Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.

MGMT expression is a critical determinant for therapeutic resistance to DNA alkylating agents. We previously demonstrated that MGMT expression is post-transcriptionally regulated by miR-181d and other miRNAs. Here, we performed a genome-wide screen to identify MGMT regulating miRNAs. Candidate miRNAs were further tested for inverse correlation with MGMT expression in clinical specimens. We identified 15 candidate miRNAs and characterized the top candidate, miR-603. Transfection of miR-603 suppressed MGMT mRNA/protein expression in vitro and in vivo; this effect was reversed by transfection with antimiR-603. miR-603 affinity-precipitated with MGMT mRNA and suppressed luciferase activity in an MGMT-3'UTR-luciferase assay, suggesting direct interaction between miR-603 and MGMT 3'UTR. miR-603 transfection enhanced the temozolomide (TMZ) sensitivity of MGMT-expressing glioblastoma cell lines. Importantly, miR-603 mediated MGMT suppression and TMZ resistance were reversed by expression of an MGMT cDNA. In a collection of 74 clinical glioblastoma specimens, both miR-603 and miR-181d levels inversely correlated with MGMT expression. Moreover, a combined index of the two miRNAs better reflected MGMT expression than each individually. These results suggest that MGMT is co-regulated by independent miRNAs. Characterization of these miRNAs should contribute toward strategies for enhancing the efficacy of DNA alkylating agents.

Despite the critical role of Epidermal Growth Factor Receptor (EGFR) in glioblastoma pathogenesis [1], [2], EGFR targeted therapies have achieved limited clinical efficacy [3]. Here we propose an alternate therapeutic strategy based on the conceptual framework of non-oncogene addiction [4], [5]. A directed RNAi screen revealed that glioblastoma cells over-expressing EGFRvIII [6], an oncogenic variant of EGFR, become hyper-dependent on a variety of DNA repair genes. Among these, there was an enrichment of Base Excision Repair (BER) genes required for the repair of Reactive Oxygen Species (ROS)-induced DNA damage, including poly-ADP ribose polymerase 1 (PARP1). Subsequent studies revealed that EGFRvIII over-expression in glioblastoma cells caused increased levels of ROS, DNA strand break accumulation, and genome instability. In a panel of primary glioblastoma lines, sensitivity to PARP1 inhibition correlated with the levels of EGFR activation and oxidative stress. Gene expression analysis indicated that reduced expression of BER genes in glioblastomas with high EGFR expression correlated with improved patient survival. These observations suggest that oxidative stress secondary to EGFR hyper-activation necessitates increased cellular reliance on PARP1 mediated BER, and offer critical insights into clinical trial design.

Glioblastoma is the most common form of primary brain cancer and remains one of the most aggressive forms of human cancer. Current standard of care involves maximal surgical resection followed by concurrent therapy with radiation and the DNA alkylating agent temozolomide. Despite this aggressive regimen, the median survival remains approximately 14 months. Meaningful strategies for therapeutic intervention are desperately needed. Development of such strategies will require an understanding of the therapeutic concepts that have evolved over the past three decades. This article reviews the key principles that drive the formulation of therapeutic strategies in glioblastoma. Specifically, the concepts of tumour heterogeneity, oncogene addiction, non-oncogene addiction, tumour initiating cells, tumour microenvironment, non-coding sequences and DNA damage response will be reviewed.

With advances in genomic profiling and sequencing technology, we are beginning to understand the landscape of the genetic events that accumulated during the neoplastic process. The insights gleamed from these genomic profiling studies with regards to glioblastoma etiology has been particularly satisfying because it cemented the clinical pertinence of major concepts in cancer biology-concepts developed over the past three decades. This article will review how the glioblastoma genomic data set serves as an illustrative platform for the concepts put forward by Hanahan and Weinberg on the cancer phenotype. The picture emerging suggests that most glioblastomas evolve along a multitude of pathways rather than a single defined pathway. In this context, the article will further provide a discussion of the subtypes of glioblastoma as they relate to key principles of developmental neurobiology.

BC survivors are more likely to be diagnosed with earlier stage NSCLC versus first primary NSCLC patients, perhaps reflecting heightened surveillance compared with the general population. In contrast to prior studies of NSCLC in survivors of lymphopoietic malignancies, BC history does not appear to adversely affect OS after NSCLC.

Melanoma-the deadliest form of skin cancer-leads to thousands of deaths each year. Although melanoma is less common than basal cell and squamous cell skin cancers, melanoma is more dangerous because it is more likely to spread to other parts of the body, such as lymph nodes, if not diagnosed and treated early. Data from the National Cancer Institute indicate a steady rise in new cases of melanoma and, unfortunately, a steady rate in the number of deaths through 2013. Ninety percent of melanomas are linked to inadequate sun protection from ultraviolet rays or the tanning habits of young adults. Over the past 5 years, however, there have been a variety of new pharmacologic treatments for advanced melanoma including immunotherapy, targeted agents (BRAF and MEK inhibitors), and oncolytic viral therapy. In this article, we review the current literature on the treatment of melanoma, with a focus on emerging therapies.

Our results suggest mechanisms such as miRNA mediated regulation for post-transcriptional regulation of MGMT. Identification of these mechanisms should enhance the value of MGMT based prognostic or predictive biomarker strategies.