Poster Presentation 35th Lorne Cancer Conference 2023

In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma (#350)

Jacqueline Whitehouse 1 2 , Hilary Hii 1 , Chelsea Mayoh 3 4 , Marie Wong 3 4 , Pamela Ajuyah 3 , Paulette Barahona 3 , Louise Cui 3 , Hetal Dholaria 1 2 , Christine White 5 6 7 , Molly Buntine 5 6 , Jacob Byrne 1 , Keteryne Rodrigues da Silva 1 , Meegan Howlett 1 2 , Emily Girard 8 9 , Maria Tsoli 3 10 , David Ziegler 3 10 11 , Jason Dyke 2 12 , Sharon Lee 13 , Paul Ekert 3 10 14 15 , Mark Cowley 3 10 , Nick Gottardo 1 2 13 , Raelene Endersby 1 2
  1. Telethon Kids Institute, Nedlands, WA, Australia
  2. University of Western Australia, Nedlands, WA, Australia
  3. Children's Cancer Institute, Kensington, NSW, Australia
  4. School of Clinical Medicine, UNSW Sydney, Kensington, NSW, Australia
  5. Hudson Institute of Medical Research, Clayton, Victoria , Australia
  6. Monash University, Melbourne, Victoria, Australia
  7. Victorian Clinical Genetics Services, Parkville, VIC, Australia
  8. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
  9. Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, USA
  10. University of New South Wales, Kensington, NSW, Australia
  11. Kids Cancer Centre, Sydney Children’s Hospital, Randwick , NSW, Australia
  12. PathWest Laboratory Medicine, Perth, WA, Australia
  13. Perth Children's Hospital, Nedlands, WA, Australia
  14. Murdoch Children’s Research Institute, Parkville, Victoria, Australia
  15. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive often suffer long-term neurological side effects as a result of therapy. There is a clear need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of Posterior Fossa A (PFA) EPN, derived from a metastatic cranial lesion. Patient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing. Both patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo. Comparison with successful models developed across six independent laboratories suggests that 1q gain, predictive of tumor aggression and poor outcome clinically, may be an indicator of likely PDOX generation success.