PARP inhibition in UV-associated angiosarcoma preclinical models

Marije E Weidema,Yvonne M H Versleijen-Jonkers,M C H Hogenes,Anke E M Van Erp,Palga-Group ,Melissa H S Hillebrandt-Roeffen,Ingrid M E Desar,Mikio Masuzawa,J W R Meyer,Uta E Flucke,Winette T A Van Der Graaf

doi:10.1007/s00432-021-03678-4

Abstract

PurposeAngiosarcoma (AS) is a rare vasoformative sarcoma, with poor overall survival and a high need for novel treatment options. Clinically, AS consists of different subtypes, including AS related to previous UV exposure (UV AS) which could indicate susceptibility to DNA damage repair inhibition. We, therefore, investigated the presence of biomarkers PARP1 (poly(ADP-ribose)polymerase-1) and Schlafen-11 (SLFN11) in UV AS. Based on experiences in other sarcomas, we examined (combination) treatment of PARP inhibitor (PARPi) olaparib and temozolomide (TMZ) in UV AS cell lines.MethodsPreviously collected UV AS (n = 47) and non-UV AS (n = 96) patient samples and two UV AS cell lines (MO-LAS and AS-M) were immunohistochemically assessed for PARP1 and SLFN11 expression. Both cell lines were treated with single agents PARPi olaparib and TMZ, and the combination treatment. Next, cell viability and treatment synergy were analyzed. In addition, effects on apoptosis and DNA damage were examined.ResultsIn 46/47 UV AS samples (98%), PARP1 expression was present. SLFN11 was expressed in 80% (37/46) of cases. Olaparib and TMZ combination treatment was synergistic in both cell lines, with significantly increased apoptosis compared to single agent treatment. Furthermore, a significant increase in DNA damage marker γH2AX was present in both cell lines after combination therapy.ConclusionWe showed combination treatment of olaparib with TMZ was synergistic in UV AS cell lines. Expression of PARP1 and SLFN11 was present in the majority of UV AS tumor samples. Together, these results suggest combination treatment of olaparib and TMZ is a potential novel AS subtype-specific treatment option for UV AS patients.

Highlights

Angiosarcoma (AS) is a rare sarcoma with endothelial properties and an incidence of 0.15 per 100.000 persons per year (NCIN 2012)
A total of 47 UV AS patients were assessed for immunohistochemical expression of poly(ADPribose) polymerase-1 (PARP1) and SLFN11
Tumor samples of 96 non-UV AS patients were assessed for PARP1 and SLFN11 expression, showing 89–100% PARP1 positivity and 63–66% cases positive for SLFN11 expression

Summary

Introduction

Angiosarcoma (AS) is a rare sarcoma with endothelial properties and an incidence of 0.15 per 100.000 persons per year (NCIN 2012). AS) or due to external damaging factors such as UV exposure, radiation therapy or chronic lymphedema (secondary AS). Localized AS treatment consists of surgery, combined with (neo-)adjuvant radiation therapy or chemotherapy. Patients with metastatic disease usually receive chemotherapy, either anthracycline-based regimens or paclitaxel (Penel et al 2012). Later lines of treatment can include other chemotherapeutic agents such as gemcitabine (Stacchiotti et al 2012) or targeted therapy with pazopanib (van der Graaf et al 2012; Kollar et al 2017). Reported overall survival (OS) of all AS patients is poor with a 5-year survival rate of around 22–40% (Lahat et al 2010; Wang et al 2017; Weidema et al 2019), dropping to only 15% for metastatic patients (Lahat et al 2010). Small case series have suggested a role for immunotherapy in selected AS patients

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