acute kidney injury) resulted in treatment discontinuation. The ORR was 31.0% (95% CI, 17.6 to 47.1) in 42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Responses are ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range, 4.1+ to 49.3+ weeks). CONCLUSION Durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pretreated.

MicroRNA Gene Networks in Oncogenesis

MicroRNAs are small non-coding RNAs that regulate gene expression at the transcriptional or posttranscriptional level. They are involved in cellular development, differentiation, proliferation and apoptosis and play a significant role in cancer. Examination of tumor-specific microRNA expression profiles has revealed widespread deregulation of these molecules in diverse cancers. Several studies have shown that microRNAs function either as tumor suppressor genes or oncogenes, whose loss or overexpression respectively has diagnostic and prognostic significance. It seems that microRNAs act as major regulators of gene expression. In this review, we discuss microRNAs’ role in cancer and how microRNAs exert their functions through regulation of their gene targets. Bioinformatic analysis of putative miRNA binding sites has indicated several novel potential gene targets involved in apoptosis, angiogenesis and metastatic mechanisms. Matching computational prediction analysis together with microarray data seems the best method for microRNA gene target identification. MicroRNAs together with transcription factors generate a complex combinatorial code regulating gene expression. Thus, manipulation of microRNA-transcription factor gene networks may be provides a novel approach for developing cancer therapies.

Immunotherapy for the Treatment of Urothelial Carcinoma

Purpose: We review the biological mechanisms of action, clinical safety and efficacy of immunotherapies for urothelial carcinoma. We also describe current areas of research in immunotherapy, and highlight ongoing trials and promising and novel investigational agents. Materials and Methods: Data were obtained by a search of PubMed®, ClinicalTrials.gov and Cochrane databases for English language articles published through February 2016. Applicable abstracts from recent Society of Urologic Oncology, European Association of Urology, American Urological Association and ASCO® meetings were used. Results: Bacillus Calmette‐Guérin is one of the most successful immunotherapies in cancer treatment and remains the gold standard of care for patients with high risk, nonmuscle invasive bladder cancer, with initial response rates of approximately 70%. However, with the exception of valrubicin and standard chemotherapeutics there is a paucity of available treatment options for patients with recurrence or progression to more advanced disease. Recently there has been significant interest in novel immunotherapeutic agents in the management of cases where bacillus Calmette‐Guérin fails, as well as cases of more advanced cancer. These investigational therapies can generally be classified into several broad categories, including recombinant bacillus Calmette‐Guérin and cell wall derived therapies, cytokines, gene therapy, cancer vaccines, immune checkpoint inhibitors, oncolytic viruses, adoptive immunotherapies and immune agonists, as well as several additional immunomodulatory agents. The majority of these agents are currently under investigation in phase I or II clinical trials. Recently investigators reported evidence that inhibition of the PD‐1/PD‐L1 pathway has clinical activity in patients with advanced bladder cancer. These findings, along with successful phase III trials and U.S. Food and Drug Administration approvals of other checkpoint inhibitors in melanoma, nonsmall cell lung cancer and renal cell carcinoma, ultimately led to Food and Drug Administration approval of atezolizumab for advanced disease, the first new treatment approved for advanced urothelial carcinoma in 20 years. Conclusions: While bacillus Calmette‐Guérin has demonstrated significant clinical efficacy in the treatment of patients with bladder cancer, additional therapies are needed for those in whom bacillus Calmette‐Guérin fails, as well as for those with advanced disease. Immunotherapy for urothelial carcinoma remains a promising and active area of research, and numerous agents, particularly the monoclonal antibodies targeting checkpoint inhibition pathways, are showing encouraging signs of clinical activity.

Risk of second primary malignancies among cancer survivors in the United States, 1992 through 2008.

In the current study, the authors attempted to describe the incidence, most common sites, and mortality of second primary malignancies among survivors of common cancers.

Functional microRNA high throughput screening reveals miR-9 as a central regulator of liver oncogenesis by affecting the PPARA-CDH1 pathway.

BackgroundHepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths, reflecting the aggressiveness of this type of cancer and the absence of effective therapeutic regimens. MicroRNAs have been involved in the pathogenesis of different types of cancers, including liver cancer. Our aim was to identify microRNAs that have both functional and clinical relevance in HCC and examine their downstream signaling effectors.MethodsMicroRNA and gene expression levels were measured by quantitative real-time PCR in HCC tumors and controls. A TargetScan algorithm was used to identify miR-9 downstream direct targets.ResultsA high-throughput screen of the human microRNAome revealed 28 microRNAs as regulators of liver cancer cell invasiveness. MiR-9, miR-21 and miR-224 were the top inducers of HCC invasiveness and also their expression was increased in HCC relative to control liver tissues. Integration of the microRNA screen and expression data revealed miR-9 as the top microRNA, having both functional and clinical significance. MiR-9 levels correlated with HCC tumor stage and miR-9 overexpression induced SNU-449 and HepG2 cell growth, invasiveness and their ability to form colonies in soft agar. Bioinformatics and 3′UTR luciferase analyses identified E-cadherin (CDH1) and peroxisome proliferator-activated receptor alpha (PPARA) as direct downstream effectors of miR-9 activity. Inhibition of PPARA suppressed CDH1 mRNA levels, suggesting that miR-9 regulates CDH1 expression directly through binding in its 3′UTR and indirectly through PPARA. On the other hand, miR-9 inhibition of overexpression suppressed HCC tumorigenicity and invasiveness. PPARA and CDH1 mRNA levels were decreased in HCC relative to controls and were inversely correlated with miR-9 levels.ConclusionsTaken together, this study revealed the involvement of the miR-9/PPARA/CDH1 signaling pathway in HCC oncogenesis.

MicroRNA-gene signaling pathways in pancreatic cancer.

Pancreatic cancer is the fourth most frequent cause of cancer-related deaths and is characterized by early metastasis and pronounced resistance to chemotherapy and radiation therapy. Despite extensive esearch efforts, there is not any substantial progress regarding the identification of novel drugs against pancreatic cancer. Although the introduction of the chemotherapeutic agent gemcitabine improved clinical response, the prognosis of these patients remained extremely poor with a 5-year survival rate of 3-5%. Thus, the identification of the novel molecular pathways involved in pancreatic oncogenesis and the development of new and potent therapeutic options are highly desirable. Here, we describe how microRNAs control signaling pathways that are frequently deregulated during pancreatic oncogenesis. In addition, we provide evidence that microRNAs could be potentially used as novel pancreatic cancer therapeutics through reversal of chemotherapy and radiotherapy resistance or regulation of essential molecular pathways. Further studies should integrate the deregulated genes and microRNAs into molecular networks in order to identify the central regulators of pancreatic oncogenesis. Targeting these central regulators could lead to the development of novel targeted therapeutic approaches for pancreatic cancer patients.

The importance of optimal drug sequencing in metastatic colorectal cancer: biological rationales for the observed survival benefit conferred by first-line treatment with EGFR inhibitors

Introduction: Use of both the vascular endothelial growth factor (VEGF) inhibitor bevacizumab and the epidermal growth factor receptor (EGFR) inhibitors cetuximab and panitumumab as potential first-line therapies for patients with RAS-wild-type metastatic colorectal cancer presents clinicians with an important decision. We review clinical data evaluating first-line treatment with EGFR inhibitors. Additionally, by undertaking an integrated ‘bench-to-bedside’ approach, we provide potential models, testable hypotheses and biological rationales that might account for these clinical observations. Areas covered: A literature search encompassing PubMed and the ASCO/ESMO websites was undertaken in October 2014. Search terms included ‘colorectal cancer’, ‘cetuximab’, ‘panitumumab’ and ‘bevacizumab’. Expert opinion: A number of clinical studies indicate a survival benefit for patients receiving EGFR inhibitors in combination with chemotherapy in the first-line setting, relative to both chemotherapy alone and VEGF inhibitors plus chemotherapy. Existing preclinical and clinical data suggest that a biological basis exists for providing RAS-wild-type patients with first-line EGFR inhibitors, followed by second-line VEGF inhibitors. More specifically, first-line treatment with EGFR inhibitors may elicit unique biological changes that sensitize tumors to subsequent lines of therapy; conversely, first-line treatment with VEGF inhibitors may elicit biological changes that desensitize tumors to subsequent lines of therapy.

Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA

Biomarker‐guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell‐free circulating DNA (cfDNA) next‐generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC).

Adjuvant Therapy for High Risk Localized Kidney Cancer: Emerging Evidence and Future Clinical Trials

Purpose We reviewed the literature on adjuvant therapies for patients with high risk localized kidney cancer following surgical resection. In this analysis we merge 2 recently published prospective trials with conflicting results within the context of their respective designs. In addition, we spotlight upcoming trials that use novel immunotherapy based checkpoint inhibitors and have the potential to establish a new standard of care. Materials and Methods We searched PubMed® for English language articles published through January 2017 using the keywords “renal cell carcinoma,” “kidney cancer,” “immunotherapy,” “targeted therapy” and “adjuvant therapy.” ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings are also included. Results Adjuvant therapies for high risk localized kidney cancer can be grouped into the categories of 1) traditional immunotherapy, 2) inhibitors of the vascular endothelial growth factor and mTOR (mammalian target of rapamycin) pathways, 3) vaccines and antibody dependent cytotoxic agents, and 4) immune checkpoint inhibitors. Several trials of traditional immunotherapy, such as interferon‐&agr; and high dose interleukin‐2, failed to demonstrate benefit as adjuvant treatment and were associated with significant adverse events. Vascular endothelial growth factor and mTOR inhibitors have less severe toxicity in metastatic disease and, therefore, are natural considerations for adjuvant trials. However, current data are conflicting. The ASSURE (Sunitinib Malate or Sorafenib Tosylate in Treating Patients with Kidney Cancer that was Removed by Surgery, NCT00326898) trial found no recurrence‐free survival benefit of sorafenib or sunitinib over placebo, while S‐TRAC (Clinical Trial Comparing Efficacy and Safety of Sunitinib versus Placebo for the Treatment of Patients at High Risk of Recurrent Renal Cell Cancer, NCT00375674) revealed that 1 year of sunitinib improved recurrence‐free survival by 1.2 years. Vaccine based treatments and antibody dependent cytotoxic agents have had mixed results. New trials evaluating immune checkpoint inhibitors are planned, given the impressive efficacy and tolerability as second line agents in metastatic disease. Future adjuvant trials are likely to be guided by molecular signatures to treat patients most likely to benefit. Conclusions Based on the available data, there appears to be no role for traditional immunotherapy as adjuvant treatment in patients with high risk localized kidney cancer following surgical resection. S‐TRAC provides evidence that 1 year of adjuvant sunitinib in patients with higher risk locoregional disease increases the median time to recurrence. However, the data on overall survival are immature and adverse effects are common. Results from trials investigating immune checkpoint inhibitors are highly anticipated.