scholarly journals Multiregional genetic evolution of metastatic uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Daniel A. Rodriguez ◽  
Jessica Yang ◽  
Michael A. Durante ◽  
Alexander N. Shoushtari ◽  
Stergios J. Moschos ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Tumor Development ◽  
Genetic Evolution ◽  
Metastatic Progression ◽  
Therapeutic Approaches ◽  
Primary Tumors ◽  
Early Tumor ◽  
Rapid Autopsy ◽  
Genetic Events ◽  
Novel Therapeutic

AbstractUveal melanoma (UM) is the most common primary intraocular malignancy in adults and leads to deadly metastases for which there is no approved treatment. Genetic events driving early tumor development are well-described, but those occurring later during metastatic progression remain poorly understood. We performed multiregional genomic sequencing on 22 tumors collected from two patients with widely metastatic UM who underwent rapid autopsy. We observed multiple seeding events from the primary tumors, metastasis-to-metastasis seeding, polyclonal seeding, and late driver variants in ATM, KRAS, and other genes previously unreported in UM. These findings reveal previously unrecognized temporal and anatomic complexity in the genetic evolution of metastatic uveal melanoma, and they highlight the distinction between early and late phases of UM genetic evolution with implications for novel therapeutic approaches.

scholarly journals Multi-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

2019 ◽  
Author(s):  
Zheng Hu ◽  
Zan Li ◽  
Zhicheng Ma ◽  
Christina Curtis
Keyword(s):  
Clonal Evolution ◽  
Tumor Development ◽  
Distant Metastases ◽  
Driver Mutations ◽  
Sequencing Data ◽  
Primary Tumors ◽  
Lung Cancer Patients ◽  
Systemic Spread ◽  
Cancer Spread ◽  
Early Tumor

AbstractMetastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and impact of treatment are poorly understood. We analyzed exome sequencing data from 457 paired primary tumor and metastatic samples from 136 breast, colorectal and lung cancer patients, including untreated (n=99) and treated (n=100) metastatic tumors. Treated metastases often harbored private ‘driver’ mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in untreated lymph node metastases (n=17/29, 59%) and distant metastases (n=20/70, 29%), but less frequent in treated distant metastases (n=9/94, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which we estimated commonly occurred 2-4 years prior to diagnosis across these cancers. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but instead associated with drug resistance.

scholarly journals New Insights into Molecular Oncogenesis and Therapy of Uveal Melanoma

Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 694 ◽  
Author(s):  
Sara Silvia Violanti ◽  
Ilaria Bononi ◽  
Carla Enrica Gallenga ◽  
Fernanda Martini ◽  
Mauro Tognon ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Target Genes ◽  
Therapeutic Strategies ◽  
Biomedical Sciences ◽  
Therapeutic Approaches ◽  
Common Cancer ◽  
Multistep Process ◽  
Systemic Adjuvant Therapy ◽  
Novel Therapeutic

Uveal melanoma (UM), which is the most common cancer of the eye, was investigated in recent years by many teams in the field of biomedical sciences and eye clinicians. New knowledge was acquired on molecular pathways found to be dysregulated during the multistep process of oncogenesis, whereas novel therapeutic approaches gave significant results in the clinical applications. Uveal melanoma-affected patients greatly benefited from recent advances of the research in this eye cancer. Tumour biology, genetics, epigenetics and immunology contributed significantly in elucidating the role of different genes and related pathways during uveal melanoma onset/progression and UM treatments. Indeed, these investigations allowed identification of new target genes and to develop new therapeutic strategies/compounds to cure this aggressive melanoma of the eye. Unfortunately, the advances reported in the treatment of cutaneous melanoma have not produced analogous benefits in metastatic uveal melanoma. Nowadays, no systemic adjuvant therapy has been shown to improve overall survival or reduce the risk of metastasis. However, the increasing knowledge of this disease, and the encouraging results seen in clinical trials, offer promise for future effective therapies. Herein, different pathways/genes involved in uveal melanoma onset/progression were taken into consideration, together with novel therapeutic approaches.

scholarly journals Genetic Alterations of Metastatic Colorectal Cancer

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 414
Author(s):  
Ugo Testa ◽  
Germana Castelli ◽  
Elvira Pelosi
Keyword(s):  
Tumor Development ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Primary Tumors ◽  
Sequencing Studies ◽  
Microsatellite Stability ◽  
Tumor Types ◽  
Genetic Events ◽  
Metastatic Spreading

Genome sequencing studies have characterized the genetic alterations of different tumor types, highlighting the diversity of the molecular processes driving tumor development. Comprehensive sequencing studies have defined molecular subtypes of colorectal cancers (CRCs) through the identification of genetic events associated with microsatellite stability (MSS), microsatellite-instability-high (MSI-H), and hypermutation. Most of these studies characterized primary tumors. Only recent studies have addressed the characterization of the genetic and clinical heterogeneity of metastatic CRC. Metastatic CRC genomes were found to be not fundamentally different from primary CRCs in terms of the mutational landscape or of genes that drive tumorigenesis, and a genomic heterogeneity associated with tumor location of primary tumors helps to define different clinical behaviors of metastatic CRCs. Although CRC metastatic spreading was traditionally seen as a late-occurring event, growing evidence suggests that this process can begin early during tumor development and the clonal architecture of these tumors is consistently influenced by cancer treatment. Although the survival rate of patients with metastatic CRC patients improved in the last years, the response to current treatments and prognosis of many of these patients remain still poor, indicating the need to discover new improvements for therapeutic vulnerabilities and to formulate a rational prospective of personalized therapies.

Adipocytes-released Peptides Involved in the Control of Gastrointestinal Motility

2019 ◽  
Vol 20 (6) ◽  
pp. 614-629 ◽  
Author(s):  
Eglantina Idrizaj ◽  
Rachele Garella ◽  
Roberta Squecco ◽  
Maria Caterina Baccari
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Adipose Tissue ◽  
Gastrointestinal Motility ◽  
Diagnostic Tools ◽  
Therapeutic Approaches ◽  
Motor Responses ◽  
Gastrointestinal Motor ◽  
Treatment Of Obesity ◽  
Novel Therapeutic

The present review focuses on adipocytes-released peptides known to be involved in the control of gastrointestinal motility, acting both centrally and peripherally. Thus, four peptides have been taken into account: leptin, adiponectin, nesfatin-1, and apelin. The discussion of the related physiological or pathophysiological roles, based on the most recent findings, is intended to underlie the close interactions among adipose tissue, central nervous system, and gastrointestinal tract. The better understanding of this complex network, as gastrointestinal motor responses represent peripheral signals involved in the regulation of food intake through the gut-brain axis, may also furnish a cue for the development of either novel therapeutic approaches in the treatment of obesity and eating disorders or potential diagnostic tools.

scholarly journals Methyltransferases in the Pathogenesis of Keratinocyte Cancers

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3402
Author(s):  
Eun Kyung Ko ◽  
Brian C. Capell
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Basal Cell ◽  
Histone Methylation ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Therapeutic Approaches ◽  
Novel Therapeutic

Recent evidence suggests that the disruption of gene expression by alterations in DNA, RNA, and histone methylation may be critical contributors to the pathogenesis of keratinocyte cancers (KCs), made up of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), which collectively outnumber all other human cancers combined. While it is clear that methylation modifiers are frequently dysregulated in KCs, the underlying molecular and mechanistic changes are only beginning to be understood. Intriguingly, it has recently emerged that there is extensive cross-talk amongst these distinct methylation processes. Here, we summarize and synthesize the latest findings in this space and highlight how these discoveries may uncover novel therapeutic approaches for these ubiquitous cancers.

scholarly journals Current and Future Treatments for Classic Galactosemia

2021 ◽  
Vol 11 (2) ◽  
pp. 75 ◽  
Author(s):  
Britt Delnoy ◽  
Ana I. Coelho ◽  
Maria Estela Rubio-Gozalbo
Keyword(s):  
Standard Of Care ◽  
Type I ◽  
Therapeutic Approaches ◽  
Restricted Diet ◽  
Galactose Metabolism ◽  
Galt Activity ◽  
Classic Galactosemia ◽  
Pathogenic Factors ◽  
Future Treatments ◽  
Novel Therapeutic

Type I (classic) galactosemia, galactose 1-phosphate uridylyltransferase (GALT)-deficiency is a hereditary disorder of galactose metabolism. The current therapeutic standard of care, a galactose-restricted diet, is effective in treating neonatal complications but is inadequate in preventing burdensome complications. The development of several animal models of classic galactosemia that (partly) mimic the biochemical and clinical phenotypes and the resolution of the crystal structure of GALT have provided important insights; however, precise pathophysiology remains to be elucidated. Novel therapeutic approaches currently being explored focus on several of the pathogenic factors that have been described, aiming to (i) restore GALT activity, (ii) influence the cascade of events and (iii) address the clinical picture. This review attempts to provide an overview on the latest advancements in therapy approaches.

scholarly journals LAT1 and ASCT2 Related microRNAs as Potential New Therapeutic Agents against Colorectal Cancer Progression

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 195
Author(s):  
Francisca Dias ◽  
Cristina Almeida ◽  
Ana Luísa Teixeira ◽  
Mariana Morais ◽  
Rui Medeiros
Keyword(s):  
Colorectal Cancer ◽  
Amino Acid ◽  
Cancer Progression ◽  
Cell Metabolism ◽  
Tumor Development ◽  
Amino Acid Transporters ◽  
Epigenetic Alterations ◽  
Therapeutic Approaches ◽  
Colorectal Cancer Progression ◽  
Made In

The development and progression of colorectal cancer (CRC) have been associated with genetic and epigenetic alterations and more recently with changes in cell metabolism. Amino acid transporters are key players in tumor development, and it is described that tumor cells upregulate some AA transporters in order to support the increased amino acid (AA) intake to sustain the tumor additional needs for tumor growth and proliferation through the activation of several signaling pathways. LAT1 and ASCT2 are two AA transporters involved in the regulation of the mTOR pathway that has been reported as upregulated in CRC. Some attempts have been made in order to develop therapeutic approaches to target these AA transporters, however none have reached the clinical setting so far. MiRNA-based therapies have been gaining increasing attention from pharmaceutical companies and now several miRNA-based drugs are currently in clinical trials with promising results. In this review we combine a bioinformatic approach with a literature review in order to identify a miRNA profile with the potential to target both LAT1 and ASCT2 with potential to be used as a therapeutic approach against CRC.

scholarly journals MBRS-48. IDENTIFICATION OF NOVEL THERAPEUTIC APPROACHES FOR MYC-DRIVEN MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii406-iii406
Author(s):  
Kübra Taban ◽  
David Pauck ◽  
Mara Maue ◽  
Viktoria Marquardt ◽  
Hua Yu ◽  
...  
Keyword(s):  
New Drugs ◽  
Current Therapy ◽  
Cancer Drug ◽  
Mrna Levels ◽  
Cell Models ◽  
Therapeutic Approaches ◽  
Group 3 ◽  
Novel Therapeutic

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children and is frequently metastatic at diagnosis. Treatment with surgery, radiation and multi-agent chemotherapy may leave survivors of these brain tumors with long-term deficits as a consequence. One of the four consensus molecular subgroups of MB is the MYC-driven group 3 MB, which is the most malignant type and has a poor prognosis under current therapy. Thus, it is important to discover more effective targeted therapeutic approaches. We conducted a high-throughput drug screening to identify novel compounds showing efficiency in group 3 MB using both clinically established inhibitors (n=196) and clinically-applicable compounds (n=464). More than 20 compounds demonstrated a significantly higher anti-tumoral effect in MYChigh (n=7) compared to MYClow (n=4) MB cell models. Among these compounds, Navitoclax and Clofarabine showed the strongest effect in inducing cell cycle arrest and apoptosis in MYChigh MB models. Furthermore, we show that Navitoclax, an orally bioavailable and blood-brain barrier passing anti-cancer drug, inhibits specifically Bcl-xL proteins. In line, we found a significant correlation between BCL-xL and MYC mRNA levels in 763 primary MB patient samples (Data source: “R2 https://hgserver1.amc.nl”). In addition, Navitoclax and Clofarabine have been tested in cells obtained from MB patient-derived-xenografts, which confirmed their specific efficacy in MYChigh versus MYClow MB. In summary, our approach has identified promising new drugs that significantly reduce cell viability in MYChigh compared to MYClow MB cell models. Our findings point to novel therapeutic vulnerabilities for MB that need to be further validated in vitro and in vivo.

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