Poster Presentation 37th Lorne Cancer Conference 2025

Effect of endocytosis inhibition on the safety and efficacy of trastuzumab and trastuzumab-deruxtecan therapy to treat HER2+ breast cancer using humanised patient-derived xenograft murine models (#169)

Jason J Lee 1 , Emma-Anne Karlsen 1 2 , Shannon R Joseph 1 , Benedict Lum 1 , Lilia Merida de Long 1 , Elgene Lim 3 4 , Euan Walpole 2 5 , Fiona Simpson 1
  1. Frazer Institute, The University of Queensland, Brisbane, Queensland, Australia
  2. Princess Alexandra Hospital, Brisbane, Queensland, Australia
  3. University of New South Wales, Sydney, New South Wales, Australia
  4. St Vincent's Hospital Sydney, Darlinghurst, New South Wales, Australia
  5. Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia

Temporary and reversible endocytosis inhibition of receptor-monoclonal antibody (mAb) complexes at the cancer cell surface by repurposing prochlorperazine (PCZ) as a dynamin inhibitor is an emerging strategy to increase immune-mediated killing of several cancer types. The overarching aim of this study sought to characterise the endocytosis pathways used by cancer cells in vivo to internalise therapeutic mAbs and highlight changes in immune cell populations between mAb and mAb-PCZ combination therapies. Concurrently, this study assessed the safety and efficacy of PCZ with mAb therapy in a clinically relevant in vivo human epidermal growth factor receptor 2-postive (HER2+) breast cancer murine model.

Mice bearing HER2+ patient derived xenograft (PDX) tumours were humanised with peripheral blood mononuclear cells prior to therapy commencement. Mice were treated with therapeutic agents comprising the current standard of care (SoC) for stage IV HER2+ breast cancer (trastuzumab, pertuzumab, paclitaxel) as monotherapies or combination therapies with PCZ at dynamin inhibitory concentrations. Tumour clearance efficacy and safety of cytotoxic antibody-drug conjugate trastuzumab deruxtecan (T-DXd) was also assessed as a monotherapy or together with PCZ.

No major adverse outcomes were observed in any treatment group. Only treatments involving SoC and T-DXd were effective in clearing tumours and improving survival. PCZ reverses therapeutic resistance but in this model, tumours were sensitive to therapy. PCZ instead altered recurrent growth after therapy cessation in SoC-treated mice as rebound tumour growth was delayed. This extension in survival did not reach statistical significance as some mice were sacrificed at an earlier timepoint for electron microscopy analysis of tumours. This effect on recurrence and metastases has been previously reported with statistical significance for PCZ-cetuximab combination therapy (Chew et al., Cell 2020).

These results indicate that temporary and reversible inhibition of dynamin via PCZ administration is safe with HER2-targeted therapies in a humanised breast cancer murine setting and has the potential to delay the onset and/or growth of recurrent tumours after therapy cessation. The potential for PCZ in improving therapy-resistant tumours remains, addressing “fear of recurrence” commonly experienced by breast cancer survivors.

  1. Chew, H. Y., De Lima, P. O., Gonzalez Cruz, J. L., Banushi, B., Echejoh, G., Hu, L., . . . Simpson, F. (2020). Endocytosis inhibition in humans to improve responses to ADCC-mediating antibodies. Cell, 180(5), 895-914. doi:10.1016/j.cell.2020.02.019