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1.
Eur J Cancer ; 207: 114145, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38936103

ABSTRACT

Phosphatidylinositol 3-kinase (PI3-K) signalling pathway is a crucial path in cancer for cell survival and thus represents an intriguing target for new paediatric anti-cancer drugs. However, the unique clinical toxicities of targeting this pathway (resulting in hyperglycaemia) difficulties combining with chemotherapy, rarity of mutations in childhood tumours and concomitant mutations have resulted in major barriers to clinical translation of these inhibitors in treating both adults and children. Mutations in PIK3CA predict response to PI3-K inhibitors in adult cancers. The same mutations occur in children as in adults, but they are significantly less frequent in paediatrics. In children, high-grade gliomas, especially diffuse midline gliomas (DMG), have the highest incidence of PIK3CA mutations. New mutation-specific PI3-K inhibitors reduce toxicity from on-target PI3-Kα wild-type activity. The mTOR inhibitor everolimus is approved for subependymal giant cell astrocytomas. In paediatric cancers, mTOR inhibitors have been predominantly evaluated by academia, without an overall strategy, in empiric, mutation-agnostic clinical trials with very low response rates to monotherapy. Therefore, future trials of single agent or combination strategies of mTOR inhibitors in childhood cancer should be supported by very strong biological rationale and preclinical data. Further preclinical evaluation of glycogen synthase kinase-3 beta inhibitors is required. Similarly, even where there is an AKT mutation (∼0.1 %), the role of AKT inhibitors in paediatric cancers remains unclear. Patient advocates strongly urged analysing and conserving data from every child participating in a clinical trial. A priority is to evaluate mutation-specific, central nervous system-penetrant PI3-K inhibitors in children with DMG in a rational biological combination. The choice of combination, should be based on the genomic landscape e.g. PTEN loss and resistance mechanisms supported by preclinical data. However, in view of the very rare populations involved, innovative regulatory approaches are needed to generate data for an indication.


Subject(s)
Glycogen Synthase Kinase 3 beta , Neoplasms , Proto-Oncogene Proteins c-akt , TOR Serine-Threonine Kinases , Humans , Child , Adolescent , Neoplasms/drug therapy , Neoplasms/genetics , Glycogen Synthase Kinase 3 beta/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta/metabolism , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors/therapeutic use , Phosphoinositide-3 Kinase Inhibitors/pharmacology , MTOR Inhibitors/therapeutic use , MTOR Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/pharmacology , Signal Transduction/drug effects
2.
Orphanet J Rare Dis ; 19(1): 44, 2024 Feb 06.
Article in English | MEDLINE | ID: mdl-38321508

ABSTRACT

BACKGROUND: Proteus syndrome is an ultra-rare mosaic overgrowth disorder. Individuals with Proteus syndrome can develop emphysematous and cystic changes of the lung that may lead to progressive respiratory symptoms and require surgical intervention. This retrospective study seeks to quantify the radiographic features of Proteus syndrome-associated lung disease using computed tomography (CT) of the chest. The first method derives a Cystic Lung Score (CLS) by using a computer-aided diagnostic tool to quantify the fraction of cystic involvement of the lung. The second method yields a Clinician Visual Score (CVS), an observer reported scale of severity based on multiple radiographic features. The aim of this study was to determine if these measurements are associated with clinical symptoms, pulmonary function test (PFT) measurements, and if they may be used to assess progression of pulmonary disease. RESULTS: One hundred and thirteen imaging studies from 44 individuals with Proteus syndrome were included. Dyspnea and oxygen use were each associated with higher CLS (p = 0.001 and < 0.001, respectively) and higher CVS (p < 0.001 and < 0.001). Decreases in percent predicted FVC, FEV1, and DLCO each correlated with increased CLS and CVS. The annual increase of CLS in children, 5.6, was significantly greater than in adults, 1.6. (p = 0.03). The annual increase in CVS in children, 0.4, was similar to adults, 0.2 (p = 0.36). CONCLUSIONS: Proteus syndrome-associated lung disease is progressive. The rate of cystic progression is increased in children. Increased scores in CLS and CVS were associated with clinical symptoms and decreased pulmonary function. Both methods were able to detect change over time and were associated with clinically meaningful outcomes which may enable their use in interventional studies.


Subject(s)
Lung Diseases , Proteus Syndrome , Adult , Child , Humans , Proteus Syndrome/complications , Proteus Syndrome/diagnosis , Proteus Syndrome/surgery , Retrospective Studies , Lung , Tomography, X-Ray Computed , Lung Diseases/complications
3.
Am J Med Genet A ; 191(5): 1430-1433, 2023 05.
Article in English | MEDLINE | ID: mdl-36808868

ABSTRACT

Proteus syndrome is an extremely rare overgrowth condition caused by a somatic variant of the AKT1 gene. It can involve multiple organ systems though rarely is there symptomatic cardiac involvement. Fatty infiltration of the myocardium has been described but has not been reported to cause functional or conduction abnormalities. We present an individual with Proteus syndrome who suffered a sudden cardiac arrest.


Subject(s)
Heart Arrest , Proteus Syndrome , Tachycardia, Ventricular , Humans , Adolescent , Proteus Syndrome/complications , Proteus Syndrome/diagnosis , Proteus Syndrome/genetics , Arrhythmias, Cardiac , Tachycardia, Ventricular/diagnosis , Tachycardia, Ventricular/genetics , Heart Arrest/diagnosis , Heart Arrest/genetics , Death, Sudden, Cardiac
4.
Orphanet J Rare Dis ; 17(1): 173, 2022 04 23.
Article in English | MEDLINE | ID: mdl-35461279

ABSTRACT

BACKGROUND: Clinical outcome assessments are important tools for measuring the natural history of disease and efficacy of an intervention. The heterogenous phenotype and difficult to quantity features of Proteus syndrome present challenges to measuring clinical outcomes. To address these, we designed a global clinical assessment for Proteus syndrome, a rare mosaic overgrowth disorder. The Clinical Gestalt Assessment (CGA) aims to evaluate change over time in this phenotypically diverse disorder. RESULTS: We gathered paired serial photographs and radiographs obtained at 12-to-36-month intervals from our natural history study of Proteus syndrome. The chronologic order of each set was blinded and presented to clinicians familiar with overgrowth disorders. They were asked to determine the chronologic order and, based on that response, rate global clinical change using a seven-point scale (Much Worse, Worse, Minimally Worse, No Change, Minimally Improved, Improved, Much Improved). Following a pilot, we tested the inter-rater reliability of the CGA using eight cases rated by eight clinicians. Raters identified the correct chronologic order in 53 of 64 (83%) of responses. There was low inter-rater variance and poor to moderate reliability with an intraclass correlation coefficient of 0.46 (95% CI 0.24-0.75). The overall estimate of global change was Minimally Worse over time, which is an accurate reflection of the natural history of Proteus syndrome. CONCLUSIONS: The CGA is a tool to evaluate clinical change over time in Proteus syndrome and may be a useful adjunct to measure clinical outcomes in prospective therapeutic trials.


Subject(s)
Proteus Syndrome , Humans , Outcome Assessment, Health Care , Phenotype , Proteus Syndrome/diagnosis , Reproducibility of Results
5.
Am J Med Genet A ; 188(9): 2766-2771, 2022 09.
Article in English | MEDLINE | ID: mdl-35441778

ABSTRACT

Proteus syndrome (PS) is a rare segmental overgrowth disorder caused by a mosaic activating variant in AKT1. The features of PS are often not present at birth but develop during the first few years of life. We describe a 55-year-old female, whose first symptom of overgrowth, a cerebriform connective tissue nevus, occurred at 19 years of age. We report the identification of the AKT1 c.49G > A p.(Glu17Lys) variant in this progressive lesion, the bony overgrowth, and recurrence after surgical intervention. In the sixth decade of life, this individual developed intraductal papillomas within her right breast which were confirmed to contain the same activating AKT1 variant as the connective tissue nevus. While similar neoplasms have been described in an individual with Proteus syndrome, none has been evaluated for the presence of the AKT1 variant. The tumor also contained two likely pathogenic variants in PIK3R1, c.1392_1403dupTAGATTATATGA p.(Asp464_Tyr467dup) and c.1728_1730delGAG p.(Arg577del). The finding of additional genetic variation putatively affecting the PI3K/AKT pathway in the neoplastic tissue may provide preliminary evidence of a molecular mechanism for tumorigenesis in PS. The late onset of symptoms and molecular characterization of the breast tumor expand the clinical spectrum of this rare disorder.


Subject(s)
Breast Neoplasms , Nevus , Papilloma, Intraductal , Proteus Syndrome , Breast Neoplasms/genetics , Female , Humans , Infant, Newborn , Middle Aged , Nevus/diagnosis , Nevus/genetics , Nevus/pathology , Phosphatidylinositol 3-Kinases , Proteus Syndrome/diagnosis , Proteus Syndrome/genetics , Proteus Syndrome/pathology , Proto-Oncogene Proteins c-akt/genetics
7.
Article in English | MEDLINE | ID: mdl-34649967

ABSTRACT

Proteus syndrome is a rare overgrowth disorder caused by postzygotic activating variants in AKT1 Individuals may develop a range of skin, bone, and soft tissue overgrowth leading to functional impairment and disfigurement. Therapy for this disorder is limited to supportive care and surgical intervention. Inhibitors of AKT, originally designed as cancer therapeutics, are a rational, targeted pharmacologic strategy to mitigate the devastating morbidity of Proteus syndrome. We present the 5-yr follow-up of an 18-yr-old male with Proteus syndrome treated with miransertib (MK-7075), an oral pan-AKT inhibitor. At completion of a planned 48-wk phase 1 pharmacodynamic study, the individual derived sufficient benefit that the study was amended to permit continued use and assess the long-term safety of miransertib. The treatment has been well-tolerated with mild treatment-attributed side effects including headache, transient hyperglycemia, and transient elevations of aspartate aminotransferase, alanine aminotransferase, and bilirubin. The patient has experienced sustained improvement of pain and slowed growth of bilateral plantar cerebriform connective tissue nevi. This case report supplements the data from our prior study extending those findings out to 5 years. It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. Although an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.


Subject(s)
Proteus Syndrome , Proto-Oncogene Proteins c-akt , Aminopyridines , Humans , Imidazoles , Male
8.
Clin Case Rep ; 9(5): e04143, 2021 May.
Article in English | MEDLINE | ID: mdl-34026175

ABSTRACT

Proteus syndrome (PS) is a complex disorder characterized by variable clinical findings of overgrowth and tumor susceptibility. This report presents the first known association between PS and an ovarian germ cell tumor in an adolescent with immature teratoma. A review of the diagnosis of PS and associated tumors is included.

9.
Blood Cancer Discov ; 2(3): 226-237, 2021 05.
Article in English | MEDLINE | ID: mdl-34027416

ABSTRACT

Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by detectable hematopoietic-associated gene mutations in a person without evidence of hematologic malignancy. We sought to identify additional cancer-presenting mutations useable for CHIP detection by performing a data mining analysis of 48 somatic mutation studies reporting mutations at diagnoses of 7,430 adult and pediatric patients with hematologic malignancies. Following extraction of 20,141 protein-altering mutations, we identified 434 significantly recurrent mutation hotspots, 364 of which occurred at loci confidently assessable for CHIP. We then performed an additional large-scale analysis of whole exome sequencing data from 4,538 persons belonging to three non-cancer cohorts for clonal mutations. We found the combined cohort prevalence of CHIP with mutations identical to those reported at blood cancer mutation hotspots to be 1.8%, and that some of these CHIP mutations occurred in children. Our findings may help to improve CHIP detection and pre-cancer surveillance for both children and adults.


Subject(s)
Hematologic Neoplasms , Neoplasms , Adult , Child , Clonal Hematopoiesis , Hematologic Neoplasms/diagnosis , Hematopoiesis/genetics , Humans , Mutation , Neoplasms/diagnosis
11.
Mol Cell Biol ; 39(13)2019 07 01.
Article in English | MEDLINE | ID: mdl-30988160

ABSTRACT

Growth factor independence 1B (GFI1B) coordinates assembly of transcriptional repressor complexes comprised of corepressors and histone-modifying enzymes to control gene expression programs governing lineage allocation in hematopoiesis. Enforced expression of GFI1B in K562 erythroleukemia cells favors erythroid over megakaryocytic differentiation, providing a platform to define molecular determinants of binary fate decisions triggered by GFI1B. We deployed proteome-wide proximity labeling to identify factors whose inclusion in GFI1B complexes depends upon GFI1B's obligate effector, lysine-specific demethylase 1 (LSD1). We show that GFI1B preferentially recruits core and putative elements of the BRAF-histone deacetylase (HDAC) (BHC) chromatin-remodeling complex (LSD1, RCOR1, HMG20A, HMG20B, HDAC1, HDAC2, PHF21A, GSE1, ZMYM2, and ZNF217) in an LSD1-dependent manner to control acquisition of erythroid traits by K562 cells. Among these elements, depletion of both HMG20A and HMG20B or of GSE1 blocks GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B-LSD1 binding. These findings demonstrate the central role of the GFI1B-LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.


Subject(s)
Erythroid Cells/cytology , Histone Demethylases/metabolism , Proto-Oncogene Proteins/metabolism , Repressor Proteins/metabolism , Animals , COS Cells , Cell Differentiation , Chlorocebus aethiops , Down-Regulation , Erythroid Cells/metabolism , Histone Deacetylases/metabolism , Humans , K562 Cells , Phenotype , Tetradecanoylphorbol Acetate/pharmacology , Transcription, Genetic
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