Aquatic Larva May Serve as Predictors of Chemotherapy Response

Are zebrafish larva the future of personalized cancer treatment? Scientists believe so.

In a study published in the Proceedings of the National Academy of Sciences, investigators for the first time were able to demonstrate how the larva could one day become the preferred model for predicting malignant tumor response to therapeutic agents.

Mice serve as adequate models for cancer research because the tumor response to treatments is predictive of its behavior in patients; however, the process is extremely long. If zebrafish larva proves to be a good model for these tests, determining the best chemotherapy to use could be determined in less than 2 weeks.

“We demonstrated for the first time that zebrafish and mice react to treatments in the same way: with the same drugs, we obtain the same results in mice and in zebrafish larva,” said author Miguel Godinho Ferreira.

In 2013, authors Rita Fior and Godinho Ferreira were joined together by a common colleague because both were conducting basic research, but sought ways to help people faster, according to a press release.

Fior, who specialized in developmental biology and studies zebrafish, said she was always “very frustrated about the fact 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.”

Author Godinho Ferreira’s primary interest was how malignant tumors can be not only heterogeneous, but also evolve over time, making it difficult to find an effective chemotherapy agent, according to the release.

“In some cases, the efficacy rate of chemotherapies can be low, sometimes around 35%,” Godinho 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.”

Upon some of the first meetings between Godinho Ferreira and Fior, the investigators shared a common goal, in which they sought to transplant human tumor cells into zebrafish larva without growing them in the lab first.

With the help of financial support from the Champalimaud Foundation and access to the lab at CCU, the investigators could bring their goals to fruition.

The CCU lab was located next to the anatomical pathology service of the clinical center, and the investigators had access to the hospital pharmacy allowing them to integrate into the hospital circuits and transplanting fragments of patients’ tumors into the larva and conducting the same chemotherapy protocols on the fish that are given to the patient.

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

The results of the study showed the fish model had sufficient resolution to detect different treatment requirements, even in genetically similar tumors. The investigators also confirmed that it only required a single mutation to a RAS gene to change a tumor’s response to a chemotherapy agent.

“We obtained incredible resolution power, a sensitivity at the allele level,” Godinho Ferreira said.

Although prior studies have used this type of approach in zebrafish, the current study differed.

“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,” Fior said.

For the last piece of their research, the investigators conducted a preliminary study of predictions by the “zebrafish avatars” for 5 patients.

“We transplanted into the fish tumoral masses from 5 patients with colorectal cancer being treated either at the Champalimaud Clinical Center or at the Amadora-Sintra Hospital,” Fior said.

Typically, patients with colorectal cancer receive chemotherapy following surgery to reduce the risk of relapse. In the study, the avatars of the 5 patients received the same chemotherapy. The treatment response was then compared between the fish and the human patient.

“For the 2 of the patients, the tumors transplanted into the larva did not respond to the chosen chemotherapy,” Fior said. “And in fact, consistent with our results, a short time afterwards those patients relapsed.”

Contrastingly, 2 additional patients whose avatars responded to the treatment continue to do well, according to the release.

The next step in the research is to utilize the same type of comparisons in hundreds of patients to confirm the efficacy of the tests’ predictive power. The investigators estimate it will take approximately 2 years to complete.

“If everything goes well, we will be able to inform oncologists on the results 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,” Godinho 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.”