The gingivostomatitis and painful dentition both resolvedĪfter a week of supportive treatment. His pediatricĭentist attributed loose painful dentition, noted after 3 mo treatment at the 25 mg/m 2/day dose and attributable to known preexistent periodontal disease. No previous similar lesions could be recalled. The patient and his family reported that dryness of the mouth appeared soon after starting treatment, and this persisted unchanged.Īn episode of gingivostomatitis was treated with local analgesics. On a compassionate use basis and report that experience here. Of efficacy for CCTN reduction and pain reduction, although these were secondary endpoints not evaluated for statistical significance.īased on these suggestions of efficacy and apparently tolerable adverse effects, we treated a young man with PS with miransertib That study reached a pharmacodynamic endpoint of 50% inhibition of AKT in five of six treated patients and suggestions Institutes of Health (NIH) ( Keppler-Noreuil et al. Six of these individuals, all with PS, were treated with miransertib in a research project being run by the U.S. Presently, 29 participants with either PS or PROS haveīeen treated with miransertib in two ongoing research projects and under compassionate use programs (B Schwartz, unpubl. The only available alternative treatments of PS are palliative. More recently, metastatic tumors and some skeletal deformities improved after 22 mo of treatment of a teenager with PSĪnd metastatic ovarian cancer ( Leoni et al. An abstract describing patients with ovarian cancers bearing PIK3CA or AKT1 variants treated with miransertib reported favorable efficacy and side effects ( Hyman et al.
Patients with PIK3CA-related overgrowth syndrome (PROS) and PS ( Lindhurst et al.
In in vitro and in vivo experiments, it demonstrated antiproliferative activity in cancer and in cells derived from Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor that inhibits both active and inactive forms AKT1 is a serine-threonine kinase that participates in the AKT/PI3K/mTOR pathway: The p.Glu17Lys variant constitutivelyĪctivates the protein, limiting apoptosis and promoting growth, among other effects ( Carpten et al. It makes weight-bearing and footwear uncomfortable, and hygiene is difficultĪ somatic variant in the AKT1 gene-c.49G > A, p.Glu17Lys-is the only reported cause of PS ( Lindhurst et al. Is a specific, but not pathognomonic finding. The cerebriform connective tissue nevus (CCTN) of the soles found in many patients Common syndromic manifestations include large superficial or deep lipomatous overgrowths, intellectual disability, seizuresĪnd other neurological problems, and severe skeletal deformities with skull overgrowth, kyphoscoliosis, asymmetric macrodactylyĪnd valgus, or varus deformities of the knees. 2011), or malignant transformation in an overgrown tissue such as a parotid tumor, ovarian cystadenoma, or testicular tumor ( Cohen 2005). 2017), respiratory disease associated with pulmonary cysts ( Newman et al. 2017), either by distortion or compression of vital structures by overgrown tissues, thromboembolism ( Keppler-Noreuil et al. It is progressive and causes death ( Sapp et al. Patients with Proteus syndrome (PS) have severe, progressive overgrowth that can affect nearly any region of the body ( Biesecker 2006). Previous Section Next Section INTRODUCTION neoplasia of the male external genitalia.attention deficit hyperactivity disorder.abnormal subcutaneous fat tissue distribution.We conclude that 1 yr of treatment with miransertib was beneficial in this case. Stable without apparent disease progression. Improved general well-being, increased mobility of the ankle, spine, and hands, a subjective decrease in size of the rightįacial bone overgrowth, and reduced areas of cerebriform connective tissue nevi on the soles. After 11 mo of treatment, the patient reported Adverse events included dry mouth, one episode of gingivostomatitis, and loose, painful dentitionĭue to preexisting periodontal disease, all of which resolved spontaneously.
Unblinded treatment of 10 mg oral miransertib daily (∼5 mg/m 2/day), escalated to 30 mg daily (∼15 mg/m 2/day), and then to 50 mg daily (∼25 mg/m 2/day) after 3 mo of treatment. After baseline evaluation, the patient started Miransertib (ARQ 092) is an oral, allosteric, selective pan-AKT inhibitor initiallyĭeveloped for cancer therapeutics, now being evaluated for the treatment of PS. With thoracolumbar scoliosis, dilatation of the inferior vena cava, testicular cystadenoma, bilateral knee deformities, macrodactyly,Īnd apparent intellectual disability. A 20-yr-old man with Proteus syndrome (PS) and somatic mosaicism of the AKT1 c.49G > A p.(E17K) variant had asymmetric overgrowth of the right frontal and facial bones, asymmetric spinal overgrowth
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