At a glance a summary of our key research activities are as follows:
As of July 2024 a total of approximately £21.7 million in funding has been committed for research, with individual funding in the range of £10,000 – £1,000,000+, and we are actively seeking new funding applications.
On this page is a summary of our current and completed projects with links to case studies, and a list of publications.
Current projects include:
Type of study: Clinical – natural history
Description: Retrospective analysis of data from a European cohort of PHTS patients to understand outcomes for those PHTS patients who develop cancer. The INSPECT study.
Description: Develop a UK PHTS patient registry to allow for the collection of high-quality clinical and epidemiological data to better understand PHTS.
Type of study: Clinical – classification system development
Description: Validation of a PHTS specific classification system for vascular anomalies through radiologic/pathologic review of cases by international experts. This grant has been developed by the members of our Vascular anomalies Clinical Development Working Group.
Type of study: Clinical – better describe the neurological characteristics of PHTS
Description: Generation of a clinical picture of the neurological characteristics of PHTS to support a more sophisticated understanding of the disease phenotype, to develop clinical management guidelines and meaningful clinical trial endpoints.
Type of study: Clinical – guideline development
Description: This grant provides funds for a research assistant supporting the development of PHTS Management Guidelines by a multidisciplinary working group of PHTS experts and other key stakeholders.
Type of study: Pre-clinical – PHTS model
Description: Generate patient-derived iPSC lines to support future research on treatments.
Type of study: Clinical – natural history and translational
Description: Perform whole genome sequencing of a cohort of PHTS patients to assess how genetic variation contributes to phenotypic differences in people with PHTS.
Description: Repurposing studies focused on testing small molecule inhibitors of the PI3K pathway in pre-clinical models of PHTS vascular malformations, tissue overgrowth and oncology.
Description: Repurposing studies focused on testing small molecule inhibitors of the PI3K pathway in pre-clinical models of PHTS neurodevelopmental delay.
Type of study: Pre-clinical – PHTS model and translational
Description: Develop models of vascular malformation associated with PHTS to better understand their pathobiology and the contribution of various signalling molecules/pathways, and to test potential therapeutics.
Type of study: Pre-clinical – translational
Description: Assess the ability of potential therapeutics targeting the various nodes of the PI3K pathway to prevent cancer development in pre-clinical models of PHTS.
Type of study: Basic research
Description: Validation, using pre-clinical models of PHTS, of a novel target as a potential novel therapeutic strategy for PHTS.
Type of study: Basic Research
Description: Study of non-canonical functions of PTEN (mTOR-independent mechanism) and their impact on neuronal activity in pre-clinical models of PTEN loss in the brain, with the aim of developing novel and more efficient drug treatments to cognitive deficits in PHTS patients.
Type of Study: Basic Research
Description: Study to investigate how PHTS-associated missense variants impact PTEN function and contribute to PHTS pathophysiology and distinct disease states, facilitating the identification of targets for development of novel therapeutics.
Type of study: Pre-clinical - Translational
Description: Utilise novel pre-clinical and patient derived models of PTEN deficiency in the brain to evaluate a class of drugs called Flt3 kinase inhibitors and assess their potential future use as treatment of the neurological manifestations of PHTS.
Type of study: Clinical – enhancing diagnosis of PHTS
Description: Development and validation of the first computational phenotype for identifying adult individuals who may benefit from PTEN genetic testing based on electronic medical record information.
Type of study: Clinical – enhancing diagnosis of PHTS
Description: The assessment of immunohistochemistry (IHC) staining of PTEN in non-malignant tissue samples for early detection of individuals who would benefit from genetic PTEN testing. This collaborative grant has been developed by the members of our Oncology and Overgrowth Clinical Development Working Group.
Type of study: Pre-clinical – PHTS model and translational
Description: Integrate preclinical studies and clinical observations to pinpoint the cellular and genetic origins of PTEN-related vascular anomalies, mapping the molecular role of each vascular cell lineage and assessing environmental triggers of lesion formation.
Past projects include:
Type of study: Various
Description: PHTS registry and biorepository, Longitudinal study, Stem cells, Mouse Models and Eye Tracking in ASD.
Publications:
Yehia et al. PTEN-opathies: from biological insights to evidence-based precision medicine. J Clin Invest. 2019 Feb 1;129(2):452-464. doi: 10.1172/JCI121277
Yehia et al. PTEN hamartoma tumour syndrome: what happens when there is no PTEN germline mutation? Hum Mol Genet. 2020 Oct 20;29(R2):R150-R157. doi: 10.1093/hmg/ddaa127
Mighell et al. An Integrated Deep-Mutational-Scanning Approach Provides Clinical Insights on PTEN Genotype-Phenotype Relationships. Am J Hum Genet. 2020 Jun 4;106(6):818-829.doi: 10.1016/j.ajhg.2020.04.014
Yehia et al. Copy Number Variation and Clinical Outcomes in Patients With Germline PTEN Mutations. JAMA Netw Open. 2020 Jan 3;3(1):e1920415. doi: 10.1001/jamanetworkopen.2019.20415
Jia et al. Interplay Between Class II HLA Genotypes and the Microbiome and Immune Phenotypes in Individuals With PTEN Hamartoma Tumor Syndrome. JCO Precis Oncol. 2021 Feb 9;5:PO.20.00374. doi: 10.1200/PO.20.00374
Yehia et al. Distinct metabolic profiles associated with autism spectrum disorder versus cancer in individuals with germline PTEN mutations. NPJ Genom Med. 2022 Mar 3;7(1):16. doi: 10.1038/s41525-022-00289-x
Type of study: Basic research
Description: Characterisation of the biochemical properties of PTEN missense protein.
Type of study: Basic research
Description: Dataset characterising biochemical properties of PTEN mutants associated with ASD or cancer.
Type of study: Clinical – natural history
Description: Assessing the prevalence of PTEN mutations in Turkish children. The prevalence of PTEN mutations in a cohort of 131 patients with ASD and macrocephaly was 3.8% (VUS included) or 2.29% (VUS omitted).
Publications:
Kaymakcalan et al. Prevalence and clinical/molecular characteristics of PTEN mutations in Turkish children with autism spectrum disorders and macrocephaly. Mol Genet Genomic Med. 2021 Aug;9(8):e1739 doi: 10.1002/mgg3.1739
Type of study: Pre-clinical – translational
Description: The foundation has carried out a study with Imagen Therapeutics utilising their imaging technology to investigate the response of PTEN wild type and homozygous PTEN loss mouse embryonic fibroblasts to small molecule inhibitors targeting the PI3K signalling pathway. In addition to the PI3K pathway targeted agents, Imagen also tested their collection of oncology standard of care inhibitors and identified some unexpected differential sensitivity in the PTEN loss cells. These inhibitors have been incorporated into the ongoing studies in PHTS drug repurposing screens with our CRO partners.
Type of study: Clinical – natural history
Description: Survey done by Trinity Partners based on interviews of 22 patients/caregivers and 10 clinicians to understand the PHTS patient journey. The results emphasized the fact that each PHTS patient journey is unique but that there are certain manifestation combinations such as developmental delay combined with macrocephaly that leads to quicker diagnosis whereas patients with milder symptoms often go undiagnosed. The survey also identified challenges such as the uncertainty of cancer risk affecting the quality of life of patients. Other challenges identified included lack of physician awareness of PHTS and lack of patient-specific resources although Facebook groups were identified as the most helpful way for patients to find information and share their experience. Many patients and caregivers would be receptive to trying novel treatment options targeting PHTS.
Type of study: Translational medicine
Description: Cancer prevention with rapamycin in PHTS mouse model.
Publications:
Tibarewal P et al. Long‐term treatment of cancer‐prone germline PTEN mutant mice with low‐dose rapamycin extends lifespan and delays tumour development. The J Pathol. 2022; 258(4), 382–394. doi: 10.1002/path.6009
Type of study: Clinical – natural history
Description: Retrospective analysis of data from a European cohort of PHTS patients to refine the risk of cancer and the occurrence of other manifestations associated with PHTS.
Description: Phase I/II 6-month, randomized, double-blind placebo-controlled trial of everolimus in individuals, ages 5 to 45 years with a PTEN mutation, with safety and neurocognition as the primary endpoints. NCT02991807
Publications:
Hardan et al. A randomized double-blind controlled trial of everolimus in individuals with PTEN mutations: Study design and statistical considerations. 2021 Contemporary Clinical Trials Communications, 21.doi: 10.1016/j.conctc.2021.100733
Srivastava et al. A randomized controlled trial of Everolimus for neurocognitive symptoms in PTEN hamartoma tumor syndrome. Human Molecular Genetics 2022.doi: 10.1093/HMG/DDAC111
Type of Study: Basic Research
Description: Characterise a series of PTEN antibodies to develop new research tools to better define and understand the biology and function of PTEN
Publications:
Torices et al. Functional analysis of PTEN variants of unknown significance from PHTS patients unveils complex patterns of PTEN biological activity in disease. Eur J Hum Genet. 2023 May; 31(5):568-577. doi: 10.1038/s41431-022-01265-w
Type of study: Pre-clinical - PHTS model
Description: Develop and characterise a novel pre-clinical model of PTEN loss in the brain for testing of potential therapeutics.
Type of study: Clinical – tool development
Description: Adapting and refining existing neurobehavioural instruments for use in the PHTS population.
Uljarević, M., Cai, R. Y., Hardan, A. Y., & Frazier, T. W. (2023). Development and validation of the Executive Functioning Scale. Frontiers in Psychiatry, 13. doi: 10.3389/fpsyt.2022.1078211
Uljarević, M., Spackman, E. K., Cai, R. Y., Paszek, K. J., Hardan, A. Y., & Frazier, T. W. (2023). Daily living skills scale: Development and preliminary validation of a new, open-source assessment of daily living skills. Frontiers in Psychiatry, 13. doi: 10.3389/fpsyt.2022.1108471
Type of study: Clinical – tool development
Description: Develop a novel online tool for neurobehavioural evaluation of PHTS patients. NCT05671107
Recruitment of participants for this study was supported by individual grants to the University Hospital Southampton NHS Foundation trust, UK and Cleveland Clinic, USA.
Frazier, T. W., Busch, R. M., Klaas, P., Lachlan, K., Jeste, S., Kolevzon, A., … Uljarević, M. (2023). Development of informant‐report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes. American Journal of Medical Genetics Part A. doi: 10.1002/ajmg.a.63195
Frazier, T. W., Busch, R. M., Klaas, P., Lachlan, K., Jeste, S., Kolevzon, A., … Uljarević, M. (2023). Development of webcam‐collected and artificial‐intelligence‐derived social and cognitive performance measures for neurodevelopmental genetic syndromes. American Journal of Medical Genetics Part C: Seminars in Medical Genetics. doi: 10.1002/ajmg.c.32058
Type of study: Interventional clinical trial
Description: Phase II, 1-year, open-label, pilot study to examine the effects of sirolimus on colon polyp burden in Cowden syndrome. NCT04094675
Publications
Listed here are publications associated with the projects identified on our website, or related activities in which PTEN Research (or its forerunner organisation) have been acknowledged.
