2023-04-23 02:24:47
Scientists from the UB, IBEC and Ciberbbn are working on a tool based on nanotechnology and intended for routine use in the clinical environment.
A team from the Faculty of Medicine and Health Sciences of the University of Barcelona (UB), the Institute of Bioengineering of Catalonia (IBEC) and the Center for Biomedical Research in Bioengineering, Biomaterials and Nanomedicine Networks (Ciberbbn) has designed a functional microfluidic device, called microfluidic dynamic BH3 profiling (μDBP), based on nanotechnology, which is intended to routinely predict in the clinical setting the efficacy of the different therapeutic options against a patient’s cancer quickly (24 hours), automated (without the need for specialized technical personnel) and using a small sample of solid or liquid tumor cells.
This technology is based on the fact that each tumor is unique and has its own characteristics, so having predictive indicators of the patient’s response to each treatment is a great step forward in the advancement of oncology.
“What we do is keep the tumor cells alive and we perturb them with different drugs to see which of them causes their death (apoptosis)”, explained Joan Montero, professor of the Department of Biomedicine of the UB and the IBEC. The response to this test would help oncologists, along with the results of others, to more accurately select the most appropriate therapy for each patient; especially for the advanced ones and/or those that are more complex -“those in which there are more doubts”-.
Similar to antibiogram
It would be one more tool for precision medicine in which what is currently conventional is, after the biopsy, to isolate the tumor cells, kill them, separate cellular components and analyze them to try to predict whether they would respond better to this or that therapy. Conceptually, according to the scientist, μDBP is more similar to antibiograms that are used to try to establish the most correct antibiotic treatment for the patient; In this case, it is necessary to know if the microorganism responsible for the infection has mechanisms that confer resistance to some antibiotic in order not to include it as a therapy.
It also specifies that, for now, the technology they are developing is to test the usefulness of conventional drugs and therapies targeted (kinase inhibitors), but they are convinced that the tool could be adapted so that also contribute to prescribing better immunotherapies and CAR-T. In fact, they already have a project planned to achieve the latter, if they get specific funding first.
He dynamic BH3 profilingreports Montero, who is one of its inventors, was initially developed in the laboratory of Anthony Letai, a professor and medical oncologist at the Dana-Farber Cancer Institute in Boston, in the United States, which is the center that patented it in 2015. And he indicates that there are currently more groups working on the same technology and fifty articles (some by Montero himself) have already been published in the world medical literature.
GIST cell study
In fact, a paper has recently been published in npj Precision Oncology (December 2022) directed by him and by Javier Ramón Azcón, ICREA research professor at IBEC, and whose first author is Albert Manzano (UB-IBEC), who received his doctorate at the UB in 2022 with a thesis on precision medicine in the fight against cancer. Experts from the Faculty of Physics of the UB have also participated; César Serrano, from the Vall d’Hebron Institute of Oncology (VHIO) and Ciberbbn.
In their work on μDBP, they first examined its predictive ability using gastrointestinal stromal tumor (GIST) cell lines, comparing imatinib-sensitive and resistant cells, and were able to detect differences in apoptotic priming and anticipate cytotoxicity. They then validated µDBP in a refractory GIST patient sample and identified that the combination of dactolisib and venetoclax increased apoptotic prime. With this evidence, they conclude that “this new technology could represent an important advance for precision medicine by providing a fast, easy-to-use and scalable microfluidic device to perform dynamic BH3 profiling in situ as a routine trial to identify the best treatment for cancer patients.”
The new technology, of which the team has a first prototype but it is already working on the design of a new one with more technical improvements, it has been used to identify the efficacy of treatments on a preclinical and clinical scale in other different types of cancer, both solid and liquid. These studies have used cell lines, animal models and primary samples, “with great predictive capacity in all cases.”
“One of the main limitations of the dynamic BH3 profiling is the number of cells needed to perform the assay. When a patient is biopsied, the number of tumor cells obtained is very limited, which does not allow a study to be carried out with many different treatments and limits the ability to identify an effective one”, highlights Albert Manzano.
The state-of-the-art μDBP technology works like this: when a biopsy sample is received, it is dissociated so that individual cells can be obtained using mechanical and enzymatic treatment. Once processed, the sample is filtered to obtain individual cells that are then subjected to the relevant treatments for about 16 hours; they are seeded and incubated in the microfluidic device (with synthetic peptides), they are stained and a value is obtained by flow cytometry that makes it possible to identify the drugs or combinations of drugs that cause apoptosis (they have the capacity to eliminate the tumor). The whole process can take about 24 hours.
“Thanks to our μDBP microfluidic platform, which is equipped with small wells to seed the cells, we can reduce the number of cells required to test a treatment. This is a decisive innovation to increase the number of drugs that can be evaluated”, adds Manzano.
His is the first work in which microfluidics is applied to carry out the functional test of this technology. Unlike other versions developed so far, such as the high-throughput DBP (Bhola et al., Science Signaling, 2020), with plates and automatic dispensers to test hundreds of treatments, the μDBP device is aimed at testing treatments in situ in a way very fast —which prevents the deterioration of the samples—, simple and automated, without the need for expensive machinery or specialized personnel.
Automation of the entire process
“The greatest advantage of the μDBP device is also the automation of the entire process, which would help to implement this functional methodology on a clinical scale. Taken together, all these advantages would facilitate the adoption of μDBP in hospitals as a routine assay”, the team affirms.
“We have developed this new tool with the idea of making it available to oncologists. This automated system makes it possible to obtain personalized information on the patient and the treatment”, affirms Javier Ramón Azcón, from IBEC, involved in the project, like María A. Ortega and Josep Samitier, from the same center.
He explains that nanotechnology -especially the application of microfluidics to different processes- is driving various improvements in the design of these devices to reduce the amount of reagents, reduce costs, automate processes or increase analysis capacity.
Research on μDBP continues, now with a proof-of-concept grant from the Ministry of Science, and the team’s goal is to continue advancing “hand-in-hand” with medical oncologists. Carmen Fernandez
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