Journal article
Targeting the ribosome to treat multiple myeloma
Kylee H Maclachlan, Kezia Gitareja, Jian Kang, Andrew Cuddihy, Yuxi Cao, Nadine Hein, Carleen Cullinane, Ching-Seng Ang, Natalie Brajanovski, Richard B Pearson, Amit Khot, Elaine Sanij, Ross D Hannan, Gretchen Poortinga, Simon J Harrison
Molecular Therapy - Oncolytics | Elsevier | Published : 2024
Abstract
The high rates of protein synthesis and processing render multiple myeloma (MM) cells vulnerable to perturbations in protein homeostasis. The induction of proteotoxic stress by targeting protein degradation with proteasome inhibitors (PIs) has revolutionized the treatment of MM. However, resistance to PIs is inevitable and represents an ongoing clinical challenge. Our first-in-human study of the selective inhibitor of RNA polymerase I transcription of ribosomal RNA genes, CX-5461, has demonstrated a potential signal for anti-tumor activity in three of six heavily pre-treated MM patients. Here, we show that CX-5461 has potent anti-myeloma activity in PI-resistant MM preclinical models in vitr..
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Grants
Awarded by International Myeloma Society
Funding Acknowledgements
This research was funded by Cancer Council Victoria (project grant#1184873) , Tour de Cure Foundation, and the Barrie Dalgleish Centre for Myeloma and Related Blood Cancers. K.H.M. was supported by PhD grants from Leukaemia Foundation of Australia, the Royal Australasian College of Physicians, the Royal College of Pathologists of Australasia, the Multiple Myeloma Research Foundation, the American Society of Hematology, and the International Myeloma Society. E.S. received support from the Victorian Cancer Agency (Research Fellowship MCRF19007) . J.K. received support from the 5Point Foundation (Christine Martin Fellowship) .