Abstract PR13:Inhibition of RNA polymerase I transcription activates targeted DNA damage response and enhances the efficacy of PARP inhibitors in high-grade ovarian cancer

Elaine Sanij; Kate Hannan; Jiachen Xuan; Shunfei Yan; Jessica Ahern; Anna S Trigos; Natalie Brajanovski; Jinbae Son; Keefe Chan; Olga Kondrashova; Elizabeth Lieschke; Matthew Wakefield; Sarah Ellis; Gretchen Poortinga; C Cullinane; Kum Kum Khanna; Linda Mileshkin; Grant McArthur; John Soong; Els M Berns; Ross Hannan; Clare L. Scott; Karen E.  Sheppard; Richard B Pearson

doi:10.1158/1557-3265.OVCA19-PR13

Abstract PR13:Inhibition of RNA polymerase I transcription activates targeted DNA damage response and enhances the efficacy of PARP inhibitors in high-grade ovarian cancer

Elaine Sanij, Kate Hannan, Jiachen Xuan, Shunfei Yan, Jessica Ahern, Anna S Trigos, Natalie Brajanovski, Jinbae Son, Keefe Chan, Olga Kondrashova, Elizabeth Lieschke, Matthew Wakefield, Sarah Ellis, Gretchen Poortinga, C Cullinane, Kum Kum Khanna, Linda Mileshkin, Grant McArthur, John Soong, Els M BernsRoss Hannan, Clare L. Scott, Karen E. Sheppard, Richard B Pearson

Research output: Contribution to journal › Article › peer-review

Abstract

PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient high-grade serous ovarian cancer (HGSOC). However, acquired resistance to PARPi is a major challenge in the clinic. The specific inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) has demonstrated single-agent antitumor activity in p53 wild-type and p53-mutant hematologic malignancies (first-in-human trial, dose escalation study of CX-5461 at Peter MacCallum Cancer Centre) (Khot et al., Cancer Discov 2019). CX-5461 has also been reported to exhibit synthetic lethality with BRCA1/2 deficiency through stabilization of G-quadruplex DNA (GQ) structures. Here, we investigate the efficacy of CX-5461 in treating HGSOC.

Original language	English
Journal	Clinical Cancer Research
Volume	26
Issue number	13_Supplement
DOIs	https://doi.org/10.1158/1557-3265.OVCA19-PR13
Publication status	Published - 2020

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Sanij, E., Hannan, K., Xuan, J., Yan, S., Ahern, J., Trigos, A. S., Brajanovski, N., Son, J., Chan, K., Kondrashova, O., Lieschke, E., Wakefield, M., Ellis, S., Poortinga, G., Cullinane, C., Khanna, K. K., Mileshkin, L., McArthur, G., Soong, J., ... Pearson, R. B. (2020). Abstract PR13:Inhibition of RNA polymerase I transcription activates targeted DNA damage response and enhances the efficacy of PARP inhibitors in high-grade ovarian cancer. Clinical Cancer Research, 26(13_Supplement). https://doi.org/10.1158/1557-3265.OVCA19-PR13

@article{5b3671b4d15e48088e4fac0da5950cda,

title = "Abstract PR13:Inhibition of RNA polymerase I transcription activates targeted DNA damage response and enhances the efficacy of PARP inhibitors in high-grade ovarian cancer",

abstract = "PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient high-grade serous ovarian cancer (HGSOC). However, acquired resistance to PARPi is a major challenge in the clinic. The specific inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) has demonstrated single-agent antitumor activity in p53 wild-type and p53-mutant hematologic malignancies (first-in-human trial, dose escalation study of CX-5461 at Peter MacCallum Cancer Centre) (Khot et al., Cancer Discov 2019). CX-5461 has also been reported to exhibit synthetic lethality with BRCA1/2 deficiency through stabilization of G-quadruplex DNA (GQ) structures. Here, we investigate the efficacy of CX-5461 in treating HGSOC.",

author = "Elaine Sanij and Kate Hannan and Jiachen Xuan and Shunfei Yan and Jessica Ahern and Trigos, {Anna S} and Natalie Brajanovski and Jinbae Son and Keefe Chan and Olga Kondrashova and Elizabeth Lieschke and Matthew Wakefield and Sarah Ellis and Gretchen Poortinga and C Cullinane and Khanna, {Kum Kum} and Linda Mileshkin and Grant McArthur and John Soong and Berns, {Els M} and Ross Hannan and Scott, {Clare L.} and Sheppard, {Karen E.} and Pearson, {Richard B}",

year = "2020",

doi = "10.1158/1557-3265.OVCA19-PR13",

language = "English",

volume = "26",

journal = "Clinical Cancer Research",

publisher = "American Association for Cancer Research",

number = "13_Supplement",

}

Sanij, E, Hannan, K, Xuan, J, Yan, S, Ahern, J, Trigos, AS, Brajanovski, N, Son, J, Chan, K, Kondrashova, O, Lieschke, E, Wakefield, M, Ellis, S, Poortinga, G, Cullinane, C, Khanna, KK, Mileshkin, L, McArthur, G, Soong, J, Berns, EM, Hannan, R, Scott, CL, Sheppard, KE & Pearson, RB 2020, 'Abstract PR13:Inhibition of RNA polymerase I transcription activates targeted DNA damage response and enhances the efficacy of PARP inhibitors in high-grade ovarian cancer', Clinical Cancer Research, vol. 26, no. 13_Supplement. https://doi.org/10.1158/1557-3265.OVCA19-PR13

TY - JOUR

T1 - Abstract PR13:Inhibition of RNA polymerase I transcription activates targeted DNA damage response and enhances the efficacy of PARP inhibitors in high-grade ovarian cancer

AU - Sanij, Elaine

AU - Hannan, Kate

AU - Xuan, Jiachen

AU - Yan, Shunfei

AU - Ahern, Jessica

AU - Trigos, Anna S

AU - Brajanovski, Natalie

AU - Son, Jinbae

AU - Chan, Keefe

AU - Kondrashova, Olga

AU - Lieschke, Elizabeth

AU - Wakefield, Matthew

AU - Ellis, Sarah

AU - Poortinga, Gretchen

AU - Cullinane, C

AU - Khanna, Kum Kum

AU - Mileshkin, Linda

AU - McArthur, Grant

AU - Soong, John

AU - Berns, Els M

AU - Hannan, Ross

AU - Scott, Clare L.

AU - Sheppard, Karen E.

AU - Pearson, Richard B

PY - 2020

Y1 - 2020

N2 - PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient high-grade serous ovarian cancer (HGSOC). However, acquired resistance to PARPi is a major challenge in the clinic. The specific inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) has demonstrated single-agent antitumor activity in p53 wild-type and p53-mutant hematologic malignancies (first-in-human trial, dose escalation study of CX-5461 at Peter MacCallum Cancer Centre) (Khot et al., Cancer Discov 2019). CX-5461 has also been reported to exhibit synthetic lethality with BRCA1/2 deficiency through stabilization of G-quadruplex DNA (GQ) structures. Here, we investigate the efficacy of CX-5461 in treating HGSOC.

AB - PARP inhibitors (PARPi) have revolutionized disease management of patients with homologous recombination (HR) DNA repair-deficient high-grade serous ovarian cancer (HGSOC). However, acquired resistance to PARPi is a major challenge in the clinic. The specific inhibitor of RNA polymerase I (Pol I) transcription of ribosomal RNA genes (rDNA) has demonstrated single-agent antitumor activity in p53 wild-type and p53-mutant hematologic malignancies (first-in-human trial, dose escalation study of CX-5461 at Peter MacCallum Cancer Centre) (Khot et al., Cancer Discov 2019). CX-5461 has also been reported to exhibit synthetic lethality with BRCA1/2 deficiency through stabilization of G-quadruplex DNA (GQ) structures. Here, we investigate the efficacy of CX-5461 in treating HGSOC.

U2 - 10.1158/1557-3265.OVCA19-PR13

DO - 10.1158/1557-3265.OVCA19-PR13

M3 - Article

VL - 26

JO - Clinical Cancer Research

JF - Clinical Cancer Research

IS - 13_Supplement

ER -

Abstract PR13:Inhibition of RNA polymerase I transcription activates targeted DNA damage response and enhances the efficacy of PARP inhibitors in high-grade ovarian cancer

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