Miransertib and the PI3K/AKT pathway: an emerging therapeutic approach for Proteus syndrome

Introduction

Proteus syndrome is a rare disorder characterized by disproportionate overgrowth of the limbs, multiple hamartomas, and vascular malformations. Cerebriform connective tissue nevi, also known as cerebriform plantar hyperplasia, are present in most patients and constitute the main hallmark of the syndrome. When present, even in isolation, they may be considered a pathognomonic sign. The syndrome is thought to be associated with mosaicism involving a somatic activating mutation in the AKT1 gene, located on chromosome 14q32.3. Several allelic mutations occur at the locus of the gene responsible for Proteus syndrome, triggering somatic tissue overgrowth.

This syndrome is poorly described, and its estimated prevalence ranges from 1:1,000,000 to 1:10,000,000 inhabitants. Fewer than 100 cases have been reported in the literature. Its rare occurrence justifies this report (Soriano et al., 2017). In this literature review, several confirmed cases of the disease are presented.

Description of the PI3K/AKT1 Pathway in Patients with Proteus Syndrome

Proteus syndrome is related to dysregulation of the PI3K–AKT pathway. On one hand, phosphorylated PI3K activates transcription of vascular endothelial growth factor (VEGF) and expression of hypoxia-inducible factor 1α (HIF1α), promoting angiogenesis, growth, senescence, and other biological processes (Fig. 15), through mechanisms such as those illustrated in Fig. 17 (Pinzón C, Serrano M, Sanabria M, 2009).

The AKT gene encodes a protein involved in regulation of cell growth, division (proliferation), and cell death. AKT phosphorylates cyclin-dependent kinase inhibitors (CKIs) p21^CIP1/WAF1 and p27^KIP1, which translocate to the cytoplasm and are subsequently degraded. CKI proteins exert an antiproliferative effect; therefore, their degradation results in dysregulated and increased cellular proliferation. In addition, AKT inhibits glycogen synthase kinase 3 (GSK3) through phosphorylation, thereby affecting glucose metabolism.

In patients with Proteus syndrome who harbor a somatic mosaic AKT1 mutation (c.49G>A, p.Glu17Lys) (Fig. 16), AKT or PDK remains constitutively active. As a result, regulatory processes within the organism are disrupted due to overproduction of transcription factors and increased cellular growth rates, allowing cells to continue dividing without undergoing apoptosis. The increased proliferation of cells in certain tissues and organs leads to the characteristic features of the syndrome, including abnormal growth and an increased risk of tumor development (National Institutes of Health, 2017).

Description of the Mechanism of Action of Miransertib on the PI3K/AKT Pathway

The drug miransertib binds to the allosteric site of the AKT protein, interfering with its activation and preventing its phosphorylation, thereby reducing downstream signaling throughout the PI3K/AKT pathway. This drug inhibits both the active and inactive forms of AKT, effectively preventing its activation and reducing phosphorylation of proteins involved in cellular growth in patients with Proteus syndrome.

Similarly, AKT blockade promotes apoptosis and prevents positive feedback activation of PI3K.

In the context of Proteus syndrome, this reduction in AKT activity has demonstrated efficacy in slowing excessive tissue growth and improving clinical symptoms.

Description of Treatment With Miransertib in Patients With Proteus Syndrome

Case 1

In the first clinical trial, a daily dose of 5 mg was administered to a group of six patients—three adults and three children—over a one-year period. During this time, a reduction in lesion size was observed, with two patients showing a significant decrease in cerebriform connective tissue lesions (Fig. 8). In addition, stabilization of excessive tissue growth was noted in all treated patients, suggesting a positive therapeutic response in terms of lesion growth control (Fig. 9). These findings were determined through qualitative assessment and visual evaluations, demonstrating differences in growth rates of cerebriform connective tissue nevi (CCTN).

Case 2

In the second trial, a 20-year-old male patient was treated. Following initial evaluation, open-label treatment with miransertib was initiated at an oral daily dose of 10 mg (approximately 5 mg/m²/day). The dose was progressively increased to 30 mg/day (15 mg/m²/day) and, after three months of treatment, adjusted to 50 mg/day (25 mg/m²/day).

After 11 months of treatment, an improvement in the patient’s overall well-being was observed according to the IPI (Fig. 10). Increased mobility of the ankle, spine, and hands was noted, along with a subjective reduction in excessive growth of the right facial bone. A reduction in areas affected by cerebriform connective tissue nevi on the plantar surfaces of the feet was also reported. Whole-body magnetic resonance imaging showed stable findings, with no evidence of apparent disease progression. A total reduction of 14–17% in the CCTN growth area was observed (Fig. 10).

Case 3

The individual is an 18-year-old male who has participated in the Proteus Syndrome Natural History Study (ClinicalTrials.gov NCT00001403) since the age of 6 and enrolled in the pharmacodynamic study at age 13. At enrollment in the phase 1 study (ClinicalTrials.gov NCT02594215), his medical history included leg length discrepancy requiring multiple surgeries, bilateral plantar CCTN, musculoskeletal pain in the lower back and lower extremities, eczema, seasonal allergies, iron deficiency anemia, and irritable bowel syndrome. The mosaic AKT1 variant c.49G>A, p.(Glu17Lys) was identified in cultured fibroblasts from an affected skin biopsy.

After completing the originally planned 48 weeks of miransertib treatment as part of the phase 1 study, the patient requested continuation of therapy due to improvement in pain and deceleration of CCTN growth. The protocol was modified to allow continued use of miransertib in order to evaluate long-term safety and durability of response, including sustained pain reduction and continued slowing of CCTN growth.

A 9-month treatment interruption occurred before miransertib was resumed at a dose of 5 mg/m² once daily. Based on demonstrated safety at doses of 15 mg/m² and 25 mg/m²/day in an industry-sponsored expanded access program and a perceived reduction in effect, the dose was increased to 10 mg/m²/day 16 weeks after resuming treatment. The dose escalation, doubling daily drug exposure, was selected to minimize the risk of adverse events and was based on the dose level used in the original 3+3 phase 1 study design. At the time of publication, the patient continued taking 10 mg/m² (20 mg per dose) daily.

The individual had bilateral plantar CCTN, with the left foot more severely affected than the right. Before initiating miransertib, CCTN affected 39.2% of the left plantar surface and 9.5% of the right plantar surface. After 48 weeks of treatment, involvement increased slightly to 40.3% on the left and 10.5% on the right. Five years after initiating miransertib, CCTN affected 44.6% of the left plantar surface and 15.2% of the right plantar surface (Fig. 13). The annual increase in plantar surface area affected by CCTN during the seven years prior to miransertib treatment was 5.3% and 4.8% on the left and right sides, respectively. During the five years following initiation of miransertib, the annual increase was reduced to 1.2% on both sides.

Case 4

In this case, a 17-year-old female patient was treated with miransertib beginning at 15 years of age. She had been diagnosed with Proteus syndrome shortly after birth due to excessive hand overgrowth, resulting in multiple surgical interventions, including digital amputations in both hands and cervical vertebral fusion, ultimately confining the patient to a wheelchair by the age of 10.

At 13 years of age, she underwent bilateral salpingo-oophorectomy, hysterectomy, and peritoneal staging for low-grade serous ovarian carcinoma, suggestive of a borderline ovarian serous tumor. Twenty months after surgery, pelvic recurrence was reported, associated with pelvic ascites and partial thrombosis of the extrahepatic segment of the portal vein.

Due to potential complications, surgical intervention was not pursued despite the clinical relevance of portal vein involvement. Additionally, given the presence of thrombosis, neither chemotherapy nor hormonal therapy with an aromatase inhibitor was recommended.

In light of the lack of effective standard treatments, experimental therapy was considered, and miransertib was selected. Prior to treatment initiation, computed tomography (CT) revealed a secondary pelvic neoplastic mass (sum of diameters: 52 mm) and multiple peritoneal implants with moderate-volume ascites.

Treatment was initiated at 15 years and 5 months of age with an initial dose of 50 mg/day for 5 days followed by a 9-day rest period every two weeks. No adverse effects were reported during the first four weeks.

At week 5, the dose was increased to 100 mg/day for 5 days with a 5-day rest period every two weeks.

The first disease assessment performed two months after treatment initiation showed resolution of ascites and a significant reduction in CA-125 levels (38 U/mL), with stable measurable disease. CA-125 levels normalized by week 12.

At week 24, CT imaging demonstrated a partial response (PR) according to RECIST 1.1 criteria, with a marked reduction in pelvic mass size (sum of diameters: 39.2 mm), resolution of peritoneal implants, and complete resolution of portal vein thrombosis (Figure 1B).

Trends in selected laboratory values (CA-125, platelet count, white blood cell count, blood glucose levels) and tumor volume are shown in Figure 3. CT scans performed at 12 and 19 months of treatment confirmed an ongoing PR, with residual pelvic mass volumes of 16.7 mL and 6.6 mL, respectively (Figure 1C, D). At the last follow-up at 22 months of treatment, CT imaging demonstrated complete clinical remission of the secondary lesion.

The patient reported a reduction in plantar CCTN folds on the left foot, increased range of motion in the upper extremities and joints (hands, spine, and knees), and these observations were confirmed by treating physicians during regular visits.

Additionally, the patient reported decreased pain in the spine, hands, and feet. She was ultimately able to transfer independently from her wheelchair to bed and lie in a supine position. Images illustrating overgrowth lesions during overall treatment (hands and feet) are shown in Figure 15.

The results of our study indicate that miransertib, an AKT inhibitor, reduces the size and growth of certain lesions—particularly in tissues with excessive overgrowth—and improves mobility in most patients. A notable reduction in CCTN growth and a decrease in characteristic cutaneous manifestations, such as atypical plantar folds, were observed. Additionally, benefits were reported in pain reduction and stabilization of pulmonary and skeletal conditions.

The data suggest stabilization of abnormal growth progression in patients, highlighting the impact of AKT inhibition on the PI3K/AKT pathway by blocking the atypical activity characteristic of Proteus syndrome.

When compared with previous research, these findings support the therapeutic effect of AKT inhibitors. Prior studies have demonstrated that miransertib can slow the growth of certain lesions, consistent with the results observed in clinical trials.

Mild side effects were reported, including fatigue, nausea, and headache. Adverse events such as dry mouth and one episode of gingivostomatitis were also observed.

Overall, these results suggest that miransertib may represent a viable therapeutic option for symptom management in patients with Proteus syndrome. However, further studies are required to assess its long-term safety and efficacy.

Conclusion

Patients with Proteus syndrome show clinical improvement due to selective inhibition of the PI3K/AKT pathway by miransertib, whose mechanism of action involves blocking the abnormally elevated activity of AKT1—a key driver of dysregulated cellular growth and proliferation in Proteus syndrome. Administration of miransertib not only slowed lesion growth but also improved mobility and stabilized associated symptoms such as pain and pulmonary and skeletal complications, reinforcing the therapeutic potential of AKT inhibitors in this context.

However, considering the results obtained and the limitations of our study, we propose conducting longer-term studies with larger patient cohorts to evaluate the sustained safety and effectiveness of miransertib. We also suggest exploring combination therapies involving miransertib and other targeted agents to enhance therapeutic efficacy and mitigate potential adverse effects.

Finally, it would be important to investigate the existence of specific biomarkers capable of predicting response to AKT inhibitor therapy, which would enable a more personalized and effective treatment approach for patients with Proteus syndrome.