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

Ian S Miller,Patrick Dicker,William M Gallagher,Liam P Shiels,Emer Conroy,John Crown,Kate Connor,Annette T Byrne,Norma O’ Donovan,Robert S Kerbel

doi:10.1038/s41598-019-45444-0

Abstract

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 10 mg/kg Trast +5 mg/kg paclitaxel (PAC) IP once weekly for 6 cycles +/− weekly BVZ (5 mg/kg IP). Metastasis was monitored by imaging. Using these models our data confirms that the addition of the anti-angiogenic antibody BVZ to adjuvant Trast + chemotherapy provides no additional benefit 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.

Highlights

In a seminal paper published in 1971, Dr Judah Folkman hypothesized that tumor growth was dependent on the production of new blood vessels or angiogenesis and inhibition of angiogenesis could be of therapeutic benefit[1]
Supporting pre-clinical xenograft studies indicated that the combination of trastuzumab (Trast, anti-Her2+ monoclonal antibody) plus BVZ was synergistic compared with either treatment delivered as a monotherapy[6]
Analysis of two orthotopic surgical resection models of Her2+ breast cancer show no significant difference in tumour re-growth or survival after treatment with either PT or PTB

Summary

Introduction

In a seminal paper published in 1971, Dr Judah Folkman hypothesized that tumor growth was dependent on the production of new blood vessels or angiogenesis and inhibition of angiogenesis could be of therapeutic benefit[1]. Several clinical trials were initiated in the adjuvant setting with all showing a disappointing lack of efficacy[7] One such adjuvant trial (NSABP-B44 “BETH”) sought to determine whether a treatment regimen of chemotherapy plus Trast and BVZ would improve invasive disease-free survival (IDFS), compared with a regimen of chemotherapy plus Trast. There was an associated increase in adverse events in the BVZ arm[8] These clinical results, being in stark contrast to the supporting pre-clinical data[6], highlight the need for better, more accurate pre-clinical models, which can faithfully predict patient outcomes to novel therapeutics targeting the TME and which might be used in the adjuvant setting. We further employed 18F- Fluoro-deoxyglucose positron emission tomography (18F-FDG PET) as a treatment response marker

Methods

Results

Conclusion