Fish Larvae Used to Test Effects of Cancer Drugs

A zebrafish with a tumor from a cancer patient (in red). (Rita

(CN) – Zebrafish larvae could eventually supplant mice as the preferred model for optimizing cancer treatments, scientists said Monday.

The efficacy of a specific form of anticancer chemotherapy is generally not tested at a personalized level, which forces doctors to prescribe drug treatments based on success rates determined through large-scale clinical trials, according to the study, published in the journal Proceedings of the National Academy of Sciences.

Current individual-level testing requires transplanting human tumor cells into mice – a process that can only be performed in cancer centers and large hospitals and which takes months to finish.

However, a team of Portuguese scientists have shown for the first time that zebrafish larvae can be a more efficient tool for treating cancer patients.

“We demonstrated for the first time that zebrafish and mice react to treatments in the same way,” said co-lead author Miguel Godinho Ferreira, a cancer researcher at the Instituto Gulbenkian de Ciencia (IGC) in Oeiras, Portugal.

Ferreira and co-lead author Rita Fior, a cancer researcher at Fundacau Champalimaud in Lisbon, Portugal, connected after a colleague informed them that they had the same goal: to improve cancer treatment outcomes.

Fior – who specialized in developmental biologies and studies zebrafish – said she has always been “very frustrated about the fact (that) although we have so much technology, we can put people on the moon, etc., if someone has a tumor we still don’t know which drug is best for that specific tumor, within the several approved therapeutic options.”

Focused on the evolution of tumors, Ferreira had long been concerned about the fact that tumors change over time and are diverse, which makes them difficult to treat with chemotherapy.

“In some cases, the efficacy rate of chemotherapies can be low, sometimes around 35 percent,” Ferreira said. “This means that some patients risk taking inadequate drugs that weaken them – and without a proper test, there is no way to know who will benefit and who won’t.”

The researchers quickly agreed on a common goal of transplanting human tumor cells directly into zebrafish larvae without first being grown in a lab, which can lead to damaging alterations. They wanted to simulate the tumors in the larvae in a manner that is as similar as possible to what actually happens in a patient’s body.

The team worked out of the Champalimaud Centre for the Unknown in Lisbon, Portugal, where they were able to take their assay to patients undergoing therapy. Fior and her colleagues were able to transplant an individual’s tumor into larvae fragments and use the same chemotherapy protocols that were given to the patient.

“The drugs Rita tests on the larvae are what remains of the treatment received by the patient, which would normally be returned to the pharmacy and discarded,” Ferreira said.

The researchers, including clinicians and pathologists, found that the fish model had sufficient resolution to identify different treatment requirements – even among very genetically similar tumors. The team also confirmed that it took a single mutation in a gene called RAS, known for routinely being altered in cancerous tumors, to adjust a cancer’s response to a given treatment.

“There were some previous independent studies on this type of approach in the zebrafish,” Fior said. “What is new in our work is that we challenged the model to see if it could detect even small differences, screened the available therapeutic options to test their efficacy, compared fish with mouse and then did proof-of-concept experiments using patient samples.”

The team then completed a preliminary study of the predictions supplied by examples of five colorectal cancer patients. After surgery, these patients are typically given chemotherapy to limit the probability of relapse. The researchers submitted the patients’ samples to the same chemotherapy, after which they compared the response to treatment in both the fish and patients.

“For two of the patients, the tumors transplanted into the larvae did not respond to the chosen chemotherapy,” said Fior.

Ferreira added, “Consistent with our results, a short time afterwards those patients relapsed.” The samples offered the correct answer in four of five cases.

The researchers now plan to apply the same type of comparison to hundreds of patients in order to confirm the test’s predictive power. This could take about two years to complete.

“If everything goes well, we will be able to inform oncologists on the result of the different therapies in the avatars; they will always have the final word in terms of deciding which therapy to choose, but they will be able to base themselves on individual tests,” Ferreira said.

“Our dream is to develop an ‘antibiogram’ for cancer. Just as we currently do this today for bacterial infections, we hope to obtain a kind of matrix for each patient of the efficacy of the various drugs that will allow physicians to choose the most indicated therapy for each person.”

 

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