Accelerating the Delivery of New Treatments for Children with Neuroblastoma 2024.pptx

Neuroblastoma is a tumour arising from anomalies in the development of the sympathic nervous system and still accounts for 13% of all cancer-related death in children due to resistant, relapsing and metastatic diseases. There is an urgent need for the development of new treatment against high-risk relapsed neuroblastoma.

Overview:

Here we will discuss the ICR Paediatric Mouse Hospital approach which integrates more advanced mouse modelling, such as the use of genetically-engineered mouse (GEM) models and patient-derived xenografts to accelerate the discovery and evaluation of novel therapeutic strategies and help shape the clinical trial pipeline priorities for children with high-risk relapsing/refractory neuroblastoma.

We will also highlight the pivotal role of MRI within the Mouse Hospital which includes:

Enhancing and accelerating preclinical trials
Quantitatively inform on tumour phenotype and tumour response to treatment to:
Develop in vivo models that emulate the clinical treatment resistant phenotype using chemotherapy-dose escalation protocol
Characterize tumour spatial heterogeneity and evolution over treatment and guide the pathological and molecular characterization of the resistant phenotype


Finally we will also discuss how the compact, cryogen-free and user-friendly Aspect Imaging M-Series has transformed our way of working within the mouse hospital by providing a shared and easily accessible resource for tumour screening (with minimal onboarding) .

1. Accelerating the Delivery of New Treatments for Children with Neuroblastoma with the MRI-Guided Paediatric Mouse Hospital Dr. Evon Poon Senior Scientist The Institute of Cancer Research, London Yann Jamin Children with Cancer UK Research Fellow The Institute of Cancer Research, London, UK Applications Specialist Scintica Instrumentation Inc, Evon Poon Senior Scientist, Paediatric Solid Tumour Biology Team The Institute of Cancer Research, London, UK Dr. Yann Jamin Application Specialist, Scintica

2. Accelerating the Delivery of New Treatments for Children with Neuroblastoma with the MRI-Guided Paediatric Mouse Hospital Part 1 : ICR Paediatric Mouse Hospital and preclinical trials of new therapeutics strategies for the children with neuroblastoma Part 2 : The practical aspects and challenges of implementing and running MRI-embedded preclinical trials

3. Accelerating the Delivery of New Treatments for Children with Neuroblastoma with the MRI-Guided Paediatric Mouse Hospital Evon Poon Chesler Lab, Institute of Cancer Research, UK

4. Precision Medicine for High-Risk Neuroblastoma The Mouse Hospital and Co-Clinical Trial Approach Multiplex imaging Immuno-proteomics Regional and Cell Classification Spatial transcriptomic Genomic Non invasive Imaging The application of the mouse hospital and co-clinical trial concept represents a clear paradigm shift in NB translational research. This approach integrates more advanced mouse modelling to accelerate the discovery and evaluation of novel therapeutic strategies Integrate imaging and all these information to better understand the resistance and heterogeneity.

5. Precision Medicine for High-Risk Neuroblastoma The Mouse Hospital and Co-Clinical Trial Approach Multiplex imaging Immuno-proteomics Regional and Cell Classification Spatial transcriptomic Genomic Non invasive Imaging Novel models (iPSC) Immunology models Transgenic mice modelling genetic drivers PDX models Chemoresistant models

6. Neuroblastoma – A neural crest tumour Sympathetic nerve and adrenal gland tumours Most common tumour after brain Causes 15% of childhood deaths The older you are the worse it is (>18 months) Hereditary and sporadic forms MYCN amp diploid MYCN

7. Clinical characteristics of neuroblastoma Fischer, Science 2018 Transgenic mice modelling genetic drivers such as MYCN, p53, RAS, ALK, etc

8. GEMM for Pre-clinical Trials in Neuroblastoma Th- MYCN GEM Model Th -MYCN : Increase in MYCN dosage augments tumorigenesis. (Weiss et al, 1997) Human MYCN cDNA Tyrosine-OH promotor Reviewed in Chesler, SCB, 2011, CCR 2013 Tissue specific promotor (Tyr-OH) restricted gene overexpression in neural crest workhorse model, MYCN-dependent, recapitulates all major features and 2 o genomics. Trials: 14-21 day single-agent trials on 1 o tumour with surrogate imaging (MRI).

9. Th- MYCN GEM Model Undifferentiated neuroblastoma 50 m m Th- MYCN mouse A robust platform to evaluate novel therapy and imaging biomarkers The most established model of NB, which emulates the major genomic and histopathological hallmarks of high-risk MYCN -amplified disease.

10. Neuroblastoma GEM models (subclass driver) x Th- MYCN /Th- ALK F1174L (Chesler, 2012) Th- MYCN/Trp53 KI ( Chesler , 2016) x Th promoter ALK F1174L Th promoter MYCN Th- MYCN Th promoter MYCN Th- MYCN Th- ALK F1174L x

11. Targeting MYCN degradation in neuroblastoma Poon, Chesler, Buechel and Eilers Labs MYCN -amplified neuroblastoma cells express elevated levels of Aurora-A. Aurora-A associates with MYCN (N- Myc ) and prevents Fbxw7-mediated proteasomal degradation of MYCN. Aurora A inhibitors dissociate AURKA from MYCN Aurora A inhibitors downregulate MYCN

12. Targeting MYCN degradation in neuroblastoma Aurora A inhibitors decrease colony formation and proliferation of MYCN -amplified NB cells

13. Multimodality imaging driven trials LHS Kidney RHS Kidney RHS Kidney LHS Kidney IAUGC 60 0.13 ± 0.01mM Gd min RHS Kidney LHS Kidney Anatomic Volumetric (T 1 vol) -/+10% Functional (DCE-MRI) RHS Kidney Day 0 randomise (N=4/arm) Precision Medicine for High-Risk Neuroblastoma The Mouse Hospital and Co-Clinical Trial Approach

14. Multimodality imaging driven trials RHS Kidney Volumetric (T 1 vol) -/+10% RHS Kidney Day 0 randomise (N=4/arm) Precision Medicine for High-Risk Neuroblastoma The Mouse Hospital and Co-Clinical Trial Approach Day 7

15. Targeting MYCN degradation in neuroblastoma MLN8054 MLN8237 Aurora A inhibitors regress tumours and extend survival of Th- MYCN mice.

16. Targeting MYCN degradation in neuroblastoma Tumours relapse while still on treatment

17. Targeting transcription-replication conflict in neuroblastoma Aurora A interacts with MYCN at S-phase to prevent transcription-replication stress Induction of transcription-replication conflicts opens a wide therapeutic window Aurora A inhibitors activate ATR Combination of Aurora-A and ATR inhibitors cures a subset of mice

18. Transgenic mice modelling genetic drivers PDX models Novel models (neural crest cell) Chemoresistant models Immunology models Th- MYCN GEM Model A robust platform to evaluate novel therapy and imaging biomarkers

19. Audience Poll

20. The practical aspects and challenges of implementing and running MRI-embedded preclinical trials Yann Jamin Children with Cancer Research Fellow Centre for Cancer Imaging Division of Radiotherapy and Imaging Institute of Cancer Research, UK

21. The Centre for Cancer Imaging @ The Institute of Cancer Research London 7T MRI SPECT/PET/CT m CT High-frequency US Photo-acoustics Optical CT “The Centre for Cancer Imaging is a leading edge preclinical research facility that brings together multi-disciplinary research teams with an ethos of collaboration and innovation. Its core purpose is to develop and implement state-of-the-art non-invasive imaging technologies in order to support the discovery and development of personalized cancer therapies and ultimately deliver improved outcomes for cancer patients.”

22. 23 Adult glioma ( o.t ) Pediatric glioma ( o.t ) Medulloblastoma (GEMM) Craniopharyngioma (GEMM) Multiple Myeloma ( o.t .) Prostate bone metastasis ( o.t ) Breast cancer ( o.t .) Pancreatic cancer ( o.t ., GEMM) Neuroblastoma ( GEMM) Colon cancer metastasis ( o.t ., PD organoids) … Prostate cancer ( GEMMM) Wilm’s tumour ( o.t .) Supporting the research community at ICR Fat suppressed T2-weighted anatomical MRI

23. The Neuroblastoma Mouse Hospital Undifferentiated neuroblastoma 50 m m Th- MYCN mouse A robust platform to evaluate novel therapy and imaging biomarkers

24. The Neuroblastoma Mouse Hospital A robust platform to evaluate novel therapy and imaging biomarkers Diagnosis 10 Jan After 2 cycles of chemotherapy 3 Mar   Temozolomide 9 months old

25. The Neuroblastoma Mouse Hospital Preclinical Trial Design Palpation T 2 w-MRI DOB Genotyping Palpation ~ Size 5 Hemizygous Th- MYCN +/- Homozygous Th- MYCN +/+ Penetrance 25% Doubling time ~7days Penetrance 100% Doubling time ~3days Th- MYCN +/+

26. The Neuroblastoma Mouse Hospital Preclinical Trial Design Palpation T 2 w-MRI DOB Genotyping Palpation ~ Size 5 Survival trial D D 3 MRI MRI D 1 : Cdk2/9 inh PK/PD Path Intervention trial Cdk2/9 inh 1 and inh 2 Cdk2/9 inh 1 Cdk2/9 inh 2

27. Imaging data sets – Tumour volume segmentation

28. Imaging data sets – Tumour volume segmentation Dicom format: 2-3Mb/data sets Many software available for segmentation

29. The Neuroblastoma Mouse Hospital Preclinical Trial Design Palpation T 2 w-MRI DOB Genotyping Palpation ~ Size 5 Survival trial D D 3 MRI MRI D 1 : Cdk2/9 inh PK/PD Path Intervention trial Cdk2/9 inh 1 and inh 2 Cdk2/9 inh 1 Cdk2/9 inh 2

30. The Neuroblastoma Mouse Hospital Preclinical Trial Design Total mice for single drug efficacy studies: Palpation-guided: 32 MRI-guided: 16 Increase accuracy: Compared to physical palpation Reduced bias: Compared to physical palpation Reduction in animal used: Enhanced statistical power Enhanced data curation

31. The Neuroblastoma Mouse Hospital Preclinical Trial Design Palpation T 2 w-MRI DOB Genotyping Palpation ~ Size 5 Survival trial D D 3 MRI MRI D 1 : Cdk2/9 inh PK/PD Path Intervention trial Cdk2/9 inh 1 and inh 2 Cdk2/9 inh 1 Cdk2/9 inh 2

32. Chemoresistant neuroblastoma provides new insights into chemorefractory disease and metastasis Yogev et al., 2019 Th- MYCN mice develop cyclophosphamide resistance following individualized multicycle treatment. Resistant Th- MYCN  tumours acquire genomic changes reflective of human neuroblastoma.

33. Establishing a Screening Facility Behind the Clean Barrier M- Series TM Compact MRI 34 Main surgical procedure room Drug trials animal holding room M- Series TM Compact MRI Permanent magnet : No cryogen or water needed for cooling Normal electrical sockets Fully-shielded Silent scanning for T2-weighted images Low running and maintenance cost

34. Establishing a Screening Facility Behind the Clean Barrier M- Series TM Compact MRI 35 Main surgical procedure room Drug trials animal holding room M- Series TM Compact MRI Permanent magnet : No cryogen or water needed for cooling Normal electrical sockets Fully-shielded Silent scanning for T2-weighted images Low running and maintenance cost

35. Establishing a Screening Facility Behind the Clean Barrier M- Series TM Compact MRI 36 Accessible to anyone Following 20 minutes onboarding No worries about quenching, or metals ! Streamline processes Integrated physiological maintenance and monitoring Simple acquisition software

36. Establishing a Screening Facility Behind the Clean Barrier M- Series TM Compact MRI 37 1 Tesla

37. Establishing a Screening Facility Behind the Clean Barrier M- Series TM Compact MRI 38 7 Tesla 1 Tesla

38. Establishing a Screening Facility Behind the Clean Barrier M- Series TM Compact MRI Tumour k k Acquisition time 6 min 3 min 1 min 30 s 50 s 7 Tesla 1 Tesla

39. Establishing a Screening Facility Behind the Clean Barrier M- Series TM Compact MRI O.t. brain tumour Fat-suppressed T2 weighted: FSE (TE/TR=10-60/4000ms, Inversion time = 100ms) Th- MYCN GEMM 2min scan 8min scan TRAMP GEMM 8min scan 3min scan KPC GEMM O.t. Prostate bone marrow metastasis 12min scan RH-41 xenograft 4min scan 10min scan

40. Footer 41 41 WWW.SCINTICA.COM M-Series Compact, Cryogen-free, Self-shielded 1T MRI system

41. Conclusions MRI is a pivotal component of the Pediatric Mouse Hospital at ICR MRI is helping accelerate the delivery of preclinical trials of novel treatment against neuroblastoma. Aspect Imaging M- Series TM a cost-effective, user-friendly compact system that improves access to MRI to the wider cancer research community

42. Acknowledgements Chesler lab: Louis Chesler Karen Barker Barbara Martins da Costa Kevin Greenslade Sara Heuss Kate Liodaki Andrea Lampis Claire Lynn Lizzie Tucker Quinty Vellema Giuseppe Barone Paul Workman MRI (ICR): Yann Jamin Simon Robinson Alumni: Orli Yogev Libby Calton Federica Lorenzi Collaborators: Sally George (ICR) Karen Liu (KCL) Franki Spelemen (Ghent) John Anderson (UCL) Walter Koach (Dublin) Karin Straathof (UCL) Anna Philpott (Cambridge) Anestis Tsakiridis (Sheffield) Martin Eilers, Gabriele Buechel (Wurzburg) Charles Lin, Tong Liang (BCM)

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