A plan to find the most precise weapon against little Logan's aggressive leukemia

Childhood cancer is a rarity, the worst of all, arising from some random alteration during embryonic development: some cells do not function well and, at some point, begin to grow uncontrollably until forming a tumor. It is a rare disease – there is one case in every 200 in adults – and although 80% of patients are cured, in some children, the tumor reappears and therapeutic alternatives are exhausted. The scientific community struggles to stop initial pediatric cancer and also relapses, such as the one suffered by little Logan Jenner, diagnosed with acute myeloid leukemia at the age of three and who, after 14 months of treatment, reappeared. Without many other treatment options, the boy embarked on an experimental plan by researchers at the University of Florida to find the most precise weapon against his aggressive leukemia: the project, whose results They are published this Thursday in Nature Medicine, consisted of testing a hundred drugs in the laboratory on the patients' tumor cells and identifying the most accurate drug to kill them in the patient's body. The research, still in very early stages and with few patients, worked with Jenner and the little boy has now been cancer-free for two years.

No two tumors are the same: each one has its molecular peculiarities, its more or less protective microenvironment, its resistance mechanisms and its Achilles heels. Oncology knows this and that is why it has turned, in recent years, towards an extremely personalized therapeutic approach to cancer, with increasingly targeted treatments. In search of a window of opportunity to attack the most resistant childhood tumors, researchers from the University of Florida (USA) have also developed a new precision approach where they combine the genetic analysis of the tumor with an individualized drug analysis system – they have a range of 120 treatments, oncological or not, approved by the US Food and Drug Administration (FDA)—to find the best therapeutic option against cancer cells. The objective of this preliminary investigation was to see the feasibility of using this precision oncology guided by molecular techniques to decide treatment in refractory pediatric tumors that no longer responded to conventional therapies.

“Every individual is different and we need to be able to identify and understand the unique properties of the patient's tumor. By personalizing cancer treatments, we will be more precise and provide safer treatment options. Current treatments are based on a one-size-fits-all approach, and that is not ideal because each patient responds uniquely to medications,” reflects Diana Azzam, researcher in the Department of Environmental Health Sciences at the University of Florida and creator of this investigation. To test her technique, Azzam's team recruited around twenty children with various recurrent tumors, from Jenner's myeloid leukemia to glioblastomas, Ewing sarcomas or neuroblastomas, among others. All of them had already received several lines of treatment to try to contain their tumors, but they had relapsed.

The researchers took samples of the participants' tumors and took them to the laboratory to grow them, as if reproducing the natural evolution they would have in the body, to later test those hundred medications on them. In addition, they performed the genomic profile of these tumors in search of alterations in the DNA of the cancer cells that would serve as potential therapeutic targets. “This has helped us, first of all, to recapitulate what is happening in the patient's tumor, but also to offer many options for each person. It allows many medications to be tested in a short response time,” explains Azzam.

In no more than 10 days, the combination of the genomic results and the different response of the patient's cancer cells to the exposed medications allowed the researchers to provide oncologists with the most effective therapeutic plan for each patient. “Patients who were guided by our trial actually had better outcomes compared to their own previous regimens and compared to patients who were not guided by our approach. We have shown that everything that works in the tumor in the laboratory really works in the patient,” celebrates the researcher.

According to the scientists, 21 patients underwent these drug sensitivity tests and 20 of the participants also completed the genomic analysis. The researchers returned treatment recommendations for 19 and of them, 14 received therapeutic interventions: in eight cases, the oncologists were not guided by the indications reported by the project, but in the other six patients, they were and five of them improved. Among them, Jason.

The little boy had been battling aggressive myeloid leukemia since he was three years old that kept coming back. He had undergone several oncological treatments and also a bone marrow transplant, but he relapsed again. However, after entering the study, his doctors treated him with the therapeutic options recommended by Azzam's model and, in just 33 days, he entered remission. “He was able to receive a second bone marrow transplant and has now been cancer-free for two years,” says Arlet María de la Rocha, co-author of the study.

In his case, Azzam explains, the investigation showed three findings that could work in his favor. On the one hand, the little boy had a specific mutation in the tumor for which several inhibitors are available, but with trial and error of drugs in the laboratory, the researchers were able to select the most effective treatment for the child. Another positive effect is that they were able to show that some drugs that would have been given to her were not going to be effective: “We were able to tell her doctor which drugs might not be effective and that helped her make the decision to withdraw medications that she thought might work. in the case of Logan, but in the end it turned out that they were not effective and could have toxic effects,” says Azzam. Her case study also found that the child's tumor cells produced “an unexpected increase in commonly used steroids,” which is a medication used to suppress the immune system when performing a bone marrow transplant. “Our results showed that steroids actually increased the growth of cancer cells. And that could have been counterproductive,” says the researcher. This finding allowed us to withdraw this drug during her second transplant and avoid unwanted effects.

More treatment options

The researchers admit that their findings are preliminary and require larger studies with more patients, but they highlight the benefits of their technique. Starting with the response time, they can return the results to the oncologists in just one week. “This is very important because these patients do not have the luxury of time, they have exhausted all treatments and every day counts,” explains De la Rocha. As many drugs are tested at the same time, this therapeutic approach also allows many more treatment options to be offered, the researchers highlight. And they emphasize that the laboratory results are a mirror of what would happen in the body.

The research also put the focus back on drug repositioning (repurposing, in English), which consists of exploring the potential reuse of already known medications for other therapeutic indications. “When we analyze these tumors in the laboratory and analyze hundreds of drugs, we find drugs that are widely accessible, that may not be approved for that particular indication or that type of tumor, but that can be repurposed to effectively treat another resistant tumor,” he notes. Azzam.

“A promising technology”

Lucas Moreno, head of Pediatric Oncology at Vall d'Hebron, considers this approach “a promising technology,” but emphasizes that it is still in its infancy and “it must be expanded to larger studies and in more specific tumors.” “Success cannot be measured yet, the results do not allow for a comparison with other approaches,” he clarifies. However, the oncologist, who has not participated in the research, highlights its potential usefulness, especially in a type of tumor where the genomic profile, by itself, may not be sufficient: “The majority of pediatric tumors do not depend on of an easy-to-treat genomic alteration. And when you do genomic studies, you don't find an answer,” he explains.

The doctor points out that one of the limitations of the research may be the heterogeneity of the tumor itself and that the growth of cancer cells in the laboratory is a different environment from the body and the results may not be 100% similar. Azzam, for his part, aspires to expand the implementation of his approach beyond a context of relapses and even take it to the doors of diagnosis. “To achieve this, we need to be able to demonstrate in large-scale clinical trials that our test offers a lot of value compared to genomics alone and compared to standard treatment. So there is a lot of work to do,” he assumes.

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