Angiosarcoma is the most common malignant cardiac tumor.Cardiac angiosarcoma is a highly lethal neoplasm that is largely resistant to conventional anti-cancer therapy.Mean survival of patients with cardiac angiosarcoma is only 4 months, and almost all patients will succumb to the disease within 1 year.The beta blocker propranolol is an emerging therapy against angiosarcoma.When combined with conventional therapies, propranolol increases progression free and overall survival in patients with this tumor type.It is currently unknown if propranolol is capable of showing anti-cancer efficacy as a single agent therapy.We report a case of a 61 year old woman diagnosed with primary cardiac angiosarcoma and liver and lung metastases.This patient chose to decline conventional therapy, and instead was prescribed the beta blocker propranolol as a single agent treatment.After 12 months, the mediastinal mass substantially debulked and decreased in size, and the metastatic nodules stabilized or resolved with no evidence of hyper-metabolic activity on PET-CT.This is the first reported data showing long term efficacy of the beta blocker propranolol as a single agent therapy against angiosarcoma.
// Maria Serova 1, 2, 3 , Annemilaï Tijeras-Raballand 1, 2, 3 , Celia Dos Santos 1, 2, 3 , Matthieu Martinet 1 , Cindy Neuzillet 2, 3 , Alfred Lopez 4 , Dianne C. Mitchell 4 , Brad A. Bryan 4 , Guillaume Gapihan 3, 5 , Anne Janin 3, 5 , Guilhem Bousquet 5, 6 , Maria Eugenia Riveiro 2, 3 , Ivan Bieche 7 , Sandrine Faivre 2, 3 , Eric Raymond 2, 3, * , Armand de Gramont 1, 3, 5, * 1 AAREC Filia Research, Boulogne-Billancourt, France 2 Department of Medical Oncology, Beaujon University Hospital (AP-HP - PRES Paris 7 Diderot), Clichy, France 3 INSERM, Paris, France 4 Department of Biomedical Sciences, Center of Emphasis in Cancer Research at The Paul Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA 5 Department of Pathology Saint Louis University Hospital (AP-HP - PRES Paris 7 Diderot), Paris, France 6 Department of Medical Oncology, Avicenne University Hospital (APHP- PRES Paris 13 University), Bobigny, France 7 Laboratory of Oncogenetics, Institut Curie, Hôpital René Huguenin, St-Cloud, France * These authors contributed equally to this work Correspondence to: Eric Raymond, email: eric.raymond@aphp.fr Keywords: everolimus, sunitinib, renal cell carcinoma, angiogenesis, differentiation Received: February 22, 2016 Accepted: May 04, 2016 Published: May 21, 2016 ABSTRACT Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo . Re-challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm.
The SCN2A gene encodes the Nav1.2 protein, a voltage-gated sodium channel crucial for initiating and transmitting action potentials in neurons. Dysfunction in Nav1.2, often stemming from genetic mutations in the SCN2A gene, leads to SCN2A-related disorders. Individuals harboring pathogenic SCN2A variants present with severe neurodevelopmental disorders such as epilepsy, autism spectrum disorders, movement disorders, cortical visual impairment, and intellectual disabilities. The FamilieSCN2A Foundation, a 501(c)(3) patient advocacy organization, is dedicated to enhancing the lives of those affected by SCN2A-related disorders. Fueled by a vision of a world with effective treatments and cures for all patients with SCN2A-related disorders, FamilieSCN2A Foundation has charted the course to a cure based on their core values of urgency, integrity, collaboration, and inclusion. Their strategic plan centers on building a comprehensive research-readiness infrastructure that maximizes the probability of bringing curative therapies to SCN2A patients. Appreciating that statistically most drug development initiatives will fail, creating an infrastructure that maximizes the number of drugs in development for SCN2A-related disorders in turn maximizes the net probability of success that FamilieSCN2A Foundation will achieving their vision. Through dynamic initiatives and notable achievements, including raising ~$6 million USD, funding 26 research grants totaling ~$4.7 million USD, and forging strategic partnerships across the SCN2A-related disorder ecosystem the foundation is actively executing its strategic plan. With SCN2A research advancing rapidly and a thriving ecosystem of diverse, engaged stakeholders, FamilieSCN2A Foundation believes the outlook for SCN2A-related disorders is bright.
In May 2017, 40 mg propranolol was administered daily and PET-CT scans were performed at regular intervals to assess the response of the tumor to propranolol.
Recent progress has been made on the role of oncoproteins c-Ski and related SnoN in the control of cellular transformation. c-Ski/SnoN potently repress transforming growth factor-β (TGF-β) antiproliferative signaling through physical interaction with signal transducers called Smads. Overexpression of c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN function in myogenesis is largely unknown. During our investigation on the role of sumoylation in TGF-β signaling, we inadvertently found that SnoN is modified by small ubiquitin-like modifier-1 (SUMO-1). Here, we biochemically characterize SnoN sumoylation in detail and report the physiological function of the modification. Sumoylation occurs primarily at lysine 50 (Lys-50). PIAS1 and PIASx proteins physically interact with SnoN to stimulate its sumoylation, thus serving as SUMO-protein isopeptide ligases (E3) for SnoN sumoylation. SnoN sumoylation does not alter its metabolic stability or its ability to repress TGF-β signaling. Notably, loss of sumoylation in the Lys-50 site (via a Lys-to-Arg point mutation) potently activates muscle-specific gene expression and enhances myotube formation. Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation.
Therapeutic targeting of Rho-Associated, Coiled-Coil Containing Protein Kinase (ROCK) signaling for tumor cells and tumor endothelium has shown efficacy in pre-clinical tumors models, and a better understanding of how proteins regulate tumor progression will strengthen our knowledge over disease etiology and treatment of patients with cancer. Recent reports have shown that ROCK activity is critical for the expression of a large number of mRNA transcripts across multiple cell types including endothelial cells.To examine the effects of ROCK proteins on microRNA (miRNA) expression in tumor-forming endothelial cells, we utilized microarrays to evaluate expression levels of 1088 miRNAs in vascular tumor-forming endothelial cells knocked-down for ROCK1 or ROCK2 or treated with a pharmacological inhibitor of ROCK activity.Microarray analysis demonstrated that inhibiting ROCK activity altered global miRNA expression. We confirmed our findings using qPCR and identified cell-cycle progression, calcium transport, and neurogenesis/synaptogenesis as the most highly overrepresented predicted target gene networks for the identified miRNAs whose expression was altered by ROCK inhibition.ROCK signaling induces large-scale changes in global miRNA expression and may lead to a better understanding of how these proteins affect aberrant vascular states.
Angiogenesis is largely controlled by hypoxia-driven transcriptional up-regulation and secretion of vascular endothelial growth factor (VEGF) and its binding to the endothelial cell tyrosine receptor kinases, VEGFR1 and VEGFR2. Recent expression analysis suggests that VEGF is expressed in a cell-specific manner in normoxic adult tissue; however, the transcriptional regulation and role of VEGF in these tissues remains fundamentally unknown. In this report we demonstrate that VEGF is coordinately up-regulated during terminal skeletal muscle differentiation. We reveal that this regulation is mediated in part by MyoD homo- and hetero-dimeric transcriptional mechanisms. Serial deletions of the VEGF promoter elucidated a region containing three tandem CANNTG consensus MyoD sites serving as essential sites of direct interaction for MyoD-mediated up-regulation of VEGF transcription. VEGF-null embryonic stem (ES) cells exhibited reduced myogenic differentiation compared with wild-type ES cells, suggesting that VEGF may serve a role in skeletal muscle differentiation. We demonstrate that VEGFR1 and VEGFR2 are expressed at low levels in myogenic precursor cells and are robustly activated upon VEGF stimulation and that their expression is coordinately regulated during skeletal muscle differentiation. VEGF stimulation of differentiating C2C12 cells promoted myotube hypertrophy and increased myogenic differentiation, whereas addition of sFlt1, a VEGF inhibitor, resulted in myotube hypotrophy and inhibited myogenic differentiation. We further provide evidence indicating VEGF-mediated myogenic marker expression, mitogenic activity, migration, and prosurvival functions may contribute to increased myogenesis. These data suggest a novel mechanism whereby VEGF is coordinately regulated as part of the myogenic differentiation program and serves an autocrine function regulating skeletal myogenesis.
Background: Rho kinase signaling plays an important role in the oncogenic process largely through its regulation of F-actin dynamics, and inhibition of this pathway results in reduction in tumor volume and metastasis across a number of tumor types. While the cytoskeletal- regulatory role of Rho kinase has been a topic of in-depth study, the mechanisms linking Rho kinase to altered gene expression are largely unknown. Materials and Methods: Global gene expression analysis was performed on melanoma tumors treated with sham or the small molecule inhibitor Y27632. Results: Inhibition of Rho kinase activity in melanoma tumors results in a statistically significant change in gene transcription of 94 genes, many of which are critically involved in tumor initiation and progression. Conclusion: In addition to regulating tumorigenesis through modulation of the phosphoproteome, Rho kinase signaling also contributes to the regulation of the tumor transcriptome. Rho-associated protein kinases 1 and 2 (ROCK1/2, collectively known as Rho kinase) belong to a family of serine/threonine kinases which serve as key regulators of actin cytoskeletal dynamics and thus control cell migration and motility (1). Rho kinase phosphorylates many protein targets including the catalytic subunit of myosin phosphatase, myosin light chain, intermediate filaments, ezrin/radixin/ moesin family proteins, Lin11/Isl1/Mec3 domain kinase (LIMK), collapsin response mediator protein-2, calponin, and adducin (2). Deregulation of Rho kinase signaling contributes to the metastatic behavior of many tumor types (3-6), and several preclinical and clinical studies have targeted this pathway for anticancer therapeutics in prostate, lung, melanoma, and glioblastoma tumors with good efficacy (7-10). While the role of Rho kinase in regulating the phosphoproteome is well understood, considerably less attention has been given to the function of Rho kinase signaling in regulating gene transcription. A handful of studies have identified global transcription alterations when Rho kinase is inhibited in epithelial and mesenchymal cell types grown in monolayers on plastic (11-13); however no reports examine global transcription regulation by Rho kinase using in vivo systems such as solid tumors. In this study, we utilized an in ovo melanoma cell xenograft system to perform whole-genome microarray analysis specifically on the melanoma tumor cells, while selectively excluding gene expression changes in cells of non-tumor origin such as endothelial cells, fibroblasts, stromal cells, and immune cells.
