Targeting homologous recombination deficiency in uterine leiomyosarcoma

J Exp Clin Cancer Res. 2023 May 4;42(1):112. doi: 10.1186/s13046-023-02687-0.

Genevieve Dall ^# ¹ ², Cassandra J Vandenberg ^# ³ ⁴, Ksenija Nesic ¹ ², Gayanie Ratnayake ⁵, Wenying Zhu ⁶, Joseph H A Vissers ⁶, Justin Bedő ¹ ⁷, Jocelyn Penington ¹, Matthew J Wakefield ¹ ², Damien Kee ¹ ⁸ ⁹ ¹⁰ ¹¹, Amandine Carmagnac ¹, Ratana Lim ¹, Kristy Shield-Artin ¹ ², Briony Milesi ¹ ⁵, Amanda Lobley ¹ ⁵, Elizabeth L Kyran ¹, Emily O'Grady ¹, Joshua Tram ¹, Warren Zhou ¹, Devindee Nugawela ¹, Kym Pham Stewart ⁶, Reece Caldwell ¹⁰, Lia Papadopoulos ¹ ¹⁰, Ashley P Ng ¹ ² ¹¹ ¹², Alexander Dobrovic ⁹, Stephen B Fox ¹¹, Orla McNally ⁵ ¹¹ ¹³, Jeremy D Power ¹⁴, Tarek Meniawy ¹⁵, Teng Han Tan ¹¹, Ian M Collins ¹⁶ ¹⁷, Oliver Klein ⁸ ⁹, Stephen Barnett ¹² ¹⁸, Inger Olesen ¹ ¹⁹, Anne Hamilton ⁵ ¹¹, Oliver Hofmann ⁶, Sean Grimmond ^# ⁶, Anthony T Papenfuss ^# ¹ ² ¹¹, Clare L Scott ^# ¹ ² ⁵ ¹⁰ ¹¹ ¹² ¹³, Holly E Barker ^# ¹ ²

Affiliations

1 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia.
2 Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia.
3 Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, 3052, Australia. vandenberg@wehi.edu.au.
4 Department of Medical Biology, University of Melbourne, Parkville, VIC, 3052, Australia. vandenberg@wehi.edu.au.
5 Royal Women's Hospital, Parkville, VIC, 3052, Australia.
6 Centre for Cancer Research and Department of Clinical Pathology, University of Melbourne, Parkville, VIC, 3010, Australia.
7 School of Computing and Information Systems, the University of Melbourne, Parkville, VIC, 3010, Australia.
8 Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, 3084, Australia.
9 Austin Health, Heidelberg, VIC, 3084, Australia.
10 Australian Rare Cancer Portal, BioGrid Australia, Melbourne Health, Parkville, VIC, 3052, Australia.
11 Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, The University of Melbourne, Victoria, 3010, Australia.
12 Royal Melbourne Hospital, Parkville, VIC, 3052, Australia.
13 Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, VIC, 3010, Australia.
14 Launceston General Hospital, Launceston, TAS, 7250, Australia.
15 University of Western Australia, Perth, WA, 6009, Australia.
16 SouthWest Healthcare, Warrnambool, VIC, 3280, Australia.
17 Faculty of Health, School of Medicine, Deakin University, Warrnambool, VIC, 3280, Australia.
18 Western Hospital, Footscray, VIC, 3011, Australia.
19 University Hospital Geelong, Geelong, VIC, 3220, Australia.
# Contributed equally.

PMID: 37143137 DOI: 10.1186/s13046-023-02687-0

Abstract

Background: Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy, with individuals with advanced uLMS having a five-year survival of < 10%. Mutations in the homologous recombination (HR) DNA repair pathway have been observed in ~ 10% of uLMS cases, with reports of some individuals benefiting from poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) therapy, which targets this DNA repair defect. In this report, we screened individuals with uLMS, accrued nationally, for mutations in the HR repair pathway and explored new approaches to therapeutic targeting.

Methods: A cohort of 58 individuals with uLMS were screened for HR Deficiency (HRD) using whole genome Sequencing (WGS), whole exome Sequencing (WES) or NGS panel testing. Individuals identified to have HRD uLMS were offered PARPi therapy and clinical outcome details collected. Patient-derived xenografts (PDX) were generated for therapeutic targeting.

Results: All 13 uLMS samples analysed by WGS had a dominant COSMIC mutational signature 3; 11 of these had high genome-wide loss of heterozygosity (LOH) (> 0.2) but only two samples had a CHORD score > 50%, one of which had a homozygous pathogenic alteration in an HR gene (deletion in BRCA2). A further three samples harboured homozygous HRD alterations (all deletions in BRCA2), detected by WES or panel Sequencing, with 5/58 (9%) individuals having HRD uLMS. All five individuals gained access to PARPi therapy. Two of three individuals with mature clinical follow up achieved a complete response or durable partial response (PR) with the subsequent addition of platinum to PARPi upon minor progression during initial PR on PARPi. Corresponding PDX responses were most rapid, complete and sustained with the PARP1-specific PARPi, AZD5305, compared with either olaparib alone or olaparib plus cisplatin, even in a paired sample of a BRCA2-deleted PDX, derived following PARPi therapy in the patient, which had developed PARPi-resistance mutations in PRKDC, encoding DNA-PKcs.

Conclusions: Our work demonstrates the value of identifying HRD for therapeutic targeting by PARPi and platinum in individuals with the aggressive rare malignancy, uLMS and suggests that individuals with HRD uLMS should be included in trials of PARP1-specific PARPi.

Keywords

Homologous recombination deficiency; PARP inhibitors; Patient-derived xenografts; Rare cancers; Uterine leiomyosarcoma.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-10162

Olaparib

99.98%, PARP抑制剂

PARP; Autophagy; Mitophagy

Cancer

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