Drug Trials for PROS (PIK3CA Related Overgrowth Spectrum)

• The various cells in our bodies usually follow a particular lifespan, this is the same for the growth gene PIK3CA. A normal cell will undergo a rapid death should anything become altered or damaged.
• However, if through mutation this PIK3CA gene does not die or “switch off” they become known as “oncogenes.”
• This means that the gene has the potential to cause cancer & tumour progression. however, this does not seem to be common place in PROS patients.
• This link to cancer has led to an increase in research to find potential (non-invasive) treatment for cancer patients, but which could also benefit PROS patients.

2016: Cancer drug could treat blood vessel deformities

• Conclusion of the study suggests that “Rapamycin is a drug that blocks a signalling process that happens downstream of PIK3CA, so it stops one of PIK3CA’s effects but does not block it at source,” explains lead author Dr Sandra Castillo (UCL Cancer Institute). “When we gave rapamycin to the mice, it showed clinical benefit, but in patients it can have serious side-effects and compromise the immune system”.

2017: ArQule Announces First Patient Dosed in Company Sponsored Phase 1/2 Trial of AKT Inhibitor, ARQ 092, for Rare Overgrowth Diseases

• ArQule announced that the first patient has been dosed in a company sponsored phase 1/2 trial with its AKT inhibitor, ARQ 092, in patients with Overgrowth Diseases driven by genetic alterations of the PI3K/AKT1 pathway. ARQ 092 is an orally available, selective pan-AKT inhibitor.

2017: Study of ARQ 092 in Subjects With PIK3CA-related Overgrowth Spectrum and Proteus Syndrome (MOSAIC)

• Details of the study: “this is an open label, Phase 1/2 study of oral ARQ 092 (Miransertib) administered to subjects at least 2 years of age with PIK3CA-related Overgrowth Spectrum (PROS) and Proteus syndrome (PS) (MOSAIC)”.

2017/2018: Severe PI3Kinase Overgrowth Syndrome Treated with the AKT Inhibitor Miransertib

• Results indicated as follows: “calculated volumes of fatty overgrowth declined by approximately 15% on treatment. The patient has now completed 25 months of therapy with clinically stable disease and clear radiological improvement. Miransertib was well tolerated with no significant toxicities other than hyperlipidaemia comparable to lipid profile derangement previously noted on sirolimus therapy”.

2017: Trial of Taselisib in Overgrowth (TOTEM)

• “Taselisib is a selective inhibitor of class I PI3Ks and has direct inhibitory activity of the p110α isoform with a Kiapp value of 0.29 nmol/l”. Unfortunately the trial was: “Terminated (In accordance with the protocol, following the occurrence of two SUSARs, the TOTEM trial was stopped early for safety reasons.)”

2018: In vitro efficacy of ARQ 092, an allosteric AKT inhibitor, on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS)

• Results from the trial suggest: “we demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.”

• Results showed: “BYL719 was used to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.

• Results from this study offer the following thoughts: “This study suggests that low-dose sirolimus can modestly reduce overgrowth, but cautions that the side-effect profile is significant, mandating individualized risk–benefit evaluations for sirolimus treatment in PROS.”
• As a side note, I (Mandy Sellars) began taking Rapamycin a number of years ago with amazing results. Along with a combination of exercise & healthy eating, my overgrowth stopped & began to shrink. I lost around 4/5 stone in weight from my affected areas. Unfortunately my body became tolerant of the dosage I was taking & it was recommended not to increase the dose. Therefore, sadly I had to stop taking the medication & my overgrowth started to increase again.

• An overview of research in the UK from Professor R Semple.

2019: Managed Access Program (MAP) to Provide Alpelisib (BYL719) for Patients With PIK3CA-Related Overgrowth Spectrum (PROS)

• • The purpose of the study is “to allow access to alpelisib for patients diagnosed with PIK3CA-Related Overgrowth Spectrum (PROS) who fulfill certain eligibility criteria as specified in this document. The patient’s Treating Physician should follow the suggested treatment guidelines and comply with all local health authority regulations.”
  • To reiterate, this drug is available on “compassionate use” only. Please speak to your specialist/consultant who will hopefully be able to help you with this.
  • You can also contact Novartis for more information: mailto:novartis.email@novartis.com

2020: Retrospective Chart Review Study of Patients With PIK3CA-Related Overgrowth Spectrum Who Have Received Alpelisib (EPIK-P1)

• This retrospective study aims to determine the effectiveness & safety of the drug Alpelisib. This was administered to patients through the “compassionate use” scheme for the treatment of PROS (PIK Related Overgrowth Spectrum)
• Results of this study should be available July/August 2020. Should the results be favourable, this could hopefully lead to medical trials of Alpelisib for PROS patients.

2020: https://www.sciencedirect.com/science/article/pii/S0006291X2030886X

• PIK3CA-related overgrowth spectrum is characterized by increased cell proliferation.
• Strong activation of HSF1 is found in PIK3CA-related overgrowth spectrum fibroblasts.
• AKT inhibitors reduces HSF1 activation and HSF1-dependent gene transcription.
• HSF1 inhibition blocks the PIK3CA-related overgrowth spectrum proliferation.
• As there is currently no curative treatment for PIK3CA-related overgrowth spectrum, our results identify HSF1 as a new potential therapeutic target.

2020: Novartis receives Piqray approval in Europe – the first and only targeted medicine for HR+/HER2- advanced breast cancer with a PIK3CA mutation

• Piqray (alpelisib) is the only treatment approved specifically to address PIK3CA mutation
• This is very promising for those living with a PIK3CA mutation that is causes overgrowth, trials are in the pipeline.

2020: https://www.fiercepharma.com/pharma/esmo-novartis-posts-long-awaited-survival-data-for-breast-cancer-blockbuster-hopeful-piqray

• Novartis has an ambitious development plan for the drug going forward. It’s preparing to file for approval in patients with a rare disorder called PIK3CA overgrowth syndrome.

2020: https://clinicaltrials.gov/ct2/show/NCT04409145

• VT30-101 is a 2-part first-in-human trial of topically administered VT30 to subjects with cutaneous venous malformations, lymphatic malformations, or mixed venolymphatic malformations associated with PIK3CA or TEK mutations.
• VT30 is a PI3K-inhibitor prodrug, formulated as a topical gel and dispensed from a metered dose pump; administration is once or twice daily, applied to target-treatment area(s) on the skin.

2020: https://clinicaltrials.gov/ct2/show/NCT04589650?cond=PIK3CA+Related+Overgrowth+Spectrum&draw=2&rank=2

• This is a prospective Phase II multi-center study with an upfront 16-week, randomized, double-blind, placebo-controlled period, and extension periods, to assess the efficacy, safety and pharmacokinetics of alpelisib in pediatric and adult participants with PIK3CA-related overgrowth spectrum (PROS).
• Study start date: February 2, 2021
• For further information: mailto:novartis.email@novartis.com

2020: What is Apelisib

2020: Characterization and Childhood Tumor Risk Assessment of Genetic and Epigenetic Syndromes Associated With Lateralized Overgrowth

• We suspect that it is likely that the overall risk falls below 1%
• There is a clear need for further publication of known cases and collaboration among institutions, so the denominator of patients with PROS can be further adjusted to understand true WT risk in this population.
• In terms of current recommendations, tumor screening should be performed at the discretion of the provider based on the genetic change and clinical features of the PROS presentation, as well as the family perspective.

2021: https://link.springer.com/article/10.1007/s00109-020-02030-6#Fig1

• Recently, this drug was used by us for one such case, that of a 29-year-old Canadian woman, and led to a spectacular response.
• During the last years, moreover, ~ 60 patients were treated for PROS with this drug under the care of Dr. Guillaume Canaud at Necker–Enfants Malades Hospital, and all have experienced regression over their overgrowths.

2021: https://comptes-rendus.academie-sciences.fr/biologies/articles/10.5802/crbiol.50/

• PIK3CA-related overgrowth spectrum: animal model and drug discovery
• This review recapitulates the recent knowledge accumulation on overgrowth syndrome related to gain of function of the phosphoinositide3 kinase (PI3K)-alpha. These disorders, known as PIK3CA related overgrowth syndromes (PROS) are caused by somatic PIK3CA mutation occurring during embryogenesis. We summarize here the currently available animal models and new treatments undergoing development.

2021: https://ojrd.biomedcentral.com/articles/10.1186/s13023-021-01929-8

• A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations.

• PIK3CA-related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result in activation of the PI3K/AKT/mTOR signaling pathway. The goals of this review are to provide education on the underlying mechanism of disease for this group of rare conditions and to summarize recent advancements in the understanding of, as well as current and emerging treatment options for PIK3CA-related disorders.
• Management of patients with PIK3CA-related disorders requires a multidisciplinary approach. Further results from ongoing clinical studies of agents targeting the PI3K pathway are highly anticipated.

2021: A standard of care for individuals with PIK3CA-related disorders: an international expert consensus statement

• Growth promoting variants in PIK3CA cause a spectrum of developmental disorders, depending on the developmental timing of the mutation and tissues involved. These phenotypically heterogeneous entities have been grouped as PIK3CA-Related Overgrowth Spectrum disorders (PROS). Deep sequencing technologies have facilitated detection of low-level mosaic, often necessitating testing of tissues other than blood. Since clinical management practices vary considerably among healthcare professionals and services across different countries, a consensus on management guidelines is needed. Clinical heterogeneity within this spectrum leads to challenges in establishing management recommendations, which must be based on patient-specific considerations. Moreover, as most of these conditions are rare, affected families may lack access to the medical expertise that is needed to help address the multi-system and often complex medical issues seen with PROS. In March 2019, macrocephaly-capillary malformation (M-CM) patient organizations hosted an expert meeting in Manchester, United Kingdom, to help address these challenges with regards to M-CM syndrome. We have expanded the scope of this project to cover PROS and developed this consensus statement on the preferred approach for managing affected individuals based on our current knowledge.

2021: Novartis announces findings from a real-world study of alpelisib

• Novartis announces findings from a real-world study of alpelisib demonstrating clinical benefit in people with PIK3CA-Related Overgrowth Spectrum (PROS)

• PROS is a spectrum of rare disorders caused by PIK3CA mutations and is characterized by atypical, visible overgrowths and anomalies in blood vessels, the lymphatic system and other tissues.
• At 24 weeks, 38% of patients achieved ≥20% reduction in the volume of the PROS lesions assessed in the primary endpoint analysis; no patients experienced disease progression or death.
• Alpelisib is the first potential treatment to specifically address the root cause of PROS conditions.

2021: https://www.science.org/doi/10.1126/scitranslmed.abg0809#.YV54vSeHixo.twitter

• Gain-of-function mutations in the PIK3CA gene cause lymphatic malformations (LMs), genetic disorders characterized by vascular abnormalities causing pain, inflammation, and deformities. To identify potential treatments able to prevent LMs, Delestre et al. developed a genetic mouse model that recapitulates the main features of LMs and showed that the approved drug PIK3CA inhibitor alpelisib, used in oncology, prevented LMs, and increased survival. Alpelisib administration in six patients refractory to previous pharmacological or surgical approaches improved symptoms and reduced the volume of LMs. Although two patients developed adverse events potentially related to the treatment, the results suggest that inhibiting PIK3CA could be effective in treating LMs.

2021:  Positive correlation between transcriptomic stemness and PI3K/AKT/mTOR signaling scores in breast cancer, and a counterintuitive relationship with PIK3CA genotype

• A PI3Kα-selective inhibitor has recently been approved for use in breast tumors harboring mutations in PIK3CA, the gene encoding p110α. Preclinical studies have suggested that the PI3K/AKT/mTOR signaling pathway influences stemness, a dedifferentiation-related cellular phenotype associated with aggressive cancer. However, to date, no direct evidence for such a correlation has been demonstrated in human tumors. In two independent human breast cancer cohorts, encompassing nearly 3,000 tumor samples, transcriptional footprint-based analysis uncovered a positive linear association between transcriptionally-inferred PI3K/AKT/mTOR signaling scores and stemness scores. Unexpectedly, stratification of tumors according to PIK3CA genotype revealed a “biphasic” relationship of mutant PIK3CA allele dosage with these scores. Relative to tumor samples without PIK3CA mutations, the presence of a single copy of a hotspot PIK3CA variant was associated with lower PI3K/AKT/mTOR signaling and stemness scores, whereas the presence of multiple copies of PIK3CA hotspot mutations correlated with higher PI3K/AKT/mTOR signaling and stemness scores. This observation was recapitulated in a human cell model of heterozygous and homozygous PIK3CA^H1047R expression. Collectively, our analysis (1) provides evidence for a signaling strength-dependent PI3K-stemness relationship in human breast cancer; (2) supports evaluation of the potential benefit of patient stratification based on a combination of conventional PI3K pathway genetic information with transcriptomic indices of PI3K signaling activation.

2022:  Treatment of two infants with PIK3CA-relatedovergrowth spectrum by alpelisib.

• PIK3CA-related overgrowth spectrum (PROS) includes rare genetic conditions due to gain-of-function mutations in the PIK3CA
  There is no approved medical therapy for patients with PROS, and alpelisib, an approved PIK3CA inhibitor in oncology,
  showed promising results in preclinical models and in patients. Here, we report for the first time the outcome of two infants
  with PROS having life-threatening conditions treated with alpelisib (25 mg) and monitored with pharmacokinetics. Patient
  1 was an 8-mo-old girl with voluminous vascular malformation. Patient 2 was a 9-mo-old boy presenting with asymmetrical
  body overgrowth and right hemimegalencephaly with West syndrome. After 12 mo of follow-up, alpelisib treatment was
  associated with improvement in signs and symptoms, morphological lesions and vascular anomalies in the two patients. No
  adverse events were reported during the study. In this case series, pharmacological inhibition of PIK3CA with low-dose alpelisib
  was feasible and associated with clinical improvements, including a smaller size of associated complex tissue malformations
  and good tolerability.

2022: PIK3CA mutation correlates with mTOR pathway expression but not clinical and pathological features in Fibfibroipose vascular anomaly (FAVA)

• There was no significant association between the presence of PIK3CA mutations and the clinicopathological features of FAVA, suggesting that the PIK3CA gene is not necessarily involved in the onset of FAVA. FAVAs lacking PIK3CA mutations may be caused by other gene mutations that activate 4EBP1 and S6K1.

2022: Genotypes and phenotypes heterogeneity in PIK3CA-related overgrowth spectrum and overlapping conditions: 150 novel patients and systematic review of 1007 patients with PIK3CA pathogenetic variants

• We confirm that (1) molecular diagnostic yield increases when multiple tissues are tested and by enriching NGS panels with genes of overlapping ‘vascular’ phenotypes; (2) strongly activating PIK3CA variants are found in affected tissue, rarely in blood: conversely, weakly activating mutations more common in blood; (3) weakly activating variants correlate with CNS involvement, strong variants are more common in cases without; (4) patients with vascular malformations overlapping those of PROS can harbour variants in genes other than PIK3CA.

2022: Alpelisib to treat CLOVES syndrome, a member of the PIK3CA-related overgrowth syndrome spectrum

• CLOVES syndrome is a rare congenital overgrowth disorder caused by mutations in the phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene. It is part of the PIK3CA-related overgrowth syndrome (PROS) spectrum and its treatment is challenging. PROS malformations have traditionally been treated by surgery, but research into pharmacological treatments capable of blocking the PIK/AKT/mTOR pathway has increased over the past decade. The results have been promising and suggest that compassionate use of these treatments in patients with PROS disorders could have clinical benefits. Another promising drug is alpelisib (BYL719), which is a selective inhibitor that competitively binds to the p110a subunit of PIK3 in the intracellular PI3K/AKT signalling pathway. Compassionate use of low-dose alpelisib had striking effects in an uncontrolled case series of 19 PROS patients, several with life-threatening complications. Moreover, there were few adverse effects and the treatment did not impair linear growth, despite the young age of many of the patients. We present the case of a patient with CLOVES syndrome who was started on compassionate treatment with alpelisib after surgical debulking of a cystic lymphangioma and treatment with sirolimus. This promising drug significantly reduced the size of the lymphangioma and prevented progression of the tissue overgrowth in the gluteal region. This case suggests that low-dose PI3K inhibition may provide collateral benefits that extend beyond mitigation of disease-specific features of PROS.

2022: FDA approves Novartis Vijoice® (alpelisib) as first and only treatment for select patients with PIK3CA-Related Overgrowth Spectrum (PROS)

• Vijoice is first approved treatment to specifically address the root cause of PROS conditions in select patients 2 years of age and older¹
• PROS is a spectrum of rare conditions and is characterized by atypical overgrowths and anomalies in blood vessels, the lymphatic system and other tissues^2,3  
  
• Approval based on real-world data from EPIK-P1 study, which showed patients treated with Vijoice experienced reduction in the size of PROS lesions and improvement of PROS-related signs and symptoms
• Novartis to offer robust patient support program that includes assistance to access medication, financial resources for eligible patients and continued education

2022: Sexual Function and Fertility in Males With Vascular Malformations of the Genitourinary Tract and Pelvis

• Males with VM involving or not involving the GU system may experience problems with sexual function and satisfaction. While prospective studies are needed to clarify the prevalence and extent of these symptoms, providers should be aware that such symptoms can occur in this patient population.

2022: Clinical Response to PI3K-α Inhibition in a Cohort of Children and Adults With PIK3CA-Related Overgrowth Spectrum Disorders

2022: Alpelisib Displays Clinical Benefit in Pediatric PIK3CA-Related Overgrowth Spectrum Disease

• Alpelisib decreased the need for surgery and led to improvements in performance status and disease-related signs and symptoms in pediatric patients with PIK3CA-related overgrowth spectrum disease who received treatment with the PI3K inhibitor under compassionate use.

2022: Clinical and genetic analyses of patients with lateralized overgrowth

2022: Clinical and genetic analysis of patients with segmental overgrowth features and somatic mammalian target of rapamycin (mTOR) pathway disruption: Possible novel clinical issues

• Segmental overgrowth syndromes include a group of clinical entities, all characterized by the abundant proliferation of tissues or organs in association with vascular abnormalities. These syndromes show a wide spectrum of severity ranging from limited involvement of only small areas of the body to complex cases with impressive distortions of multiple tissues and organs. It is now clear that somatic mutations in genes of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway (in brief “mTOR pathway”) are responsible for such entities. Not all the cells of the body carry the same causative mutation, which is mosaic, appearing from two (or more) distinct cell lineages after fertilization. In this article, we reconsider the clinical spectrum and surveillance programs of patients with segmental overgrowth syndromes, based on the features of six patients with diverse clinical forms of overgrowth and pathogenic variants in genes of the mTOR pathway.

2022: PIK3CA gain-of-function mutation in adipose tissue induces metabolic reprogramming with Warburg-like effect and severe endocrine disruption

• PIK3CA-related overgrowth syndrome (PROS) is a genetic disorder caused by somatic mosaic gain-of-function mutations of PIK3CA. Clinical presentation of patients is diverse and associated with endocrine disruption. Adipose tissue is frequently involved, but its role in disease development and progression has not been elucidated. Here, we created a mouse model of PIK3CA-related adipose tissue overgrowth that recapitulates patient phenotype. We demonstrate that PIK3CA mutation leads to GLUT4 membrane accumulation with a negative feedback loop on insulin secretion, a burst of liver IGFBP1 synthesis with IGF-1 sequestration, and low circulating levels. Mouse phenotype was mainly driven through AKT2. We also observed that PIK3CA mutation induces metabolic reprogramming with Warburg-like effect and protein and lipid synthesis, hallmarks of cancer cells, in vitro, in vivo, and in patients. We lastly show that alpelisib is efficient at preventing and improving PIK3CA-adipose tissue overgrowth and reversing metabolomic anomalies in both animal models and patients.

2023: Response to sirolimus in capillary lymphatic venous malformations and associated syndromes: Impact on symptomatology, quality of life, and radiographic response

• Capillary lymphatic venous malformations (CLVM) and associated syndromes, including Klippel–Trenaunay syndrome (KTS) and congenital lipomatous overgrowth, vascular malformation, epidermal nevi, skeletal, and spinal syndrome (CLOVES), are underrecognized disorders associated with high morbidity from chronic pain, recurrent infections, bleeding, and clotting complications. The rarity of these disorders and heterogeneity of clinical presentations make large-scale randomized clinical drug trials challenging. Identification of PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [gene]) mutations in CLVM has made targeted medications, such as sirolimus, attractive treatment options. The aim of this study was to investigate the safety and efficacy of sirolimus therapy in CLVM.

2023: Ultrasound-Guided Percutaneous Intercostal Cryoneurolysis for Acute-on-Chronic Pain in CLOVES Syndrome

• Cryoneurolysis is an analgesic method that has been shown to provide extended pain relief in postoperative patients. However, to date, this method has not been described in nonsurgical inpatients with chronic pain experiencing an acute exacerbation. This analgesic modality has the potential to provide pain relief for patients whose expected duration of severe acute pain would outlast that of other regional anesthetic techniques while avoiding opioid escalation and facilitating discharge.

  We present a patient with acute exacerbation of chronic pain from breast ulcerations caused by congenital lipomatous overgrowth, vascular malformations, epidermal nevis, spinal/skeletal anomalies/scoliosis (CLOVES) syndrome that was successfully treated as an inpatient with a portable cryoneurolysis device.

  This is the first reported use of cryoneurolysis in an inpatient setting to treat acute-on-chronic pain in a nonsurgical patient. The authors recommend regional anesthesiologists and acute pain specialists to utilize this technique to provide analgesia in patients with complex pain to facilitate hospital throughput.

2023: The VASCERN-VASCA Working Group Diagnostic and Management Pathways for Venous Malformations

• Objective(s): 

  To elaborate expert consensus patient pathways to guide patients and physicians toward efficient diagnostics and management of patients with venous malformations.

  Methods: 

  VASCERN-VASCA (https://vascern.eu/) is a European network of multidisciplinary centers for Vascular Anomalies. The Nominal Group Technique was used to establish the pathways. Two facilitators were identified: one to propose initial discussion points and draw the pathways, and another to chair the discussion. A dermatologist (AD) was chosen as first facilitator due to her specific clinical and research experience. The draft was subsequently discussed within VASCERN-VASCA monthly virtual meetings and annual face-to-face meetings.

  Results: 

  The Pathway starts from the clinical suspicion of a venous type malformation (VM) and lists the clinical characteristics to look for to support this suspicion. Strategies for subsequent imaging and histopathology are suggested. These aim to inform on the diagnosis and to separate the patients into 4 subtypes: (1) sporadic single VMs or (2) multifocal, (3) familial, multifocal, and (4) combined and/or syndromic VMs. The management of each type is detailed in subsequent pages of the pathway, which are color coded to identify sections on (1) clinical evaluations, (2) investigations, (3) treatments, and (4) associated genes. Actions relevant to all types are marked in separate boxes, including when imaging is recommended. When definite diagnoses have been reached, the pathway also points toward disease-specific additional investigations and recommendations for follow up. Options for management are discussed for each subtype, including conservative and invasive treatments, as well as novel molecular therapies.

  Conclusion: 

  The collaborative efforts of VASCERN-VASCA, a network of the 9 Expert Centers, has led to a consensus Diagnostic and Management Pathways for VMs to assist clinicians and patients. It also emphasizes the role of multidisciplinary expert centers in the management of VM patients. This pathway will become available on the VASCERN website (http://vascern.eu/)

• Results: