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Grupo de Análise de Mercado

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Joseph Miller
Joseph Miller

Overgrowth Torrent Download



PIK3CA-related overgrowth spectrum (PROS) refers to a group of rare disorders, caused by somatic activating mutations in PIK3CA, resulting in abnormal PI3K-AKT-mTOR pathway signalling. Significant associated morbidity is frequently observed, and approved treatments are lacking. Miransertib (ARQ 092) is a novel, orally available, selective pan-AKT inhibitor with proven in vitro efficacy. Following recent results of the use of AKT inhibitors in Proteus syndrome (PS) and AKT-mutant cancers, we investigated its therapeutic use in two patients with severe PROS who had exhausted conventional treatment methods.




Overgrowth Torrent Download



PIK3CA-related overgrowth spectrum (PROS) refers to a group of heterogeneous, rare disorders characterised by segmental progressive overgrowth, caused by somatic activating mutations in phosphatidylinositol-4 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene [1]. The PI3K/AKT/mTOR pathway is essential for normal cellular functions including growth, metabolism, and proliferation. PIK3CA encodes the p110alpha subunit of phosphoinositide 3-kinase that converts phosphatidylinositol 3,4-bisphosphate to phosphatidylinositol 3,4,5-triphosphate. Subsequent activation of AKT and mTOR signalling results in promotion of tissue growth. Dysregulation causing over-activation of the pathway results in increased cellular metabolism, angiogenesis and reduction in cellular apoptosis [2].


In recent years, next generation sequencing (NGS) has significantly expanded the understanding of the molecular aetiology of overgrowth syndromes [1, 3,4,5,6]. In 2014, the identification of PIK3CA mutations in a group of patients with heterogeneous, but overlapping, clinical features [7] resulted in the subsequent development of diagnostic criteria for the newly termed PIK3CA-related overgrowth spectrum (PROS) [1]. These disorders are extremely rare, although the exact prevalence is difficult to estimate owing to the phenotypic heterogeneity of disorders and variability of correct clinical diagnoses to date [8].


PIK3CA-related overgrowth spectrum (PROS) disorders are associated with significant morbidity and mortality. Past therapeutic approaches centred around symptomatic surgical or medical management of associated complications, with minimal success. There are no approved targeted medical treatments.


The P13K/AKT/mTOR pathway is recognised as one of the most frequently dysregulated pathways in human cancers, with PIK3CA identified as the most commonly mutated proto-oncogene in somatic cancer [9]. With the advent of increasing knowledge regarding the oncogenic implications associated with dysregulation of the P13K/AKT/mTOR pathway, the development of several small molecules targeting different key components of the pathway have come under clinical investigation. Thus, opportunities for targeted treatment of overgrowth disorders are now being recognised.


The mTOR inhibitor sirolimus has been used with partial success in overgrowth disorders. A previous open label multicentre study reported a modest mean reduction in total tissue volume at affected sites (7.2%) in 23/30 patients who were evaluable after 26 weeks treatment. Treatment was associated with a high rate of adverse events, many severe, resulting in consequent treatment withdrawal in a significant number (7/39; 18%) [10]. In addition, a previous study of its use in children with heterogeneous complex vascular disorders appeared to show greatest response rates in those with lymphatic malformations [11]. Furthermore, since sirolimus fails to effectively inhibit mTORC2, feedback activation of PI3K and AKT persists, rendering it a less attractive option in the long-term management of patients with PROS. The focus for future therapeutic options has expanded to include AKT inhibitors, PI3K inhibitors and dual PI3K-mTOR inhibitors, many of which are undergoing investigation in oncology trials [12]. More recently, Venot et al. reported a substantial clinical response in 19 patientswith PROS treated with the PI3K inhibitor alpelisib (BYL719), in an open label, non-RCT case series, along with a favourable safety profile [9], further supporting the repurposing of agents targeting the P13K/AKT/mTOR in the treatment of PROS.


To investigate the therapeutic use of pan-AKT inhibitor miransertib (ARQ 092) in two paediatric patients with severe PIK3CA-related overgrowth spectrum disorder, both of whom had exhausted conventional treatment methods.


Patient one was a 16 years old female with Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevi, Scoliosis/Skeletal/Spinal anomalies (CLOVES) phenotype [17, 18]. She was born to non-consanguineous parents with a birth weight of 2.89 kg (50th centile) and occipitofrontal circumference of 31.6 cm (10th centile) and was noted to have a large posterior thoracic wall lipoma and large feet with splayed toes at birth. Subsequent musculoskeletal examination identified a dislocated right hip and bilateral talipes equinovarus. Progressive intra-abdominal and paraspinal lipomatous overgrowth created significant difficulties with mobility and seating; these were treated with debulking procedures and liposuction during the first 10 years of life. While these procedures lead to partial but temporary improvement, the lipomatous lesions regrew within 12 months. Despite repeated orthopaedic intervention, she developed progressive lower limb discrepancy and subsequent flexed deformity of the right lower limb, resulting in loss of function.


At the age of four, she presented with a urinary tract infection and was found to have marked bladder wall thickening and irregularity on ultrasound suggestive of neuropathic bladder, along with bilateral hydronephrosis. Functional studies demonstrated focal scarring of the right kidney. Urodynamics confirmed a large, atonic bladder with incomplete voiding. Chronic renal failure, with estimated function 50% of normal range first became evident aged seven. Due to anterior displacement of the bladder by progressive infiltrative lipomatous overgrowth, an obstructive uropathy component also developed, requiring placement of a suprapubic catheter.


By the age of thirteen, she was completely wheelchair bound and had frequent hospital admissions for recurrent urinary tract infections. Chronic pain became a severely disabling problem, and her progressive intra-abdominal overgrowth resulted in difficulties with lying and seating. She was treated with mTOR inhibitor sirolimus aged fifteen for a period of 12 months. Sub-therapeutic troughs were observed despite incremental dosing increases, and treatment was stopped after one year due to progression of her disease.


Progressive respiratory compromise from diaphragm elevation caused by intra-abdominal lipomatous overgrowth, and relentless flank pain from massive lipomatous distension determined the urgency of further treatment. Surgical therapeutic approaches were not favoured due to the infiltrative nature of fatty overgrowth encasing vital structures in the retroperitoneum, thus necessitating investigation of novel medical therapeutic approaches.


During the first few years of life, profound hemifacial and soft tissue and skeletal overgrowth began to affect the oral commissure on the right side, and hemi-macroglossia and macrodontia caused progressive difficulties with articulation and oral function. Magnetic resonance imaging (MRI) showed extensive fatty hypertrophy and infiltration of the right side of the face, including the tongue and facial musculature (Fig. 2). Repeated liposuction and excision of excess tissue was undertaken for debulking and symmetrisation with a therapeutic aim of improving function. However progressive bony overgrowth was also evident which was deemed impossible to correct until skeletal maturation was reached. Executive functioning difficulties became apparent, consistent with right hemisphere abnormalities, reflected by attention and behavioural dysregulation difficulties. Additional educational support was also required due to low average scores obtained in general verbal and non-verbal skills on neuropsychological assessments.


Informed consent was obtained from the legal guardians of both patients prior to treatment commencement. Baseline pre-treatment assessments were carried out, including evaluation of complete blood count, renal, liver, bone and fasting lipid profile and urinalysis. Transthoracic echo was undertaken to assess cardiac function. Volumetric MRI analysis of the targeted overgrowth area was also performed pre-treatment and every three months thereafter.


Targeted regions of interest in MRI slices of the in-phase images were identified to define areas of fatty overgrowth. By treatment end, a 15% decline in the calculated volume of fatty overgrowth from baseline imaging was observed (Fig. 3).


Patient two commenced miransertib 10 mg once daily at 5 years of age, and continued treatment for 22 months. A subsequent reduction in seizure frequency was observed along with reported improved cognitive engagement in school and at home. Parental-reported quality of life measures, determined on clinical questioning at patient visits, improved. Treatment was very well tolerated with no adverse effects apart from loose stools (grade 1 CTCAE v.5.0), favourably comparable to that reported with previous sirolimus therapy. Objective assessment of response to treatment using volumetric MRI analysis was not possible due to ongoing surgical treatment of facial overgrowth during the treatment period.


Here, we report the first paediatric case series of the use of miransertib in two children with severe PIK3CA-related overgrowth spectrum, one with CLOVES variant and one with facial infiltrating lipomatosis with hemimegalencephaly. The first patient demonstrated clear clinical improvement with observed stability in renal function and a 15% reduction in calculated volumes of fatty overgrowth at the targeted regions of interest. Functionally, improved lying and sitting postures were achieved, most importantly evidenced by the patient being able to lie flat again. These initial improvements were not sustained into the second year of therapy, largely due to poor treatment adherence, reflected objectively by increased lipomatous volumes on MRI at 28 months. 041b061a72


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