Flash Talk and Poster Presentation 36th Lorne Cancer Conference 2024

Selective inhibition of ROCK2 co-targets elements of the fibrotic and immune microenvironment to improve the overall anti-tumour response in models of advanced pancreatic cancer (#206)

Benjamin McLean 1 , Sean Porazinski 1 , Aji Istadi 1 , Diego Chacon-Fajardo 1 , Diana Schuhmacher 1 , Simon Woodcock 2 , Caroline Phillips 2 , Emer Cahill 1 , Silvia Lombardi 1 , Yasir Mahmood 1 , Dannielle Upton 1 , Patrick Bergsma 1 , Antonia Blackwell 1 , George Sharbeen 3 , Phoebe Phillips 3 , David Goldstein 4 , Astrid Magenau 1 , Kendelle Murphy 1 , Brooke Pereira 1 , Paul Timpson 1 5 , Marina Pajic 1 5
  1. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst , Sydney, Australia
  2. RedX Pharma, Alderly Park, Chesire, UK
  3. Lowy Cancer Research Centre, UNSW, Randwick, NSW, Australia
  4. Department of Medical Oncology, Prince of Wales Hospital, Sydney, NSW, Australia
  5. St Vincent's Clinical School, Faculty of Medicine, UNSW, Sydney, NSW, Australia

Pancreatic cancer (PC) lacks effective therapies for advanced disease and has a 10% 5-year survival rate. Given the genomic heterogeneity of PC1, personalized medicine approaches are a promising strategy to improve outcomes. We have previously shown that ROCK signalling plays an important role in the promotion of chemoresistance and desmoplasia of PC2,3,4. Here, we present promising pre-clinical data on the efficacy of selective, orally administered ROCK2 inhibitors (ROCK2-i) as a way of sensitising pancreatic cancer to both contemporary chemotherapy and immunotherapy-based approaches.

Comprehensive analyses of pancreatic tumours isolated from the syngeneic KPC PC model revealed positive changes to ECM composition post-ROCK2-i treatment, specifically decreased levels of collagen I and reduced collagen fibril maturity, indicative of a looser matrix. Further immunohistochemical and immunofluorescence analysis of the tumour immune microenvironment revealed positive changes in the components of both innate (macrophage) and adaptive immunity (CD8+ T cell infiltration) in ROCK2-i treated tumours. Excitingly, ROCK2-i extended survival in combination with anti-PD1 immunotherapy compared to anti-PD1 treatment alone in the same model. This may indicate a role for ROCK2 signalling in the regulation of the immune microenvironment in PDAC, as seen in other cancer types5,6.

Furthermore, ROCK2-i improves overall survival in clinically relevant regimens in combination with current standard-of-care chemotherapies, Gemcitabine/Abraxane or FOLFIRINOX in a range of chemoresistant and metastatic patient-derived models of PC.

ROCK2-i therefore shows strong translational potential to combat chemoresistance and potentially sensitise pancreatic tumours to immunotherapy. Ongoing work includes identification of tumour and stromal biomarkers of response to ROCK2-i using single cell transcriptomics. Building on these preclinical data, a Phase I clinical study is currently being planned to assess the safety of ROCK2-i in combination with chemotherapy as frontline treatment of metastatic PC.

  1. Bailey, P. et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531: 47-52, (2016).
  2. Murphy, K. et al. Intravital imaging tehcnology guides FAK-mediated priming in pancreatic cancer precision medicine according to Merlin status. Sci Adv 7, (2021).
  3. Vennin, C. et al. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Sci Trans Med 9, (2017).
  4. Chou, A. et al. Tailored first-line and second-line CDK4-targeting treatment combination in mouse models of pancreatic cancer. Gut 67, (2018).
  5. Georgouli, M. et al. Regional Activation of Myosin II in Cancer Cells Drives Tumour Progression via a Secreoty Cross-Talk with the Immune Microenvironment. Cell 176, (2019).
  6. Orgaz, L. et al. Myosin II Reactivation and Cytoskeletal Remodelling as a Hallmark and a Vulnerability in Melanoma Therapy Resistance. Cancer Cell 37, (2020).