Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

An optimised syngeneic melanoma mouse model -  YUMMER1.7-PV1 for the assessment of sequencing targeted therapies and immunotherapies (#216)

Riyaben P Patel 1 2 , Xin Du 1 , Emily J Lelliott 1 , Anna Trigos 1 , Grant McArthur 1 3 , Karen E Sheppard 1 4
  1. Research division , Peter McCallum Cancer Centre , Melbourne , Victoria , Australia
  2. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville , VIC, Australia
  3. Department of Medicine, St. Vincent’s Hospital, University of Melbourne, Parkville, VIC, Australia
  4. Department of Biochemistry and Molecular Biology, The University of Melbourne, Parkville, VIC, Australia

Cutaneous melanoma is a lethal form of skin cancer and is the 10th most common cause of cancer-related death in Australia. The development of both targeted therapies, directed at the oncogene BRAF and its downstream mediator MEK, and the immune checkpoint inhibitors (ICIs), have revolutionized the treatment of advanced-stage melanoma and improved the outcomes of patients with this malignancy. However, both BRAFi/MEKi targeted therapies and immunotherapies have their limitations. Targeted therapies are associated with very high initial response rates that are typically short-lived for many patients, while in contrast immunotherapies provide more durable responses but have lower initial response rates. Due to these distinct yet complementary mechanisms of action, it has been proposed that sequencing immunotherapy with targeted therapy would lead to a higher frequency of durable responses. However, there are many unanswered questions regarding the choice of immunotherapy, the best sequencing strategy and the mechanism leading to this synergy. In order to address these questions, we have optimised a syngeneic mouse melanoma model, YUMMER1.7-PV1 that is sensitive to both targeted therapy and immunotherapy, responding in a manner consistent with human BRAFV600E melanoma. Importantly, this model recapitulates the known three therapeutic response phases of targeted therapies: initial response, followed by drug tolerance, and then resistance. Furthermore, it demonstrates the characteristic cellular phenotypes that have been previously described for human melanoma PDX models in response to MAPK pathway inhibitors. One such cellular state is the neural crest stem cells (NCSCs) which has previously been shown to play a vital role in the emergence of resistance to both targeted therapy and immunotherapy. Therefore, this model is appropriate to explore the time-dependent therapy-induced changes in tumour cells and the impact on the tumour immune microenvironment. This information will facilitate in determining the optimal sequencing strategy of targeted therapy and immunotherapy which will ultimately deliver better outcomes for melanoma patients.