1. Academic Validation
  2. PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation

PARP1 Inhibition Radiosensitizes Models of Inflammatory Breast Cancer to Ionizing Radiation

  • Mol Cancer Ther. 2019 Nov;18(11):2063-2073. doi: 10.1158/1535-7163.MCT-19-0520.
Anna R Michmerhuizen  # 1 2 Andrea M Pesch  # 1 3 Leah Moubadder 1 Benjamin C Chandler 1 4 Kari Wilder-Romans 1 Meleah Cameron 1 Eric Olsen 1 Dafydd G Thomas 5 6 Amanda Zhang 1 Nicole Hirsh 1 Cassandra L Ritter 1 Meilan Liu 1 Shyam Nyati 1 Lori J Pierce 1 5 Reshma Jagsi 1 7 Corey Speers 8 5
Affiliations

Affiliations

  • 1 Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
  • 2 Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
  • 3 Department of Pharmacology, University of Michigan, Ann Arbor, Michigan.
  • 4 Cancer Biology Program, University of Michigan, Ann Arbor, Michigan.
  • 5 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan.
  • 6 Department of Pathology, University of Michigan, Ann Arbor, Michigan.
  • 7 Center for Bioethics and Social Sciences, University of Michigan, Ann Arbor, Michigan.
  • 8 Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. cspeers@med.umich.edu.
  • # Contributed equally.
Abstract

Sustained locoregional control of disease is a significant issue in patients with inflammatory breast Cancer (IBC), with local control rates of 80% or less at 5 years. Given the unsatisfactory outcomes for these patients, there is a clear need for intensification of local therapy, including radiation. Inhibition of the DNA repair protein PARP1 has had little efficacy as a single agent in breast Cancer outside of studies restricted to patients with BRCA mutations; however, PARP1 inhibition (PARPi) may lead to the radiosensitization of aggressive tumor types. Thus, this study investigates inhibition of PARP1 as a novel and promising radiosensitization strategy in IBC. In multiple existing IBC models (SUM-149, SUM-190, MDA-IBC-3), PARPi (AZD2281-olaparib and ABT-888-veliparib) had limited single-agent efficacy (IC50 > 10 μmol/L) in proliferation assays. Despite limited single-agent efficacy, submicromolar concentrations of AZD2281 in combination with RT led to significant radiosensitization (rER 1.12-1.76). This effect was partially dependent on BRCA1 mutational status. Radiosensitization was due, at least in part, to delayed resolution of double strand DNA breaks as measured by multiple assays. Using a SUM-190 xenograft model in vivo, the combination of PARPi and RT significantly delays tumor doubling and tripling times compared with PARPi or RT alone with limited toxicity. This study demonstrates that PARPi improves the effectiveness of radiotherapy in IBC models and provides the preclinical rationale for the opening phase II randomized trial of RT ± PARPi in women with IBC (SWOG 1706, NCT03598257).

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