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Durability of cell line xenograft resection models to interrogate tumor micro-environment targeting agents.

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posted on 30.03.2022, 15:03 authored by Ian MillerIan Miller, Liam ShielsLiam Shiels, Emer Conroy, Kate ConnorKate Connor, Patrick DickerPatrick Dicker, William M Gallagher, Norma O'Donovan, Robert S. Kerbel, John Crown, Annette ByrneAnnette Byrne

Angiogenesis is a key tumor microenvironment (TME) event underpinning tumor growth and metastasis. Nevertheless, the relatively poor performance of anti-angiogenic therapies in clinical trials compared to pre-clinical studies implies that classical subcutaneous xenograft models have limited predictive potential in this setting. To address this issue, we established orthotopic surgical resection models of breast cancer, which replicate the phenotype of clinical post-resection micro-metastasis. To demonstrate the power and precision of these models, we recapitulated the BETH adjuvant trial (NCT00625898) where the addition of bevacizumab (BVZ) to chemotherapy plus trastuzumab (Trast) failed to provide additional benefit. SCID mice were orthotopically implanted with bioluminescent Her2+ MDA-MB-231 or HCC1954 cells and tumors resected c.5 weeks later. Following resection, mice were treated with 10mg/kg Trast +5mg/kg paclitaxel (PAC) IP once weekly for 6 cycles +/− weekly BVZ (5mg/kg IP). Metastasis was monitored by imaging. Using these models our data confrms that the addition of the anti-angiogenic antibody BVZ to adjuvant Trast+chemotherapy provides no additional beneft compared with Trast+chemotherapy alone. Previous studies using non-resection subcutaneously engrafted xenografts failed to predict this outcome. Our results provide compelling evidence for the utility of cell line xenograft resection models to predict clinical outcome for TME targeting agents.

Funding

Clinical Cancer Research Trust, the Irish Cancer Society Collaborative Cancer Research Centre under BREAST-PREDICT grant CCRC13GAL (www.breastpredict.com); Canadian Institutes for Health Research (CIHR); European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie ITN initiative (Grant Agreement # 766069)

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Comments

This article is available from Springer Nature at https://www.nature.com/articles/s41598-019-45444-0

Published Citation

Miller IS, Shiels LP, Conroy E, Connor K, Dicker P, Gallagher WM, O'Donovan N, Kerbel RS, Crown J, Byrne AT. Durability of cell line xenograft resection models to interrogate tumor micro-environment targeting agents. Scientific Reports. 2019 9(1):9204

Publication Date

2019-06-24

PubMed ID

31235775

Department/Unit

  • Data Science Centre
  • Physiology and Medical Physics