Associação Portuguesa de Investigação em Cancro
Zebrafish xenografts as a fast screening platform for bevacizumab cancer therapy
Zebrafish xenografts as a fast screening platform for bevacizumab cancer therapy
Angiogenesis is a well-recognized hallmark of cancer, critically involved in tumor growth and metastatic spread. One of the key players in tumor-induced angiogenesis is VEGF-A, which is often found upregulated in many solid tumors. Bevacizumab is a humanized monoclonal antibody, whose mechanism of action is to target and neutralize human VEGF-A. Currently, bevacizumab is used in the clinic as a single agent or combined with antineoplastic drugs for several advanced cancers.
The lack of predictive biomarkers of response/resistance does not allow a correct selection of patients that could really benefit from bevacizumab therapy.
Overall average response rates for bevacizumab as monotherapy are neither satisfactory nor consistent, ranging from 5.9% (metastatic melanoma) to 9.3% (metastatic breast cancer), but can reach 54.8% in glioblastoma. In addition, bevacizumab treatment can be associated with serious side effects, such as cardiovascular complications, bleeding and renal toxicity.
Recently, we developed zebrafish xenografts to screen therapeutic options in advanced CRC. Also, we and others have shown that zebrafish xenografts can be used to screen for cancer-driven angiogenesis and metastatic potential.
With the aim of challenging zebrafish xenografts as an in vivo screening platform for bevacizumab responses, we used several representative tumor cell models of triple negative breast cancer (TNBC) and CRC that express VEGF-A. In just 4 days, we were able to evaluate the reported heterogeneity of responses to bevacizumab treatment on angiogenesis and metastasis, along with its direct impact on tumor biology. As a proof-of-principle, we also generated breast cancer and CRC zebrafish PDX (zPDX or zAvatars) and show that we can detect similar phenotypic profiles. Importantly, we provide two case studies where the zAvatars showed resistance to bevacizumab and their corresponding patients progressed under treatment, corroborating our results. Overall, our results suggest that zAvatars constitute a promising in vivo model to decide bevacizumab treatment in a personalized manner.
Authors and Afiliations:
Cátia Rebelo de Almeida - Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Raquel Valente Mendes - Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Anna Pezzarossa - Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Joaquim Gago - Gastric Unit, Champalimaud Clinical Center, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Carlos Carvalho - Gastric Unit, Champalimaud Clinical Center, Champalimaud Foundation, 1400-038 Lisbon, Portugal
António Alves - Hospital Prof. Doutor Fernando Fonseca, Pathological Anatomy Service, 2720-276
Amadora, Portugal
Vitor Nunes - Surgery Unit B, Hospital Prof. Doutor Fernando Fonseca, 2720-276 Amadora, Portugal
Maria José Brito - Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Maria João Cardoso - Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Joana Ribeiro - Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Fátima Cardoso - Breast Unit, Champalimaud Clinical Center, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Miguel Godinho Ferreira - Institute for Research on Cancer and Aging of Nice (IRCAN), Université Côte d’Azur, U1081 UMR7284 UNS, 06107 Nice, France
Rita Fior - Champalimaud Centre for the Unknown, Champalimaud Foundation, 1400-038 Lisbon, Portugal
Abstract:
Despite promising preclinical results, average response rates to anti-VEGF therapies, such as bevacizumab, are reduced for most cancers, while incurring in remarkable costs and side effects. Currently, there are no biomarkers available to select patients that can benefit from this therapy. Depending on the individual tumor, anti-VEGF therapies can either block or promote metastasis. In this context, an assay able to predict individual responses prior to treatment, including the impact on metastasis would prove of great value to guide treatment options. Here we show that zebrafish xenografts are able to reveal different responses to bevacizumab in just 4 days, evaluating not only individual tumor responses but also the impact on angiogenesis and micrometastasis. Importantly, we perform proof-of-concept experiments where clinical responses in patients were compared with their matching zebrafish Patient-Derived Xenografts - zAvatars, opening the possibility of using the zebrafish model to screen bevacizumab therapy in a personalized manner.
Journal: Communications Biology