9/14 Activation of nucleolar DNA damage response as a novel therapeutic strategy for ovarian cancer
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Dr. Elaine Sanij
Peter MacCallum Cancer Centre in Melbourne, Australia
Activation of nucleolar DNA damage response as a novel therapeutic strategy for ovarian cancer
High-grade serous ovarian cancer (HGSOC) accounts for the majority of ovarian cancer and has dismal prognosis. PARP inhibitors (PARPi) have revolutionized the management of the ~50% of patients with homologous recombination (HR) DNA repair-deficient HGSOC. However, acquired resistance to PARPi is a major challenge in the clinic.
We developed the first-in-class drug CX-5461 that inhibits RNA polymerase I transcription of ribosomal RNA genes, selectively kills cancer cells and is currently in Phase I trials in patients with haematological (Peter Mac) and solid cancers (Canada). Our studies have identified cancer cells’ sensitivity to CX-5461 to be driven by oncogenic pathways requiring elevated synthesis of ribosomes and/or alterations in DNA damage response. CX-5461 exhibits substantial efficacy in HR- deficient PARPi-sensitive and PARPi-resistant HGSOC-PDXs in vivo. We propose that CX-5461 will have single agent efficacy in a subset of HGSOC, thus we are planning a phase I/II trial in relapsed ovarian cancer in 2019.
大阪大学微生物病研究所 遺伝子生物学分野 教授 原 英二（内線4260)