Zebrafish Avatars, towards personalised medicine

Despite advances in targeted cancer treatments, we still lack methods to predict how a specific cancer in a specific patient will respond to a given therapy. Consequently, patients undergo rounds-of-trial-and-error approaches based on guidelines to find the best treatment, often subjected to unnecessary toxicity. We have been developing zebrafish xenografts, also known as zAvatars, as sensors for cancer behavior and personalized therapy screening. This approach is based on the injection of tumor cells from patients into zebrafish embryos to then test which is the most effective therapy for that particular patient. Our data show that this model not only shows sufficient resolution to distinguish functional tumor behaviors in just 4-days, but also reveals differential sensitivity to anti-cancer therapies.
zAVATARS can predict patient clinical outcome in 91% of the cases in colorectal cancer, 100% in breast cancer and 89% in ovarian cancer. We have also expanded our assay to screen responses to radiotherapy and targeted therapies.

The zAVATAR randomized clinical trial

The outstanding predictive value of the zAVATARS have now led to a multicentric randomized clinical trial in Ovarian and Breast Cancer (see movie).
In this trial, patients will be randomized into 2 groups: clinician-choice or zAvatar-choice. All patients will be treated with a therapeutic option present in international guidelines (NCCN, ABC, ESMO, etc.). What differs between groups is whether the treatment option is chosen by the attending clinician/ patient (standard of care) or by a sensitivity test – the zAvatar-test – where the predefined options of therapy will be tested, and the one that shows the highest cytotoxic effect in tumor cells will be chosen.This trial will be fundamental to bring the zAvatar-test to the clinical setting in the future.
These studies are only possible through the solid collaborations established with in-house clinical Units at the Champalimaud Clinical Center and with different hospitals and international organizations.
The Fior LAB would also like to THANK all the patients and families for their collaboration in our clinical studies.

To escape or not to escape innate immunity

Immunotherapy is a revolutionary approach to cancer treatment. However, many patients do not respond and the potential for serious side effects exists. Therapy often fails because tumor cells are not recognized (they turn invisible) or because of other immune suppressive mechanisms in the tumor microenvironment (TME) that further block therapy. To generate more effective responses to checkpoint immunotherapy, it is critical to select patients that will benefit from therapy, but also discover new compounds that can help fully unleash the immune response. During the development of the zebrafish Avatar studies, Fior uncovered an intricate and intriguing communication between tumor cells and zebrafish innate immune system. Some human tumors can generate a suppressive TME, which blocks tumor rejection allowing tumors to thrive and progress, whereas other tumor cells are quicky rejected by the zebrafish innate immune cells (neutrophils and macrophages). This rejection occurs in just 4 days and tumor cells are completely wiped-out from the host By taking advantage of this unique model, the Fior Lab is focusing on understanding the molecular players involved in this rejection/ suppression process and discover new therapies to be combined with adaptive immunotherapy. Finally, another goal is to evaluate whether zebrafish Avatars can be used to select patients for immunotherapy.