Search Results (8)

Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 in PTEN-deficient PC. Full article

Splicing is an essential process wherein precursor messenger RNA (pre-mRNA) is reshaped into mature mRNA. In alternative splicing, exons of any pre-mRNA get rearranged to form mRNA variants and subsequently protein isoforms, which are distinct both by structure and function. On the other hand, aberrant splicing is the cause of many disorders, including cancer. In the past few decades, developments in the understanding of the underlying biological basis for cancer progression and therapeutic resistance have identified many oncogenes as well as carcinogenic splice variants of essential genes. These transcripts are involved in various cellular processes, such as apoptosis, cell signaling and proliferation. Strategies to inhibit these carcinogenic isoforms at the mRNA level are promising. Antisense oligonucleotides (AOs) have been developed to inhibit the production of alternatively spliced carcinogenic isoforms through splice modulation or mRNA degradation. AOs can also be used to induce splice switching, where the expression of an oncogenic protein can be inhibited by the induction of a premature stop codon. In general, AOs are modified chemically to increase their stability and binding affinity. One of the major concerns with AOs is efficient delivery. Strategies for the delivery of AOs are constantly being evolved to facilitate the entry of AOs into cells. In this review, the different chemical modifications employed and delivery strategies applied are discussed. In addition to that various AOs in clinical trials and their efficacy are discussed herein with a focus on six distinct studies that use AO-mediated exon skipping as a therapeutic strategy to combat cancer. Full article

Breast cancer is the most commonly diagnosed cancer in the world, with triple-negative breast cancer (TNBC) making up 12% of these diagnoses. TNBC tumours are highly heterogeneous in both inter-tumour and intra-tumour gene expression profiles, where they form subclonal populations of varying levels of aggressiveness. These aspects make it difficult to study and treat TNBC, requiring further research into tumour heterogeneity as well as potential therapeutic targets and biomarkers. Recently, it was discovered that the majority of the transcribed genome comprises non-coding RNAs, in particular long non-coding RNAs (lncRNAs). LncRNAs are transcripts of >200 nucleotides in length that do not encode a protein. They have been characterised as regulatory molecules and their expression can be associated with a malignant phenotype. We set out to explore TNBC tumour heterogeneity in vivo at a single cell level to investigate whether lncRNA expression varies across different cells within the tumour, even if cells are coming from the same cell line, and whether lncRNA expression is sufficient to define cellular subpopulations. We applied single-cell expression profiling due to its ability to capture expression signals of lncRNAs expressed in small subpopulations of cells. Overall, we observed most lncRNAs to be expressed at low, but detectable levels in TNBC xenografts, with a median of 25 lncRNAs detected per cell. LncRNA expression alone was insufficient to define a subpopulation of cells, and lncRNAs showed highly heterogeneous expression patterns, including ubiquitous expression, subpopulation-specific expression, and a hybrid pattern of lncRNAs expressed in several, but not all subpopulations. These findings reinforce that transcriptionally defined tumour cell subpopulations can be identified in cell-line derived xenografts, and uses single-cell RNA-seq (scRNA-seq) to detect and characterise lncRNA expression across these subpopulations in xenografted tumours. Future studies will aim to investigate the spatial distribution of lncRNAs within xenografts and patient tissues, and study the potential of subclone-specific lncRNAs as new therapeutic targets and/or biomarkers. Full article

Chemokines present in the tumor microenvironment are essential for the control of tumor progression. We show here that several ligands of the chemokine receptor Cxcr2 were up-regulated in the PyMT (polyoma middle T oncogene) model of breast cancer. Interestingly, the knock-down of Cxcr2 in PyMT animals led to an increased growth of the primary tumor and lung metastasis. The analysis of tumor content of PyMT-Cxcr2−/− animals highlighted an increased infiltration of tumor associated neutrophils (TANs), mirrored by a decreased recruitment of tumor associated macrophages (TAMs) compared to PyMT animals. Analysis of PyMT-Cxcr2−/− TANs revealed that they lost their killing ability compared to PyMT-Cxcr2+/+ TANs. The transcriptomic analysis of PyMT-Cxcr2−/− TANs showed that they had a more pronounced pro-tumor TAN2 profile compared to PyMT TANs. In particular, PyMT-Cxcr2−/− TANs displayed an up-regulation of the pathways involved in reactive oxygen species (ROS) production and angiogenesis and factors favoring metastasis, but reduced apoptosis. In summary, our data reveal that a lack of Cxcr2 provides TANs with pro-tumor effects. Full article

Cancer is one of the leading causes of death worldwide. Conventional therapies, including surgery, radiation, and chemotherapy have achieved increased survival rates for many types of cancer over the past decades. However, cancer recurrence and/or metastasis to distant organs remain major challenges, resulting in a large, unmet clinical need. Oligonucleotide therapeutics, which include antisense oligonucleotides, small interfering RNAs, and aptamers, show promising clinical outcomes for disease indications such as Duchenne muscular dystrophy, familial amyloid neuropathies, and macular degeneration. While no approved oligonucleotide drug currently exists for any type of cancer, results obtained in preclinical studies and clinical trials are encouraging. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in oncology, review current clinical trials, and discuss associated challenges. Full article

Circular RNAs (circRNAs) are a class of non-coding RNAs that form a covalently closed loop. A number of functions and mechanisms of action for circRNAs have been reported, including as miRNA sponge, exerting transcriptional and translational regulation, interacting with proteins, and coding for peptides. CircRNA dysregulation has also been implicated in many cancers, such as breast cancer. Their relatively high stability and presence in bodily fluids makes cancer-associated circRNAs promising candidates as a new biomarker. In this review, we summarize the research undertaken on circRNAs associated with breast cancer, discuss circRNAs as biomarkers, and present circRNA-based therapeutic approaches. Full article

Long non-coding RNAs (lncRNAs) are a rapidly expanding field of research, with many new transcripts identified each year. However, only a small subset of lncRNAs has been characterized functionally thus far. To aid investigating the mechanisms of action by which new lncRNAs act, bioinformatic tools and databases are invaluable. Here, we review a selection of computational tools and databases for the in silico analysis of lncRNAs, including tissue-specific expression, protein coding potential, subcellular localization, structural conformation, and interaction partners. The assembled lncRNA toolkit is aimed primarily at experimental researchers as a useful starting point to guide wet-lab experiments, mainly containing multi-functional, user-friendly interfaces. With more and more new lncRNA analysis tools available, it will be essential to provide continuous updates and maintain the availability of key software in the future. Full article

Recent technological advancements such as CRISPR/Cas-based systems enable multiplexed, high-throughput screening for new therapeutic targets in cancer. While numerous functional screens have been performed on protein-coding genes to date, long non-coding RNAs (lncRNAs) represent an emerging class of potential oncogenes and tumor suppressors, with only a handful of large-scale screens performed thus far. Here, we review in detail currently available screening approaches to identify new lncRNA drivers of tumorigenesis and tumor progression. We discuss the various approaches of genomic and transcriptional targeting using CRISPR/Cas9, as well as methods to post-transcriptionally target lncRNAs via RNA interference (RNAi), antisense oligonucleotides (ASOs) and CRISPR/Cas13. We discuss potential advantages, caveats and future applications of each method to provide an overview and guide on investigating lncRNAs as new therapeutic targets in cancer. Full article