Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models

Our plain-English summary of Synergistic Effect of a Mesothelin-Targeted 227Th Conjugate in Combination with DNA Damage Response Inhibitors in Ovarian Cancer Xenograft Models, by K. Wickstroem, U.B. Hagemann, V. Cruciani, et al (Journal of Nuclear Medicine, 2019).

The study

• Authors: K. Wickstroem, U.B. Hagemann, V. Cruciani, A.M. Wengner, A. Kristian, C. Ellingsen, G. Siemeister, R.M. Bjerke, J. Karlsson, O.B. Ryan, L. Linden, D. Mumberg, K. Ziegelbauer, A.S. Cuthbertson
• Journal: Journal of Nuclear Medicine
• Published: 2019;60(9):1293-1300
• Cited by: 48 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Targeted 227Th conjugates (TTCs) represent a new class of therapeutic radiopharmaceuticals for targeted α-therapy. They comprise the α-emitter 227Th complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the α-particles induce antitumor activity, driven by the induction of complex DNA double-strand breaks. We hypothesized that blocking the DNA damage response (DDR) pathway should further sensitize cancer cells by inhibiting DNA repair, thereby increasing the response to TTCs. Methods: This article reports the evaluation of the mesothelin (MSLN)-TTC conjugate (BAY 2287411) in combination with several DDR inhibitors, each of them blocking different DDR pathway enzymes. MSLN is a validated cancer target known to be overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancer, with low expression in normal tissue. In vitro cytotoxicity experiments were performed on cancer cell lines by combining the MSLN-TTC with inhibitors of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3-related (ATR), DNA-dependent protein kinase, and poly[adenosine diphosphate ribose] polymerase (PARP) 1/2. Further, we evaluated the antitumor efficacy of the MSLN-TTC in combination with DDR inhibitors in human ovarian cancer xenograft models. Results: Synergistic activity was observed in vitro for all tested inhibitors (inhibitors are denoted herein by the suffix "i") when combined with MSLN-TTC. ATRi and PARPi appeared to induce the strongest increase in potency. Further, in vivo antitumor efficacy of the MSLN-TTC in combination with ATRi or PARPi was investigated in the OVCAR-3 and OVCAR-8 xenograft models in nude mice, demonstrating synergistic antitumor activity for the ATRi combination at doses demonstrated to be nonefficacious when administered as monotherapy. Conclusion: The presented data support the mechanism-based rationale for combining the MSLN-TTC with DDR inhibitors as new treatment strategies in MSLN-positive ovarian cancer.

© 2019 by the Society of Nuclear Medicine and Molecular Imaging.

In plain English

This laboratory study tested an experimental drug, MSLN-TTC (BAY 2287411). It is an antibody that targets the protein mesothelin and carries the radioactive alpha-emitter thorium-227. The authors combined it with drugs that block DNA repair: inhibitors of ATM, ATR, DNA-PK and PARP. The study involved cancer cell lines and mice, not asbestos exposure or patients. In cell lines, all four inhibitors acted synergistically with MSLN-TTC in the ovarian cancer line OVCAR-3. The ATR inhibitor was synergistic in every line tested, including NCI-H226, listed as a lung/mesothelioma line. In mice with human ovarian tumors (OVCAR-3), a single dose of 100 kBq/kg MSLN-TTC did not significantly slow growth by itself. Combined with the ATR inhibitor, it inhibited growth significantly compared with either treatment alone, which the authors judged synergistic. The PARP inhibitor combination was judged additive. In a second ovarian model (OVCAR-8), the ATR combination also outperformed each drug alone. White blood cells and platelets fell to a similar degree with MSLN-TTC alone and with the combination. The authors concluded the data support this combination strategy for mesothelin-positive ovarian cancer.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Preclinical laboratory study: in vitro cell-line experiments and mouse xenograft (animal) experiments
• Who was studied: Human cancer cell lines: OVCAR-3 and OVCAR-8 (ovarian), NCI-H226 (lung/mesothelioma), Capan-2 (pancreatic) and HT29-MSLN (colorectal). Female immunodeficient mice (athymic nude for OVCAR-3, CB-17 SCID for OVCAR-8) carrying human ovarian tumors, 10 mice per group.
• Exposure: Mesothelin-targeted thorium-227 conjugate (MSLN-TTC) alone or combined with DNA damage response inhibitors: ATRi (BAY 1895344), ATMi (AZD0156), DNA-PKi (VX-984) and PARPi (olaparib). In mice, MSLN-TTC was given at 100, 250 or 500 kBq/kg as a single dose (OVCAR-3), or 3 x 200 kBq/kg (OVCAR-8). Not an asbestos exposure study.
• Main results:
  • In the OVCAR-3 ovarian cell line, all four DNA repair inhibitors showed synergy with MSLN-TTC.
  • Table 1 lists the ATR inhibitor combination as synergistic in all five cell lines tested, with mean combination indexes of 0.4 to 0.7. It was not the strongest in every line. In HT29-MSLN, the PARP inhibitor combination had a lower mean combination index (0.6 plus or minus 0.1) than the ATR inhibitor combination (0.7 plus or minus 0.1). In OVCAR-8, only the ATR inhibitor was tested.
  • The ATM and DNA-PK inhibitors gave less consistent synergy and produced additive and antagonistic effects in some lines.
  • In the NCI-H226 lung/mesothelioma cell line, the table gives combination indexes of 0.9 plus or minus 0.2 (additive) for the ATM inhibitor, 0.5 plus or minus 0.1 (synergistic) for the ATR inhibitor, 0.7 plus or minus 0.1 (synergistic) for the DNA-PK inhibitor and 0.8 plus or minus 0.1 (additive) for the PARP inhibitor.
  • In OVCAR-3 cells, adding a non-efficacious dose of ATR inhibitor (10 nM) to MSLN-TTC reduced the share of cells entering the G2/M phase and increased the number of cells with DNA double-strand break marking.
  • In OVCAR-3 tumor-bearing mice given MSLN-TTC alone, single doses of 250 and 500 kBq/kg significantly inhibited tumor growth compared with vehicle (p less than 0.0001).
  • In the same mice, neither the 100 kBq/kg dose of MSLN-TTC nor the isotype control differed significantly from vehicle.
  • In OVCAR-3 mice, MSLN-TTC at 100 kBq/kg plus the ATR inhibitor significantly inhibited tumor growth compared with vehicle (P less than 0.0001) and with monotherapy groups (p less than 0.01). The combination was judged synergistic by the Bliss model.
  • In OVCAR-3 mice, the PARP inhibitor combination was not significantly better than MSLN-TTC alone and was judged additive.
  • In OVCAR-8 mice, MSLN-TTC (3 x 200 kBq/kg) plus the ATR inhibitor gave a significantly greater anti-tumor effect than monotherapy (p less than 0.001). The authors described this as synergistic.
  • In OVCAR-8 mice, white blood cells and platelets were significantly reduced with both MSLN-TTC alone and the ATR combination compared with vehicle (P less than 0.001). The reduction was comparable between the two groups.
  • Body weights remained stable in the OVCAR-3 combination studies.
• The authors' conclusion: The authors concluded that the study supports combining MSLN-TTC with DNA damage response inhibitors as a new strategy for treating ovarian cancer that overexpresses mesothelin.
• Limitations the authors state:
  • Alternative dosing schedules were not studied and need further work.
  • The two ovarian models are not sufficiently comparable to judge the role of specific tumor mutations in synergy.
  • The lack of added blood toxicity was assessed only at one timepoint.
  • Whether the PARP inhibitor combination works better in tumors with BRCA1/2 defects was not tested.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Ovarian cancer.

Medical terms in this study, explained in our Lexicon: Synergistic Effect, Mesothelin, Ovarian Cancer, Monoclonal Antibody, Mesothelioma.

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