Poster Presentation 37th Lorne Cancer Conference 2025

Identifying and targeting treatment response mechanisms to improve gemcitabine/Abraxane performance in patient-derived models of pancreatic cancer (#258)

Alice Tran 1 , Katie Gordon 1 2 , Shona C Ritchie 1 2 , Daniel A Reed 1 2 , Cecilia R Chambers 1 2 , Anna Howell 1 2 , Victoria M Tyma 1 2 , Kendelle J Murphy 1 2 , Michael Trpceski 1 2 , Ying Fei Liew 1 , Ruth Lyons 1 , Australian Pancreatic Cancer Genome Initiative (APGI) 1 , Australian Pancreatic Cancer Matrix Atlas (APMA) 1 , Anthony J Gill 1 3 , Thomas R Cox 1 2 , Marina Pajic 1 2 , Brooke A Pereira 1 2 , David Herrmann 1 2 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. Faculty of Medicine, University of New South Wales, St Vincent's Clinical School, Sydney, New South Wales, Australia
  3. Anatomical Pathology, Royal North Shore Hospital, NSW Health Pathology, St Leonards, New South Wales

Pancreatic cancer (PC) is a devastating disease with an abysmal 5-year survival rate of only 13% [1]. Many PC patients are diagnosed at an advanced disease stage when PC has spread, and potentially curative surgical resection is not available. Therefore, chemotherapy remains the primary treatment option in PC. Currently, the standard-of-care chemotherapies for PC patients include gemcitabine alone or in combination with nab-paclitaxel (Abraxane) which increases survival by 6.6 months to 8.7 months, respectively. Furthermore, recent addition of FOLFIRINOX chemotherapy further increases survival by 11 months, with most patients becoming insensitive and eventually developing resistance to treatment [2,3]. Moreover, chronic exposure to chemotherapy has also been shown to induce fibrosis in the tumour microenvironment, which is known to promote PC progression and metastasis as well as prevent treatment penetration and performance into the tumour tissue. As such, this project aims to use dual transcriptomic and proteomic assessment in the gold standard KPC model as well as in our neoadjuvant-treated patient derived xenografts (PDXs) upon prolonged exposure to gemcitabine and Abraxane (GA).

We established PDXs from human PC tumour samples, where patients received neo-adjuvant FOLFIRINOX or Gemcitabine-based chemotherapy (Australian Pancreatic Cancer Matrix Atlas [APMA]). PDX tumour chunks were then orthotopically implanted into immunocompromised NSG mice and randomly assigned to treatment groups (n=10); Mice were treated twice weekly with standard-of-care gemcitabine and Abraxane (70 mg/kg and 30 mg/kg, respectively), until mice reached study endpoint. Similarly, KPC orthotopic tumours were established and enrolled for long-term vehicle or chemotherapy treatment.

Primary tumour and secondary sites were collected for dual quantitative transcriptomics and proteomics and as well as histological assessment. We also generated patient derived cells lines (PDCLs) from matched vehicle and chemotherapy-treated groups and confirmed through Fluorescent-activated cell sorting (FACS) for human epithelial cells, and Short Tandem Repeat (STR) profiling that they are unique human cell lines. Overall, assessing the transcriptomics and proteomic landscape of PC tumours upon chronic exposure to chemotherapy will uncover new targets for targeted therapy to improve chemotherapy response and patient outcomes.

  1. Siegel RL, G. A. (2024). Cancer statistics, 2024. CA Cancer J Clin, 74(1): , 74(1): 12-49. doi:10.3322/caac.21820
  2. Goldstein D, E.-M. R. (2015). nab-Paclitaxel plus gemcitabine for metastatic pancreatic cancer: long-term survival from a phase III trial. J Natl Cancer Inst, 107(2). doi:10.1093/jnci/dju413
  3. Conroy T, D. F.-B.-A.-V.-G. (2011). FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med, 12;364(19), 1817-25. doi:10.1056/NEJMoa1011923