Poster Presentation 38th Lorne Cancer Conference 2026

Co-targeting thrombospondin-1 (THBS-1) to improve KRAS inhibitor and chemotherapeutic efficacy in pancreatic cancer (#268)

Victoria M Tyma 1 2 , Katie Gordon 1 2 , Shona Ritchie 1 2 , Kendelle Murphy 1 2 , David Herrmann 1 2 , Brooke Pereira 1 2 , Paul Timpson 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia

Introduction:
Pancreatic cancer (PC) is one of the deadliest cancers, the fourth leading cause of cancer related deaths in Australia1. Most PC harbours a mutation in the KRAS gene, which is historically challenging to target. However, in the past few years, there has been a major medical advancement in developing highly effective and specific KRAS inhibitors. Mirati’s G12D KRAS inhibitor, MRTX1133, can cause a >50% decrease in mouse PC tumour burden2. Pan-KRAS inhibitors act on all KRAS mutations, including RMC-6236 (Revolution Medicines) and BI-2493 (Boehringer Ingelheim)3,4. Despite these exciting results, it is likely tumours will become resistant to KRAS inhibition, partly due to changes in pancreatic tumour microenvironment, including tumour fibrosis and vasculature changes5, 6, 7.

Methods/Results:

We aim to explore co-targeting the tumour microenvironment to improve KRAS inhibitor and/or chemotherapeutic response. From mass spectrometry proteomics data in our lab, we have identified high levels of thrombospondin 1 (THBS-1) in aggressive PC models8, presenting a unique stromal co-target that may overcome challenges with resistance. Preliminary data shows THBS-1 is largely produced by cancer-associated fibroblasts (CAFs), which are responsible for the majority of tumour fibrosis in PC9, 10. We aim to analyse the effect of genetic and pharmacological inhibition of THBS-1 in combination with KRAS inhibition, examining whether we can improve drug response using this dual targeting approach. Ongoing work includes genetic knockdown of THBS-1 in CAFs derived from the genetically engineered KPC mouse model of PC11. With access to LSKL, a potent THBS-1 inhibitor 12, we will assess the functional role of THBS-1 in context of CAF contractility and cancer cell invasion using 3D organotypic matrix contraction and invasion assays13,14, in combination with KRAS inhibitors.


Conclusion:
Future work will include trialling our novel combination therapy via subcutaneous and orthotopic (intra-pancreatic) in vivo models. Overall, we aim to assess THBS-1 as a potential co-target to improve the efficacy and durability of these promising KRAS inhibitors and standard-of-care chemotherapy.

 

 

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