sirolimus has been researched along with Hamartoma-Syndrome--Multiple* in 11 studies
1 review(s) available for sirolimus and Hamartoma-Syndrome--Multiple
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The complexity of PTEN: mutation, marker and potential target for therapeutic intervention.
Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a phosphatase that removes phosphates primarily from lipids. It has also been called mutated in multiple advanced cancers 1 and transforming growth factor-beta regulated epithelial cell-enriched phosphatase 1. The best described substrate of PTEN is phosphatidyliniositol (3,4,5)-tris-phosphate [PtdIns(3,4,5)P3]. PTEN removes the phosphate in PtdIns(3,4,5)P(3) to generate PtdIns(4,5)P(2). PTEN serves to counter-balance the effects of phosphoinositide 3' kinase, which normally adds a phosphate to PtdIns(4,5)P(2) to generate PtdIns(3,4,5)P(3). PtdIns(3,4,5)P(3) recruits kinases such as phosphoinositide-dependent kinase 1, which in turn phosphorylate Akt, which phosphorylates other downstream proteins involved in regulation of apoptosis and cell-cycle progression. PTEN removal of the phosphate from PtdIns(3,4,5)P(3) inhibits this pathway by preventing localisation of proteins with pleckstrin homology domains to the cell membrane. Alterations of the PTEN gene are associated with cancer and other diseases. Novel therapeutic approaches have been developed to counteract the deletion/mutation of PTEN in human cancer. This review will discuss the role of PTEN in signal transduction and cancer as well as pharmacological approaches to combat PTEN loss in human cancer. Topics: Animals; Apoptosis; Biomarkers, Tumor; Cell Cycle; Cell Nucleus; Female; Genes, Tumor Suppressor; Hamartoma Syndrome, Multiple; Humans; Lung Diseases; Male; Mice; Models, Biological; Neoplasm Proteins; Neoplasms; Phosphatidylinositol Phosphates; Phospholipids; Phosphoproteins; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Processing, Post-Translational; Protein Structure, Tertiary; Protein-Tyrosine Kinases; PTEN Phosphohydrolase; Receptor, Insulin; Signal Transduction; Sirolimus; Tumor Suppressor Proteins | 2004 |
10 other study(ies) available for sirolimus and Hamartoma-Syndrome--Multiple
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Long-term treatment of cancer-prone germline PTEN mutant mice with low-dose rapamycin extends lifespan and delays tumour development.
PTEN is one of the most commonly inactivated tumour suppressor genes in sporadic cancer. Germline heterozygous PTEN gene alterations also underlie PTEN hamartoma tumour syndrome (PHTS), a rare human cancer-predisposition condition. A key feature of systemic PTEN deregulation is the inability to adequately dampen PI3-kinase (PI3K)/mTORC1 signalling. PI3K/mTORC1 pathway inhibitors such as rapamycin are therefore expected to neutralise the impact of PTEN loss, rendering this a more druggable context compared with those of other tumour suppressor pathways such as loss of TP53. However, this has not been explored in cancer prevention in a model of germline cancer predisposition, such as PHTS. Clinical trials of short-term treatment with rapamycin have recently been initiated for PHTS, focusing on cognition and colon polyposis. Here, we administered a low dose of rapamycin from the age of 6 weeks onwards to mice with heterozygous germline Pten loss, a mouse model that recapitulates most characteristics of human PHTS. Rapamycin was well tolerated and led to a highly significant improvement of survival in both male and female mice. This was accompanied by a delay in, but not full blockade of, the development of a range of proliferative lesions, including gastro-intestinal and thyroid tumours and endometrial hyperplasia, with no impact on mammary and prostate tumours, and no effect on brain overgrowth. Our data indicate that rapamycin may have cancer prevention potential in human PHTS. This might also be the case for sporadic cancers in which genetic PI3K pathway activation is an early event in tumour development, such as endometrial cancer and some breast cancers. To the best of our knowledge, this is the first report of a long-term treatment of a germline cancer predisposition model with a PI3K/mTOR pathway inhibitor. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. Topics: Animals; Female; Germ Cells; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Infant; Longevity; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; PTEN Phosphohydrolase; Sirolimus; Thyroid Neoplasms | 2022 |
Sirolimus treatment of a PTEN hamartoma tumor syndrome presenting with melena.
PTEN hamartoma tumor syndrome (PHTS) is an umbrella term including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), PTEN-related Proteus syndrome (PS), and PTEN-related Proteus-like syndrome. One of the disorders in PHTS spectrum, CS is characterized by macrocephaly, mucocutaneous findings, gastrointestinal system (GIS) polyposis and an increased lifetime risk of GIS, breast, thyroid and other cancers.. In this study, we report an adolescent patient presenting with recurrent life-threatening upper GIS bleeding as a result of hamartomatous polyposis. Genetic studies revealed a known pathogenic nonsense mutation confirming the initial diagnosis of CS.. Additionally, we describe our therapeutic intervention to improve the patient`s clinical symptoms with sirolimus, which its use is infrequently addressed in the literature for pediatric age group harboring PTEN mutations. Topics: Adolescent; Child; Hamartoma Syndrome, Multiple; Humans; Melena; PTEN Phosphohydrolase; Sirolimus; Thyroid Gland | 2022 |
Oral hamartomatous lesion of Cowden's disease treated with the combination of erbium:YAG laser and topical sirolimus.
Topics: Administration, Topical; Biopsy; Female; Hamartoma Syndrome, Multiple; Humans; Immunosuppressive Agents; Laser Therapy; Lasers, Solid-State; Middle Aged; Mouth Diseases; Mouth Mucosa; Sirolimus | 2019 |
A Pilot Study of Sirolimus in Subjects with Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in
This is the first human interventional study in patients with Cowden syndrome that is driven by inactivation of germline. Cowden syndrome is characterized by inactivating germline. Adult subjects with germline. A total of 18 patients and 16 families were enrolled.. A 56-day course of sirolimus was well tolerated in subjects with Cowden syndrome and was associated with some evidence of improvement in symptoms, skin and GI lesions, cerebellar function, and decreased mTOR signaling. Topics: Adult; Aged; Anti-Bacterial Agents; Female; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Male; Middle Aged; Pilot Projects; PTEN Phosphohydrolase; Sirolimus; Young Adult | 2019 |
Hamartoma-like lesions in the mouse retina: an animal model of
Topics: Animals; Animals, Newborn; Cell Division; Disease Models, Animal; Ependymoglial Cells; Hamartoma Syndrome, Multiple; Mice, Knockout; Mosaicism; Mutation; Neuroglia; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Retina; Retinal Pigment Epithelium; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases | 2018 |
Infantile Lhermitte-Duclos Disease Treated Successfully With Rapamycin.
Lhermitte-Duclos disease is a rare hamartomatous tumor of the cerebellum resulting from a mutation in the phosphatase and tensin homolog (PTEN) gene: it has been reported in fewer than 10 infants. Rapamycin treatment has not yet been described in Lhermitte-Duclos disease. The infant underwent shunt placement shortly after birth for aqueductal stenosis. Her clinical progression included failure to thrive, seizures, episodes of decerebrate posturing, loss of respiratory drive, and pituitary insufficiency from mass effect. The characteristic "tiger stripe" sign on imaging prompted diagnosis. Rapamycin therapy was initiated at 18 months. Within 5 months, our patient has become responsive to her surroundings and had return of spontaneous breathing. Repeat magnetic resonance imaging (MRI) reveals lack of brainstem compression or distortion of pituitary stalk. Rapamycin should be considered in cases of Lhermitte-Duclos disease where surgical removal may not be an option, as in our case where the cerebellum was entirely involved. Topics: Antibiotics, Antineoplastic; Brain; Female; Hamartoma Syndrome, Multiple; Humans; Infant, Newborn; Magnetic Resonance Imaging; Sirolimus; Treatment Outcome | 2017 |
Sirolimus treatment of severe PTEN hamartoma tumor syndrome: case report and in vitro studies.
Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) is caused by germ line mutations in the PTEN gene. Symptoms include cancer predisposition, immune deviations, and lipomas/lipomatosis. No causal standard therapy is available. We describe a therapeutic attempt with the mammalian target of rapamycin (mTOR) inhibitor sirolimus for a PHTS patient suffering from thymus hyperplasia and lipomatosis. We furthermore assessed the in vitro effects of sirolimus and other inhibitors on lipoma cells of the patient.. The patient underwent clinical and blood examinations and whole-body magnetic resonance imaging to assess tumor sizes. Lipoma cells of the patient were incubated with inhibitors of the phosphoinositide-3-kinase (PI3K)/AKT/mTOR signaling pathway to analyze the effects on proliferation, adipocyte differentiation, and survival in vitro.. Sirolimus treatment improved somatic growth and reduced thymus volume. These effects diminished over the treatment period of 19 mo. Sirolimus decreased lipoma cell proliferation and adipocyte differentiation in vitro but did not cause apoptosis. PI3K and AKT inhibitors induced apoptosis significantly.. Sirolimus treatment led to an improvement of the patient's clinical status and a transient reduction of the thymus. Our in vitro findings point to PI3K and AKT inhibitors as potential treatment options for patients with severe forms of PHTS. Topics: Child, Preschool; Hamartoma Syndrome, Multiple; Humans; In Vitro Techniques; Infant; Infant, Newborn; PTEN Phosphohydrolase; Sirolimus | 2014 |
Oral rapamycin in the treatment of patients with hamartoma syndromes and PTEN mutation.
Bannayan-Riley-Ruvacalba syndrome (BRRS) belongs to the PTEN hamartoma tumor syndromes and is characterized by a high risk of malignancy in early adulthood added to local destructive effects of hamartomas in childhood. There is no standard treatment for this condition and patients are usually offered symptomatic surgical relief. Rapamycin has been reported to be effective in the management of other conditions associated with PTEN mutation. We report here a case of BRRS in a 6-year-old male with progressive loss of function of left hand and forearm associated with pain. He was treated with oral rapamycin and regained pain-free full mobility. Topics: Administration, Oral; Antibiotics, Antineoplastic; Arteriovenous Malformations; Child; Hamartoma Syndrome, Multiple; Humans; Male; Sirolimus; Upper Extremity | 2011 |
Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin.
Cowden's disease is an autosomal dominant disorder characterized by the development of multiple mucocutaneous lesions and benign tumors, and enhanced cancer predisposition. Most Cowden's disease patients harbor inactivating mutations in the PTEN tumor suppressor gene which encodes a lipid phosphatase, PTEN, which restrains the phosphatidylinositol 3-kinase-Akt signaling pathway. We observed that the epithelial-specific deletion of Pten in mice causes multiple hyperproliferative and tumor lesions that strikingly resemble Cowden's disease. This animal model system provided an opportunity to explore novel therapeutic approaches in Cowden's disease. Indeed, we show here that rapamycin administration, which inhibits a key downstream target of Akt, mammalian target of rapamycin (mTOR), promotes the rapid regression of advanced mucocutaneous lesions. Furthermore, when administered before disease manifestation, rapamycin can halt the development of Cowden's disease-like lesions, thereby prolonging animal survival. These findings suggest that mTOR inhibition with rapamycin may represent a suitable therapeutic option for the chemoprevention and treatment of Cowden disease patients and others tumor syndromes that involve defective PTEN function. Topics: Animals; Gene Deletion; Hamartoma Syndrome, Multiple; Immunohistochemistry; Mice; Mice, Knockout; Protein Kinases; PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases | 2008 |
Rapamycin treatment for a child with germline PTEN mutation.
A 9-month-old boy with Proteus syndrome and a de novo germline mutation in the tumor suppressor PTEN was referred to a specialist centre for management. Over the first years of life, the patient developed life-threatening respiratory dysfunction and malnutrition because of progressive growth of hamartomas affecting the chest, mediastinum, abdomen and pelvis.. Physical examination, CT scans of the mediastinum, pelvis and abdomen, measurement of serum insulin-like growth factor binding protein-2, and investigation of the effect of the PTEN mutation on phosphatidylinositol 3-kinase/mammalian target of rapamycin signaling in an in vitro cell model.. PTEN hamartoma tumor syndrome, specifically Proteus syndrome.. Oral rapamycin. Topics: Antibiotics, Antineoplastic; Child; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Humans; Insulin-Like Growth Factor Binding Protein 2; Male; Phosphatidylinositol 3-Kinases; Protein Kinases; PTEN Phosphohydrolase; Sirolimus; TOR Serine-Threonine Kinases | 2008 |