%0 Journal Article %J J Immunother Cancer %D 2020 %T Nivolumab and sunitinib combination in advanced soft tissue sarcomas: a multicenter, single-arm, phase Ib/II trial. %A Martin-Broto, Javier %A Hindi, Nadia %A Grignani, Giovanni %A Martinez-Trufero, Javier %A Redondo, Andres %A Valverde, Claudia %A Stacchiotti, Silvia %A Lopez-Pousa, Antonio %A D'Ambrosio, Lorenzo %A Gutierrez, Antonio %A Perez-Vega, Herminia %A Encinas-Tobajas, Victor %A de Alava, Enrique %A Collini, Paola %A Peña-Chilet, Maria %A Dopazo, Joaquin %A Carrasco-Garcia, Irene %A Lopez-Alvarez, Maria %A Moura, David S %A Lopez-Martin, Jose A %K Adult %K Aged %K Antineoplastic Agents, Immunological %K Female %K Humans %K Male %K Middle Aged %K Nivolumab %K Sarcoma %K Sunitinib %K Young Adult %X

BACKGROUND: Sarcomas exhibit low expression of factors related to immune response, which could explain the modest activity of PD-1 inhibitors. A potential strategy to convert a cold into an inflamed microenvironment lies on a combination therapy. As tumor angiogenesis promotes immunosuppression, we designed a phase Ib/II trial to test the double inhibition of angiogenesis (sunitinib) and PD-1/PD-L1 axis (nivolumab).

METHODS: This single-arm, phase Ib/II trial enrolled adult patients with selected subtypes of sarcoma. Phase Ib established two dose levels: level 0 with sunitinib 37.5 mg daily from day 1, plus nivolumab 3 mg/kg intravenously on day 15, and then every 2 weeks; and level -1 with sunitinib 37.5 mg on the first 14 days (induction) and then 25 mg per day plus nivolumab on the same schedule. The primary endpoint was to determine the recommended dose for phase II (phase I) and the 6-month progression-free survival rate, according to Response Evaluation Criteria in Solid Tumors 1.1 (phase II).

RESULTS: From May 2017 to April 2019, 68 patients were enrolled: 16 in phase Ib and 52 in phase II. The recommended dose of sunitinib for phase II was 37.5 mg as induction and then 25 mg in combination with nivolumab. After a median follow-up of 17 months (4-26), the 6-month progression-free survival rate was 48% (95% CI 41% to 55%). The most common grade 3-4 adverse events included transaminitis (17.3%) and neutropenia (11.5%).

CONCLUSIONS: Sunitinib plus nivolumab is an active scheme with manageable toxicity in the treatment of selected patients with advanced soft tissue sarcoma, with almost half of patients free of progression at 6 months. NCT03277924.

%B J Immunother Cancer %V 8 %8 2020 11 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/33203665?dopt=Abstract %R 10.1136/jitc-2020-001561 %0 Journal Article %J Br J Dermatol %D 2019 %T Fibroblast activation and abnormal extracellular matrix remodelling as common hallmarks in three cancer-prone genodermatoses. %A Chacón-Solano, E %A León, C %A Díaz, F %A García-García, F %A García, M %A Escámez, M J %A Guerrero-Aspizua, S %A Conti, C J %A Mencía, Á %A Martínez-Santamaría, L %A Llames, S %A Pévida, M %A Carbonell-Caballero, J %A Puig-Butillé, J A %A Maseda, R %A Puig, S %A de Lucas, R %A Baselga, E %A Larcher, F %A Dopazo, J %A Del Rio, M %K Adolescent %K Adult %K Biopsy %K Blister %K Case-Control Studies %K Cells, Cultured %K Child %K Child, Preschool %K Epidermolysis Bullosa %K Epidermolysis Bullosa Dystrophica %K Extracellular Matrix %K Extracellular Matrix Proteins %K Female %K Fibroblasts %K Fibrosis %K Gene Expression Regulation %K Healthy Volunteers %K Humans %K Infant %K Infant, Newborn %K Male %K Middle Aged %K mutation %K Periodontal Diseases %K Photosensitivity Disorders %K Primary Cell Culture %K RNA-seq %K Skin %K Xeroderma Pigmentosum %K Young Adult %X

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three cancer-prone genodermatoses whose causal genetic mutations cannot fully explain, on their own, the array of associated phenotypic manifestations. Recent evidence highlights the role of the stromal microenvironment in the pathology of these disorders.

OBJECTIVES: To investigate, by means of comparative gene expression analysis, the role played by dermal fibroblasts in the pathogenesis of RDEB, KS and XPC.

METHODS: We conducted RNA-Seq analysis, which included a thorough examination of the differentially expressed genes, a functional enrichment analysis and a description of affected signalling circuits. Transcriptomic data were validated at the protein level in cell cultures, serum samples and skin biopsies.

RESULTS: Interdisease comparisons against control fibroblasts revealed a unifying signature of 186 differentially expressed genes and four signalling pathways in the three genodermatoses. Remarkably, some of the uncovered expression changes suggest a synthetic fibroblast phenotype characterized by the aberrant expression of extracellular matrix (ECM) proteins. Western blot and immunofluorescence in situ analyses validated the RNA-Seq data. In addition, enzyme-linked immunosorbent assay revealed increased circulating levels of periostin in patients with RDEB.

CONCLUSIONS: Our results suggest that the different causal genetic defects converge into common changes in gene expression, possibly due to injury-sensitive events. These, in turn, trigger a cascade of reactions involving abnormal ECM deposition and underexpression of antioxidant enzymes. The elucidated expression signature provides new potential biomarkers and common therapeutic targets in RDEB, XPC and KS. What's already known about this topic? Recessive dystrophic epidermolysis bullosa (RDEB), Kindler syndrome (KS) and xeroderma pigmentosum complementation group C (XPC) are three genodermatoses with high predisposition to cancer development. Although their causal genetic mutations mainly affect epithelia, the dermal microenvironment likely contributes to the physiopathology of these disorders. What does this study add? We disclose a large overlapping transcription profile between XPC, KS and RDEB fibroblasts that points towards an activated phenotype with high matrix-synthetic capacity. This common signature seems to be independent of the primary causal deficiency, but reflects an underlying derangement of the extracellular matrix via transforming growth factor-β signalling activation and oxidative state imbalance. What is the translational message? This study broadens the current knowledge about the pathology of these diseases and highlights new targets and biomarkers for effective therapeutic intervention. It is suggested that high levels of circulating periostin could represent a potential biomarker in RDEB.

%B Br J Dermatol %V 181 %P 512-522 %8 2019 09 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/30693469?dopt=Abstract %R 10.1111/bjd.17698 %0 Journal Article %J Brain %D 2016 %T Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease. %A Sevilla, Teresa %A Lupo, Vincenzo %A Martínez-Rubio, Dolores %A Sancho, Paula %A Sivera, Rafael %A Chumillas, María J %A García-Romero, Mar %A Pascual-Pascual, Samuel I %A Muelas, Nuria %A Dopazo, Joaquin %A Vílchez, Juan J %A Palau, Francesc %A Espinós, Carmen %K Adult %K Aged %K Animals %K Axons %K Charcot-Marie-Tooth Disease %K Female %K gene expression %K Humans %K Infant %K Male %K Mice %K Middle Aged %K mutation %K Pedigree %K Phenotype %K Sciatic Nerve %K Sural Nerve %K Transcription Factors %K Young Adult %X

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.

%B Brain %V 139 %P 62-72 %8 2016 Jan %G eng %N Pt 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26497905?dopt=Abstract %R 10.1093/brain/awv311 %0 Journal Article %J Eur J Neurol %D 2015 %T The EGR2 gene is involved in axonal Charcot-Marie-Tooth disease. %A Sevilla, T %A Sivera, R %A Martínez-Rubio, D %A Lupo, V %A Chumillas, M J %A Calpena, E %A Dopazo, J %A Vílchez, J J %A Palau, F %A Espinós, C %K Adult %K Aged %K Aged, 80 and over %K Axons %K Charcot-Marie-Tooth Disease %K Early Growth Response Protein 2 %K Exome %K Female %K Humans %K Male %K Middle Aged %K mutation %K Pedigree %K Phenotype %K Severity of Illness Index %K Young Adult %X

BACKGROUND AND PURPOSE: A three-generation family affected by axonal Charcot-Marie-Tooth disease (CMT) was investigated with the aim of discovering genetic defects and to further characterize the phenotype.

METHODS: The clinical, nerve conduction studies and muscle magnetic resonance images of the patients were reviewed. A whole exome sequencing was performed and the changes were investigated by genetic studies, in silico analysis and luciferase reporter assays.

RESULTS: A novel c.1226G>A change (p.R409Q) in the EGR2 gene was identified. Patients presented with a typical, late-onset axonal CMT phenotype with variable severity that was confirmed in the ancillary tests. The in silico studies showed that the residue R409 is an evolutionary conserved amino acid. The p.R409Q mutation, which is predicted as probably damaging, would alter the conformation of the protein slightly and would cause a decrease of gene expression.

CONCLUSIONS: This is the first report of an EGR2 mutation presenting as an axonal CMT phenotype with variable severity. This study broadens the phenotype of the EGR2-related neuropathies and suggests that the genetic testing of patients suffering from axonal CMT should include the EGR2 gene.

%B Eur J Neurol %V 22 %P 1548-55 %8 2015 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/26204789?dopt=Abstract %R 10.1111/ene.12782