RESEARCH

This page is dedicated to research that has been undertaken in to PROS.

Explanations of PROS:

Research papers in to PROS (PIK Related Overgrowth Spectrum)

Drug Trials for PROS (PIK 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 NeckerEnfants 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.