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Targeting tumor angiogenesis
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Prostate Cancer: Shifting from Morphology to Biology
1 July 2013, Pages 221-231
Targeting tumor angiogenesis (Book Chapter)
Staibano, S.a , Ascierto, P.A.b
a Department of Advanced Biomedical Sciences, Faculty of Medicine and Surgery, University of Naples Federico II, via S. Pansini, n.5, Naples, Italy
b Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, Department of Melanoma, National Institute of Tumors Fondazione G. Pascale, Via Mariano Semmola 1, Naples, Italy
View references (66)
Abstract
Four decades after the seminal work of Judah Folkman, in 1971, cancer therapies based on the suppression of neo-angiogenesis (Folkman, N Engl J Med 285:1182-1186, 1971) are becoming a reality (Verheul et al., Clin Cancer Res 14(11):3589-3597, 2008). The shift toward the up-regulation of pro-angiogenic factors secretion from both tumor and stroma, results from the interplay between endothelial cell activation, proliferation, extracellular matrix degradation, migration, canalization. It leads to the generation of a chaotic vascular vessels network in prostate cancer tissue (Ahmed and Bicknell, Method Mol Biol 467:3-24, 2009), which can be detected also by modern imaging techniques based on magnetic resonance, ultrasound, and nuclear imaging through targeting of key angiogenic factors (Russo et al., BJU Int 110(11 Pt C):E794-E808, 2012). This hopefully will lead to further improvements in prostate cancer diagnosis and staging. Preclinical evidence indicates that angiogenesis inhibitors can improve the efficacy of conventional cytotoxic agents mainly by normalizing tumor blood flow, thus improving drug delivery. Although significant biological activity of most vascular growth factors-interfering agents is demonstrated in preclinical models, single-agent activity is almost universally poor (Aragon-Ching et al., J Oncol 2010:361836, 2010). Due to the redundancy within the signalling pathways that promote angiogenesis, combining anti-angiogenic agents with different mechanisms of action seems likely to significatively potentiate their therapeutic efficacy (Corcoran and Gleave 2012; Ellis and Hicklin, Nat Rev Cancer 8:579-591, 2008; Verheul et al., Cancer Chemother Pharmacol 60:29-39, 200
The potential of BRAF-associated non-coding RNA as a therapeutic target in melanoma
No full textThe advent of targeted therapies and immune checkpoints inhibitors has enhanced the treatment of metastatic melanomas. Despite striking improvements of patients' survival, drug resistance continues to limit the efficacy of such treatments. Genetic and nongenetic/adaptive mechanisms of resistance could be involved; in the latter mechanism, noncoding RNAs (ncRNAs) are emerging as key players. Areas covered: This article outlines the current knowledge of ncRNA involvement in BRAF-mutant melanomas and the development of resistance to targeted/immunotherapies. We also discuss how ncRNAs can be exploited for the development of therapeutic and diagnostic approaches. Expert opinion: ncRNAs can be envisaged as powerful diagnostics and therapeutics. Despite progress in our knowledge about their deregulation in cancer, it is still difficult to derive universal and robust ncRNAs unique signatures of malignancy for diagnostic purposes, which need validation in large cohort of patients. Also, ncRNA specific targeting to melanoma cells in vivo requires the development of improved systemic delivery tools. In this regard, the development of stable nanodelivery particles seems to offer renewed hope for success in the clinic
Colonization of heterochromatic genes by transposable elements in Drosophila.
No full textAs a further step toward understanding transposable element–host genome interactions, we investigated the molecular anatomy of introns from five heterochromatic and 22 euchromatic protein-coding genes of Drosophila melanogaster. A total of 79 kb of intronic sequences from heterochromatic genes and 355 kb of intronic sequences from euchromatic genes have been used in Blast searches against Drosophila transposable elements (TEs). The results show that TE-homologous sequences belonging to 19 different families represent about 50% of intronic DNA from heterochromatic genes. In contrast, only 0.1% of the euchromatic intron DNA exhibits homology to known TEs. Intraspecific and interspecific size polymorphisms of introns were found, which are likely to be associated with changes in TE-related sequences. Together, the enrichment in TEs and the apparent dynamic state of heterochromatic introns suggest that TEs contribute significantly to the evolution of genes located in heterochromatin
Expansion of a lymphocyte subset expressing a spliced FKBP51 isoform in melanoma patients.
No full textBackground: We identified a spliced isoform of FKBP51 (FKBP51s) as a factor associated to PDL-1. FKBP51s stains TILs and is measurable in PBMC of melanoma patients. We also provided evidence that FKBP51s is a tumor edited and tolerance associated signature. Methods: qPCR served to measure FKBP51s in RNA extracted from PBMC of 102 melanoma patients (stages III, IV) undergoing immunotherapy (IT) with ipilimumab and 125 age matched healthy donors. Flow cytometry served to analyze protein expression in PBMC subsets of 61 patients and 56 controls. Fourty patients were analyzed also at the end of IT. Results: Compared with control value, FKBP51s transcript increased in patients (p < 0.01). In non responders, such transcript further increased after IT (p = 0.02). CD8 lymphocytes resulted increased in patients (32%+10) vs controls (27%+10) (p < 0.01). CD8 double staining with FKBP51s revealed that 20%+8 and 13%+7 were CD8+FKBP51s+, in patients and controls respectively (p < 0.01). The ratio CD8tot/CD8+FKBP51s+ was 1.9+0.7 and 2.7+1.4 for patients and controls (p < 0.01). In responders, IT produced a decrease of CD8+FKBP51s+ subset to 11%+6 (p = 0.01). Accordingly, in responders, the ratio CD8tot/CD8+FKBP51s+ increased to 2.8+1.0 (p = 0.03). In non responders, no variation of CD8+FKBP51s+ count or CD8tot/CD8+FKBP51s+ ratio was registered. Total CD4 lymphocytes did not differ between patients and controls, even if the FKBP51s+ component resulted increased and FKBP51s- decreased. No significant variation of such subsets was registered before and after IT. Interestingly, FKBP51s stained 55%+25 and 36%+27 of CD25 lymphocytes, in patients and controls respectively (p < 0.01). In responders, FKBP51s stained 68%+22 and 41%+16 of CD25 lymphocytes, before and after IT respectively (p < 0.01). In non responders, FKBP51s expression in CD25 lymphocytes was 53%+26 and remained unchanged after IT. Conclusions: FKBP51s transcript level may provide a guidance for assessing IT response. CD8+/FKBP51s+ subset is very sensitive to IT efficacy and the ratio CD8tot/CD8 FKBP51s+ is a promising tool to monitor IT. FKBP51s might also be a marker of a Treg subset which decreases in response to IT. Ongoing studies will address this issue
MicroRNAs in melanoma development and resistance to target therapy
Get PDFmicroRNAs constitute a complex class of pleiotropic post-transcriptional regulators of gene expression involved in the control of several physiologic and pathologic processes. Their mechanism of action is primarily based on the imperfect matching of a seed region located at the 5' end of a 21-23 nt sequence with a partially complementary sequence located in the 3' untranslated region of target mRNAs. This leads to inhibition of mRNA translation and eventually to its degradation. Individual miRNAs are capable of binding to several mRNAs and several miRNAs are capable of influencing the function of the same mRNAs. In recent years networks of miRNAs are emerging as capable of controlling key signaling pathways responsible for the growth and propagation of cancer cells. Furthermore several examples have been provided which highlight the involvement of miRNAs in the development of resistance to targeted drug therapies. In this review we provide an updated overview of the role of miRNAs in the development of melanoma and the identification of the main downstream pathways controlled by these miRNAs. Furthermore we discuss a group of miRNAs capable to influence through their respective up- or down-modulation the development of resistance to BRAF and MEK inhibitors
Reverse transcriptase inhibition potentiates target therapy in BRAF-mutant melanomas: effects on cell proliferation, apoptosis, DNA-damage, ROS induction and mitochondrial membrane depolarization
No full textTarget therapies based on BRAF and MEK inhibitors (MAPKi) have changed the therapeutic landscape for metastatic melanoma patients bearing mutations in the BRAF kinase. However, the emergence of drug resistance imposes the necessity to conceive novel therapeutic strategies capable to achieve a more durable disease control. In the last years, retrotransposons laying in human genome mostly encompassing Long Interspersed Nuclear Element1 (LINE-1) have been shown to undergo activation during tumorigenesis, where they contribute to genomic instability. LINE-1 activation can be efficiently controlled with reverse transcriptase inhibitors (RTIs) frequently used in the treatment of AIDS. These drugs have demonstrated anti-proliferative effects in several cancer models, including also metastatic melanoma. However, to our knowledge no previous study investigated the capability of RTIs to mitigate drug resistance to target therapy in BRAF-mutant melanomas. In this short report we show that the non-nucleoside RTI, SPV122 in combination with MAPKi strongly inhibits BRAF-mutant melanoma cell growth, induces apoptosis, and delays the emergence of resistance to target therapy in vitro. Mechanistically, this combination strongly induces DNA double-strand breaks, mitochondrial membrane depolarization and increased ROS levels. Our results shed further light on the molecular activity of RTI in melanoma and pave the way to their use as a novel therapeutic option to improve the efficacy of target therapy
Cross-talk between microbiota and immune fitness to steer and control response to anti PD-1/PDL-1 treatment
Get PDFImmune Checkpoint Inhibitors (ICIs) are improving the survival of cancer patients, however only the 20-30% of treated patients present clinical benefits. Toxicity represents the major cause of reduced dosage, delayed drug administration and therapy discontinuation. Hence in the context of multiple treatment possibilities, the identification of predictive markers of response and toxicity is a challenging approach for drug selection in order to obtain the best clinical benefit while minimizing the side effects. The loss of the protective function of intestinal barriers that interacts with the environment measured as increased intestinal permeability and the changes occurring in the microbiota composition have been proposed as a mechanism potentially explaining the pathogenesis of immune related toxicity.In this review we discuss the new perspectives on the involvement of PD-1 and PDL-1 in the cross talk between gut microbiota and immune fitness and how gut microbiota impacts on the efficacy of anti-PD-1 and anti-PDL-1 treatments in cancer
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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