Researchers move closer to providing personalized medicine to cancer patients

For the first time, Purdue researchers prove that measuring mechanical movements in living cancer tissue is a viable and promising approach to predicting chemoresistance.

Chemotherapy can save lives, but often a cancer patient is resistant to the chemotherapy they have been prescribed, wasting valuable time. Chemoresistance is a topic that researchers need to better understand in order to be able to tailor the right type of chemotherapy to the right patient, known as personalized medicine.

An unusual pair of veterinary scientists and physicists believe their method of detecting chemoresistance could be the new standard in personalized medicine. Their method is unexpected: Doppler ultrasound. Many people may have heard the term Doppler, either because of weather reports to detect storm activity or from expectant parents seeing their unborn child for the first time.

Now, a team of physicists and veterinary scientists at Purdue University is using ultrasound to detect how cancer cells respond to chemotherapy. They currently have their personalized chemotherapy detection method in human phase II clinical trials at the IU School of Medicine and have also used this method in canine trials.

The concept originated in 2015 by three Purdue researchers: David Nolte, principal investigator and Edward M. Purcell Distinguished Professor of Physics and Astronomy, John Turek, professor of basic medical sciences, and Michael Childress, professor of comparative oncology. Nolte is from the Department of Physics and Astronomy in the Purdue College of Science and Turek and Childress are from the Purdue College of Veterinary Medicine.

All three are members of the Purdue University Cancer Research Institute and have published their results in Scientific reports.

“The technique developed at Purdue measures movements inside cancer cells and how those movements change when the cells are exposed to anticancer drugs,” says Nolte.

“Because movement is the result of cellular ‘machinery,’ patients who will respond positively to their chemotherapy show different mechanical responses to drugs than patients who will not respond. This has the potential to identify patients for whom chemotherapy will not be successful, so they can be referred to a more effective treatment.

The technique, called biodynamic imaging (BDI), has been under development for cancer treatments for more than eight years. The team published their results previously, noting that the technique showed potential for identifying chemoresistance, but only under fairly restricted pathological conditions. This raises the question of whether the BDI might be useful only in special cases.

“Current research shows that BDI is actually a general and robust technique,” ​​says Nolte. “It shows similar results in two species (humans and canines) and two diseases (lymphoma and esophageal cancer). This provides, for the first time, strong evidence that measuring mechanical movements in living cancer tissues is a viable and promising approach to predict patient chemoresistance.”

The idea of ​​using Doppler in cancer research seems an unlikely scenario. According to Nolte, the concept and process of this technique grew out of fundamental scientific experimentation. He said the concept was refined through the benefits of chance combined with slow and steady progress.

“We started working on cancer tissue cultures grown in the laboratory, so it was natural to eventually move on to fresh tumors from patients,” he explains. “Doppler measurements are something we were led to during our experiments because we noticed some interesting dynamic effects that we had not initially anticipated.”

This team was formed more than two decades ago. In 1999, Purdue’s Office of the Executive Vice President for Research hosted a meeting of Purdue faculty interested in various aspects of imaging.

“Dr. Nolte and I met at this meeting and we started working on using the technology with 3D tumor spheroids (small tumors grown in culture) that I grew in my lab,” says Turek .

“We worked with tumor spheroids for several years as the technology developed. When it was time to move to patient-derived tumors, we approached Dr. Childress and used samples from canine lymphoma patients to track their response to medications. Working with the dog “Samples were needed to determine the feasibility of translating the technology to human samples. From canine samples, we moved on to human samples. Our collaboration with Dr. Shadia Jalal of the IU School of Medicine was an invaluable and essential part of the research. “

“The main advantage of using canine tumors over laboratory mouse tumors is that the former better represent the heterogeneity of human cancers,” says Childress.

“Although all the dogs we studied had the same type of cancer – lymphoma – each dog’s cancer was unique, with some being more sensitive and others more resistant to chemotherapy. This provided an ideal animal model in which to study a predictive technology like BDI before progressing to human trials.

The cells of all living creatures have very finely tuned functional machinery. When external influences disrupt the cellular machinery, mechanical movements change. If scientists can see a difference in these changes between patients whose cancer is sensitive to treatment and those who are not, they will be able to learn these signatures and use them to predict chemoresistance in future patients.

“A deeper question is what the signatures mean,” says Nolte.

“Can chemoresistance signatures be interpreted in terms of changes in signaling pathways in cells and tissues and perhaps even in gene expression? This question is much more difficult to answer, but we are currently working on this question by comparing our measurements to gene expression profiles. Also use reference compounds that have known behavior in cells and we can cross-reference our measurements with known changes that occur under these drugs. This part of the research is long term.

Nolte says Purdue has strong support for interdisciplinary research, which contributes significantly to the development of this type of research. Combining this with the benefit of the Purdue University College of Veterinary Medicine Small Animal Hospital, the team can organize clinical trials with canine patients. Now that they have received these promising results, the team hopes that the next giant leap in cancer research will include “prospective” phase II trials.

“The current phase II was retrospective, in which the patient’s clinical response was cross-validated against the predicted response using the BDI. The next step is a Phase II trial which is “prospective”, meaning we will predict the patient’s response before the study begins. chemotherapy,” says Nolte.