Molecular and Cellular Mechanisms Underlying Pituitary Tumours
Lead Research Organisation:
University College London
Department Name: Institute of Child Health
Abstract
To win the war against cancer, we need to understand not only the events that take place along the way during its development, but also its origins. Advanced cancer usually contains cells that are highly abnormal compared with normal cells in the tissue where the cancer is developing. These cancer cells have the capacity to adapt to different environments and to change their genetic material, which contributes to the development of resistance to anti-cancer treatments. At the initial stages of cancer formation, however, cancer cells are physiologically more normal, carry fewer genetic changes and are easier to target and eliminate. Research aiming to develop new tools for early cancer detection as well as to target cancer cells at the initial stages of tumour formation are needed to boost survival rates and to minimise the damaging effects of both advanced cancer and the intensive treatments required to eradicate it.
To achieve this goal, we need to investigate the initial stages of cancer development, which are difficult to detect in humans, as they mostly go unnoticed. However, animal models, and in particular mice have proven to be excellent tools to understand the origins of cancer. Research from several groups has established a concept, referred to as the 'cancer stem cell paradigm', whereby tissue-specific stem cells are the origins of several tumours and cancers in mice and humans. This model proposes that when normal stem cells become mutated (i.e. the DNA changes in comparison with a normal stem cell), they give rise to cancer stem cells, which can proliferate and give rise to daughter cells that form the tumour. Essentially, cancer stem cells are the cell-of-origin of the tumours, with important implications for cancer treatment. For example, cancer stem cells are often resistant to therapies and although present in very low numbers, they can cause regrowth of the tumour if they are not destroyed. Cancer therapies should therefore aim to target the tumour mass as well as the cancer stem cells.
We have recently generated mouse models for a type of human tumour called adamantinomatous craniopharyngioma (ACP). This is an aggressive tumour that develops in the pituitary gland, an essential organ located under the brain that controls critical physiological functions such as growth, reproduction and metabolism. ACP is the most common pituitary tumour in children and young adults and the third most common brain tumour in children. ACP is associated with a poor quality of life of the patients due to compression or infiltration of the brain and can be fatal. Current treatments are surgery and/or radiotherapy, but these are not ideal and cause long-term side effects in the patients. Typical symptoms of ACP patients include obesity, diabetes mellitus type 2 and total failure of pituitary gland function.
Our research has revealed that pituitary stem cells are central players in the generation of ACP. However, contrary to the cancer stem cell paradigm, when these stem cells are mutated they do not divide and give rise to the tumour, instead they send signals to the surrounding cells, which eventually start proliferating uncontrollably to produce a pituitary tumour. Therefore, mutated stem cells instruct nearby cells to generate a tumour, a novel model that is conceptually different to the cancer stem cell paradigm. In this proposal we aim to investigate the mechanisms underlying this novel role for stem cells in cancer. Our goal is to improve our knowledge on the initial steps of tumour formation using our mouse models. This will lead to better management of ACP patients, and will also have implications in other tumours and cancers in which stem cells may have tumour-inducing capacity.
To achieve this goal, we need to investigate the initial stages of cancer development, which are difficult to detect in humans, as they mostly go unnoticed. However, animal models, and in particular mice have proven to be excellent tools to understand the origins of cancer. Research from several groups has established a concept, referred to as the 'cancer stem cell paradigm', whereby tissue-specific stem cells are the origins of several tumours and cancers in mice and humans. This model proposes that when normal stem cells become mutated (i.e. the DNA changes in comparison with a normal stem cell), they give rise to cancer stem cells, which can proliferate and give rise to daughter cells that form the tumour. Essentially, cancer stem cells are the cell-of-origin of the tumours, with important implications for cancer treatment. For example, cancer stem cells are often resistant to therapies and although present in very low numbers, they can cause regrowth of the tumour if they are not destroyed. Cancer therapies should therefore aim to target the tumour mass as well as the cancer stem cells.
We have recently generated mouse models for a type of human tumour called adamantinomatous craniopharyngioma (ACP). This is an aggressive tumour that develops in the pituitary gland, an essential organ located under the brain that controls critical physiological functions such as growth, reproduction and metabolism. ACP is the most common pituitary tumour in children and young adults and the third most common brain tumour in children. ACP is associated with a poor quality of life of the patients due to compression or infiltration of the brain and can be fatal. Current treatments are surgery and/or radiotherapy, but these are not ideal and cause long-term side effects in the patients. Typical symptoms of ACP patients include obesity, diabetes mellitus type 2 and total failure of pituitary gland function.
Our research has revealed that pituitary stem cells are central players in the generation of ACP. However, contrary to the cancer stem cell paradigm, when these stem cells are mutated they do not divide and give rise to the tumour, instead they send signals to the surrounding cells, which eventually start proliferating uncontrollably to produce a pituitary tumour. Therefore, mutated stem cells instruct nearby cells to generate a tumour, a novel model that is conceptually different to the cancer stem cell paradigm. In this proposal we aim to investigate the mechanisms underlying this novel role for stem cells in cancer. Our goal is to improve our knowledge on the initial steps of tumour formation using our mouse models. This will lead to better management of ACP patients, and will also have implications in other tumours and cancers in which stem cells may have tumour-inducing capacity.
Technical Summary
We have generated and published mouse models of human adamantinomatous craniopharyngioma (ACP) and validated that these are relevant to understand the aetiology and pathogenesis of the human tumours. Using these mice, we have recently uncovered a paracrine model of tumorigenesis, whereby mutated Sox2+ pituitary stem cells secrete signalling factors that act on surrounding cells resulting in cell transformation and tumorigenesis in a non-cell autonomous manner. Our data suggest that cell senescence and low-grade senescence-induced inflammation are critical players in tumour initiation in both mouse and human ACP. Many questions remain unanswered about this novel mechanism of oncogenesis:
(i) Which molecular pathways promote the abnormal expression of secreted factors by mutated Sox2+ stem cells?
(ii) Which are the critical secreted signals that induce the tumours?
(iii) Could inhibition of these signals result in the development of novel chemical treatments for the patients?
(iv) Which is the cell-of-origin of the tumours?
Answering these questions will provide mechanistic insights into the paracrine model of tumorigenesis to further understand the pathophysiology of pituitary tumours, and with broader implications for oncology and the role of somatic stem cells, senescence and inflammation in cancer (Aim 1). In addition, it will lead to a better understanding of the initial steps of tumour formation and the identification of the cell-of-origin of ACP (Aim 2), which will facilitate the development of new tools for early diagnosis and will allow validation of targeted treatments against oncogenic signalling pathways. To achieve this, I will use a multidisciplinary approach combining:
(i) Mouse genetics (genetic tracing, gene deletion, preclinical studies using small-molecule inhibitors).
(ii) Cell isolation by flow cytometry.
(iii) Molecular biology (gene expression and mutational profiling by RNA-Seq).
(iv) Developmental biology (generation of chimeras).
(i) Which molecular pathways promote the abnormal expression of secreted factors by mutated Sox2+ stem cells?
(ii) Which are the critical secreted signals that induce the tumours?
(iii) Could inhibition of these signals result in the development of novel chemical treatments for the patients?
(iv) Which is the cell-of-origin of the tumours?
Answering these questions will provide mechanistic insights into the paracrine model of tumorigenesis to further understand the pathophysiology of pituitary tumours, and with broader implications for oncology and the role of somatic stem cells, senescence and inflammation in cancer (Aim 1). In addition, it will lead to a better understanding of the initial steps of tumour formation and the identification of the cell-of-origin of ACP (Aim 2), which will facilitate the development of new tools for early diagnosis and will allow validation of targeted treatments against oncogenic signalling pathways. To achieve this, I will use a multidisciplinary approach combining:
(i) Mouse genetics (genetic tracing, gene deletion, preclinical studies using small-molecule inhibitors).
(ii) Cell isolation by flow cytometry.
(iii) Molecular biology (gene expression and mutational profiling by RNA-Seq).
(iv) Developmental biology (generation of chimeras).
Planned Impact
1. The long-term beneficiaries of this research include patients suffering from pituitary tumours and their families as well as health-care providers and social workers. Results of the proposed research will reveal genes and pathways that are dysregulated in adamantinomatous craniopharyngioma (ACP), which could lead to the discovery of new biomarkers of disease and specific targeted treatments. For example, around half of ACP tumours are very infiltrative into the brain and prone to recurrence, whilst others are more localised and recur less frequently, but there are no biomarkers available at present that can predict tumour behaviour. Because of the strong links to Great Ormond Street Hospital for Children (GOSH), and the established collaborations with clinicians (e.g. Thomas Jacques, neuropathologist), we will assess the potential value as a predictable biomarker of the dysregulated genes that will be identified in the proposed research.
Another unmet clinical need for these childhood tumours is that there are currently no specific treatments. Surgery and/or radiotherapy are not ideal and associated with high morbidity in the patients. Our research will highlight pathways with oncogenic potential that are dysregulated in the human tumours, which could be targeted with specific inhibitors in future research projects. We recently started a pre-clinical trial using our mouse models to assess the efficacy of hedgehog inhibitors (funded by Great Ormond Street Hospital for Children Charity (GOSHCC)). These studies are being performed in close collaboration with Dr Darren Hargrave, an oncologist at GOSH, who specialises in brain tumours and the UK coordinator for several ongoing human clinical trials worldwide. Dr Hargrave is ideally placed to translate our results into the clinical setting. Moreover, his contacts with pharmacological industries will facilitate the use of inhibitors that are currently being tested for other tumours and cancers, which will expedite the use of these drugs in children with ACP.
2. Organisations such as charities working with patients and their families, providing lay summaries and information on medical conditions, may find the results from this study of use for inclusion in their communications, which will in turn help improve social welfare and well-being. These activities usually contribute towards increasing public awareness of science and the use of mice for biomedical research, as the benefit to child health is specially highlighted and of relevance to patients and their parents/relatives/friends.
3. Finally, pharmaceutical companies could be interested in the proposed research. Usually, this industry has not been interested in specific development of drugs for childhood tumours. The reason is that only one to two per cent of all tumours and cancers affect children, and therefore the 'market' is not big enough to recover the costs of drug development and production. Because this is not ethically acceptable, there have been governmental incentives to the industry to include childhood tumours in ongoing clinical trials for adult cancers, promoting in this way the development of specific protocols and applications of the drugs specifically for children. We will use the results from the proposed research to engage with pharmaceutical industries aiming to extend the use of drugs to children with ACP. For example, through Dr Hargrave we have initiated contact with Novartis, as they are currently testing the efficacy of the hedgehog pathway inhibitor LDE-225 for the treatment of medulloblastoma (the most common brain tumour in children). Our aim is to prove the principle that LDE-225 could potentially be used for treatment of human ACP (GOSHCC grant). A similar approach will be used with those inhibitors that are shown to have a beneficial effect in the proposed preclinical studies.
Another unmet clinical need for these childhood tumours is that there are currently no specific treatments. Surgery and/or radiotherapy are not ideal and associated with high morbidity in the patients. Our research will highlight pathways with oncogenic potential that are dysregulated in the human tumours, which could be targeted with specific inhibitors in future research projects. We recently started a pre-clinical trial using our mouse models to assess the efficacy of hedgehog inhibitors (funded by Great Ormond Street Hospital for Children Charity (GOSHCC)). These studies are being performed in close collaboration with Dr Darren Hargrave, an oncologist at GOSH, who specialises in brain tumours and the UK coordinator for several ongoing human clinical trials worldwide. Dr Hargrave is ideally placed to translate our results into the clinical setting. Moreover, his contacts with pharmacological industries will facilitate the use of inhibitors that are currently being tested for other tumours and cancers, which will expedite the use of these drugs in children with ACP.
2. Organisations such as charities working with patients and their families, providing lay summaries and information on medical conditions, may find the results from this study of use for inclusion in their communications, which will in turn help improve social welfare and well-being. These activities usually contribute towards increasing public awareness of science and the use of mice for biomedical research, as the benefit to child health is specially highlighted and of relevance to patients and their parents/relatives/friends.
3. Finally, pharmaceutical companies could be interested in the proposed research. Usually, this industry has not been interested in specific development of drugs for childhood tumours. The reason is that only one to two per cent of all tumours and cancers affect children, and therefore the 'market' is not big enough to recover the costs of drug development and production. Because this is not ethically acceptable, there have been governmental incentives to the industry to include childhood tumours in ongoing clinical trials for adult cancers, promoting in this way the development of specific protocols and applications of the drugs specifically for children. We will use the results from the proposed research to engage with pharmaceutical industries aiming to extend the use of drugs to children with ACP. For example, through Dr Hargrave we have initiated contact with Novartis, as they are currently testing the efficacy of the hedgehog pathway inhibitor LDE-225 for the treatment of medulloblastoma (the most common brain tumour in children). Our aim is to prove the principle that LDE-225 could potentially be used for treatment of human ACP (GOSHCC grant). A similar approach will be used with those inhibitors that are shown to have a beneficial effect in the proposed preclinical studies.
Organisations
- University College London (Lead Research Organisation)
- Institute of Cancer Research UK (Collaboration)
- Great Ormond Street Hospital (GOSH) (Collaboration)
- Wellcome Trust (Collaboration)
- Children's Cancer and Leukaemia Group (CCLG) (Collaboration)
- Memorial Sloan Kettering Cancer Center (Collaboration)
- UNIVERSITY OF CAMBRIDGE (Collaboration)
- IMPERIAL COLLEGE LONDON (Collaboration)
Publications
Apps JR
(2020)
CTNNB1 mutations are clonal in adamantinomatous craniopharyngioma.
in Neuropathology and applied neurobiology
Apps JR
(2016)
Imaging Invasion: Micro-CT imaging of adamantinomatous craniopharyngioma highlights cell type specific spatial relationships of tissue invasion.
in Acta neuropathologica communications
Apps JR
(2023)
Contemporary Biological Insights and Clinical Management of Craniopharyngioma.
in Endocrine reviews
Apps JR
(2016)
Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice.
in Neurosurgical focus
Apps JR
(2017)
Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology.
in Brain pathology (Zurich, Switzerland)
Apps JR
(2023)
A promising future for hypothalamic dysfunction in craniopharyngioma.
in Neuro-oncology
Apps JR
(2019)
Learning from cases: Analysis of two cases of craniopharyngioma from the 19 th to the 21 st centuries.
in F1000Research
Bernal-Polo P
(2019)
Kalman Filtering for Attitude Estimation with Quaternions and Concepts from Manifold Theory.
in Sensors (Basel, Switzerland)
Boult JKR
(2018)
Preclinical transgenic and patient-derived xenograft models recapitulate the radiological features of human adamantinomatous craniopharyngioma.
in Brain pathology (Zurich, Switzerland)
Buhl JL
(2019)
The Senescence-associated Secretory Phenotype Mediates Oncogene-induced Senescence in Pediatric Pilocytic Astrocytoma.
in Clinical cancer research : an official journal of the American Association for Cancer Research
Carreno G
(2019)
SHH pathway inhibition is protumourigenic in adamantinomatous craniopharyngioma.
in Endocrine-related cancer
Carreno G
(2021)
Cell senescence in neuropathology: A focus on neurodegeneration and tumours.
in Neuropathology and applied neurobiology
Carreno G
(2017)
Hypothalamic sonic hedgehog is required for cell specification and proliferation of LHX3/LHX4 pituitary embryonic precursors.
in Development (Cambridge, England)
Carreno G
(2017)
Stem cells and their role in pituitary tumorigenesis.
in Molecular and cellular endocrinology
Donson AM
(2017)
Molecular Analyses Reveal Inflammatory Mediators in the Solid Component and Cyst Fluid of Human Adamantinomatous Craniopharyngioma.
in Journal of neuropathology and experimental neurology
Gaston-Massuet C
(2016)
Transcription factor 7-like 1 is involved in hypothalamo-pituitary axis development in mice and humans.
in Proceedings of the National Academy of Sciences of the United States of America
Gonzalez-Meljem J
(2018)
Senescence drives non-cell autonomous tumorigenesis in the pituitary gland
in Molecular & Cellular Oncology
Gonzalez-Meljem JM
(2021)
Adamantinomatous craniopharyngioma as a model to understand paracrine and senescence-induced tumourigenesis.
in Cellular and molecular life sciences : CMLS
Gonzalez-Meljem JM
(2018)
Paracrine roles of cellular senescence in promoting tumourigenesis.
in British journal of cancer
Gonzalez-Meljem JM
(2023)
An expression and function analysis of the CXCR4/SDF-1 signalling axis during pituitary gland development.
in PloS one
Gonzalez-Meljem JM
(2017)
Stem cell senescence drives age-attenuated induction of pituitary tumours in mouse models of paediatric craniopharyngioma.
in Nature communications
Guerrero A
(2020)
Galactose-modified duocarmycin prodrugs as senolytics.
in Aging cell
Guerrero A
(2019)
Cardiac glycosides are broad-spectrum senolytics.
in Nature metabolism
Haston S
(2017)
MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma.
in Development (Cambridge, England)
Haston S
(2018)
Stem/progenitor cells in pituitary organ homeostasis and tumourigenesis.
in The Journal of endocrinology
Haston S
(2017)
Insights into normal pituitary development and pathogenesis of papillary craniopharyngioma by genetic activation of the MAPK/ERK pathway
in Mechanisms of Development
Herranz N
(2015)
mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype.
in Nature cell biology
Hufnagel RB
(2015)
Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes.
in Journal of medical genetics
Kim YJ
(2018)
WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome.
in EMBO reports
Martinez-Barbera JP
(2015)
Adamantinomatous craniopharyngioma: pathology, molecular genetics and mouse models.
in Journal of pediatric endocrinology & metabolism : JPEM
Martinez-Barbera JP
(2015)
60 YEARS OF NEUROENDOCRINOLOGY: Biology of human craniopharyngioma: lessons from mouse models.
in The Journal of endocrinology
Martinez-Barbera JP
(2015)
Molecular and cellular pathogenesis of adamantinomatous craniopharyngioma.
in Neuropathology and applied neurobiology
Martinez-Barbera JP
(2016)
Concise Review: Paracrine Role of Stem Cells in Pituitary Tumors: A Focus on Adamantinomatous Craniopharyngioma.
in Stem cells (Dayton, Ohio)
Martínez-Barberá H
(2021)
Sensor Modeling for Underwater Localization Using a Particle Filter.
in Sensors (Basel, Switzerland)
McCabe MJ
(2015)
Novel application of luciferase assay for the in vitro functional assessment of KAL1 variants in three females with septo-optic dysplasia (SOD).
in Molecular and cellular endocrinology
Müller HL
(2019)
Craniopharyngioma.
in Nature reviews. Disease primers
Müller HL
(2017)
New outlook on the diagnosis, treatment and follow-up of childhood-onset craniopharyngioma.
in Nature reviews. Endocrinology
Müller HL
(2022)
Hypothalamic syndrome.
in Nature reviews. Disease primers
Pozzi S
(2019)
Genetic Deletion of Hesx1 Promotes Exit from the Pluripotent State and Impairs Developmental Diapause
in Stem Cell Reports
Selt F
(2023)
BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.
in Neuro-oncology
Tordella L
(2016)
SWI/SNF regulates a transcriptional program that induces senescence to prevent liver cancer.
in Genes & development
Xavier GM
(2015)
Activated WNT signaling in postnatal SOX2-positive dental stem cells can drive odontoma formation.
in Scientific reports
| Description | CRUK Science Committee Research Awards |
| Amount | £1,537,452 (GBP) |
| Organisation | Cancer Research UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2019 |
| End | 01/2024 |
| Description | Cancer Research UK. Clinical PhD studentship Research Fellowship |
| Amount | £250,000 (GBP) |
| Organisation | Cancer Research UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2014 |
| End | 08/2017 |
| Description | Children with Cancer UK; Collaborative grants |
| Amount | £458,728 (GBP) |
| Organisation | Children with Cancer UK |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2016 |
| End | 12/2018 |
| Description | Children's Cancer and Leukemia Group project |
| Amount | £9,975 (GBP) |
| Organisation | Children's Cancer and Leukaemia Group (CCLG) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2014 |
| End | 07/2015 |
| Description | EVEREST- Paediatric research and Innovation centre for low grade brain tumours |
| Amount | £5,000,000 (GBP) |
| Funding ID | GN-000382 |
| Organisation | The Brain Tumour Charity |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 06/2017 |
| End | 05/2022 |
| Description | Exploiting therapeutic targets in paediatric high grade gliomas with H3K27M mutations |
| Amount | £247,914 (GBP) |
| Organisation | Sparks Charity |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 01/2020 |
| End | 12/2022 |
| Description | Molecular characterisation of human childhood craniopharyngioma |
| Amount | £27,000 (GBP) |
| Organisation | Great Ormond Street Hospital (GOSH) |
| Department | NIHR Great Ormond Street Biomedical Research Centre |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 11/2014 |
| Description | Molecular profiling of relapsing craniopharyngioma |
| Amount | £10,000 (GBP) |
| Funding ID | CCLGA 2017 05 |
| Organisation | Children's Cancer and Leukaemia Group (CCLG) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2017 |
| End | 09/2018 |
| Description | Pre-clinicl tiral of anti-inflammatory antibodies in a mouse model of adamantinomatous craniopharyngioma |
| Amount | $75,000 (USD) |
| Organisation | The Morgan Adams Foundation |
| Sector | Charity/Non Profit |
| Country | United States |
| Start | 06/2017 |
| End | 05/2019 |
| Description | Project grant application to the MRC |
| Amount | £965,381 (GBP) |
| Funding ID | 164126 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2015 |
| End | 12/2017 |
| Description | SIGNAL - Striking Insensitive Paediatric Gliomas Through Network Analysis |
| Amount | £400,000 (GBP) |
| Funding ID | GN-000359 |
| Organisation | The Brain Tumour Charity |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 02/2017 |
| End | 01/2018 |
| Description | The Brain Tumour Charity: Quests for Cures |
| Amount | £1,058,220 (GBP) |
| Organisation | The Brain Tumour Charity |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 09/2018 |
| End | 08/2023 |
| Description | Undersatanding the role of senescence and NFkB signalling in pituitary tumours |
| Amount | £73,967 (GBP) |
| Funding ID | STU5 |
| Organisation | The Child Health Research Charitable Incorporated Organisation |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 10/2016 |
| End | 09/2019 |
| Title | RNA-seq and whole exome sequencing datsets |
| Description | We have performed several experiments aiming to profile specific tumour cells within human craniopharyngioma as well as the mouse models of these tumours. Whole-exome sequencing of mouse tumours have also been carried out. |
| Type Of Material | Database/Collection of data |
| Year Produced | 2017 |
| Provided To Others? | Yes |
| Impact | No impact yet |
| Description | Molecular characterisation of human adamantinomatous craniopharyngioma |
| Organisation | Children's Cancer and Leukaemia Group (CCLG) |
| Country | United Kingdom |
| Sector | Charity/Non Profit |
| PI Contribution | We are characterising these paediatric tumours and reporting our results |
| Collaborator Contribution | The CCLG will provide tumour samples, matching blood DNA, and other human tissues that are required for our projects |
| Impact | Still too early |
| Start Year | 2014 |
| Description | Molecular characterisation of human childhood craniopharyngioma |
| Organisation | Great Ormond Street Hospital (GOSH) |
| Department | Centre for Translational Genomics (GOSgene) |
| Country | United Kingdom |
| Sector | Hospitals |
| PI Contribution | GOSgene sponsored a study to perform whole genome sequencing and gene expression profiling of 5 human craniopharyngioma samples. Later, I applied to CCLG (Children's Cancer and Leukaemia Group) for a pilot grant to complement the proposed studies and increase the number of samples analysed. This grant application was also successful. The sponsorship by GOSgene was instrumental in attracting co-funding. The studies have been initiated and I aim to get sufficient data to build a programme grant application by the end of 2015. |
| Collaborator Contribution | GOSgene will perform the sequencing and subsequent bioinformatic analysis. A Clinical PhD Fellow in my lab will lead these studies and will work together with GOSgene research personnel. CCLG provided additional funds for reagents and sequencing. |
| Impact | Too early; sequencing has been performed and is currently being analysed. |
| Start Year | 2014 |
| Description | Preclinical evaluation of novel therapies against paediatric craniopharyngioma |
| Organisation | Institute of Cancer Research UK |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We are collaborating with Dr Simon Robinson (Institute of Cancer Research, Sutton) to evaluate novel therapies that have been identified through the project funding by the MRC. We will provide the mice and the drugs. |
| Collaborator Contribution | Dr Robinson's group, in particular Dr Jessica Boult, will analyse the tumour growth by MRI. |
| Impact | We have published a paper already (Boult et al 2017) and have another paper under review. |
| Start Year | 2017 |
| Description | Preclinical studies in mouse models for human adamantinomatous craniopharyngioma (ACP) |
| Organisation | Institute of Cancer Research UK |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We are transferring our mouse models and Dr. Chesler's Team is using them for testing specific small molecule inhibitors of pathogenic pathways. We have generated these unique mouse models. |
| Collaborator Contribution | Dr. Chesler runs a 'mouse hospital'. This facility contains state-of-the-art equipment for imaging (e.g. MRI), personnel and capacity to perform pre-clinical studies in mice. We cannot do these studies as well as they do. |
| Impact | Unique MRI images have been obtained which inform us on how these tumours develop in the mouse models. The first pre-clinical trial using a SHH pathway inhibitor has been finalised and data is currently being analysed. Other pre-clinical trials are under way |
| Start Year | 2014 |
| Description | Senescence consortium |
| Organisation | Memorial Sloan Kettering Cancer Center |
| Country | United States |
| Sector | Academic/University |
| PI Contribution | Prof. Scott Lowe is leading a senescence consortium and we will be applying to a Grand Challenge. I will provide expertise in the role of senescence in paediatric brain tumours and use of novel mouse model to study senescence in vivo. |
| Collaborator Contribution | The difference partners have a broad expertise in the field of senescence, from mechanisms of senescence to detection in vivo of senescence cells, CarT cells approaches, senolytic screens etc. |
| Impact | None yet |
| Start Year | 2021 |
| Description | Senolytics in paediatric brain tumours |
| Organisation | Imperial College London |
| Department | Institute of Clinical Sciences |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Screening of senolytics in vivo and in vitro in mouse models of brain tumours |
| Collaborator Contribution | My partner, Prof Jesus Gil has identified several senolytics. |
| Impact | A few publications, some of which are associated with this award. |
| Start Year | 2016 |
| Description | Study of senescence in vivo in mouse models of lung cancer |
| Organisation | University of Cambridge |
| Department | Department of Oncology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have generated a new genetic tool that allows the visualisation, isolation and ablation of senescent cells in vivo. |
| Collaborator Contribution | He has provided expertise and shared reagents |
| Impact | None yet |
| Start Year | 2019 |
| Description | Study of senescence in vivo in mouse models of oesophageal cancer |
| Organisation | Wellcome Trust |
| Department | Wellcome - MRC Cambridge Stem Cell Institute |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | We have generated and shared a new genetic tool that allow to investigate senescence in vivo |
| Collaborator Contribution | They have shared expertise and reagents and protocols |
| Impact | None yet |
| Start Year | 2019 |
| Title | Clinical trial testing IL-6 and/or MEK inhibitors on children with adamantinomatous craniopharyngioma |
| Description | The clinical trial application was presented to CONNECT and approved. Currently we are waiting to hear from Novartis, which is supplying Trametinib, a clinically approved MEK inhibitor. |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Initial development |
| Year Development Stage Completed | 2019 |
| Development Status | Actively seeking support |
| Impact | This is to our knowledge the first clinical trial testing two drugs that could be effective against the solid component of adamantinomatous craniopharyngioma. |
| Description | 8 Poster presentations and 6 invited talks in national and international scientific meetings |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Posters and talks about my group's research Colleagues and other researchers asked questions and wrote mails |
| Year(s) Of Engagement Activity | 2013,2014,2015 |
| Description | Conferences in Boston, Munich, France, Liverpool, Bad Zwischenahn (Germany) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Talks in National and international conferences and workshops |
| Year(s) Of Engagement Activity | 2016 |