New and improved organoids shed light on incurable form of prostate cancer


A multi-institutional team of researchers led by bioengineer Ankur Singh has developed research tools that shed new light on a virtually incurable form of prostate cancer, paving a way that may lead to new therapies and a glimmer of light. hope for patients.

Androgen receptor pathway inhibitors may prolong survival in patients with advanced prostate cancer. But about 20% of patients develop more advanced neuroendocrine prostate cancer in response to this type of hormone therapy, and so far researchers have not had an effective way to study this progression.

“These patients lose their addiction to hormonal processes and conventional treatments don’t work for them,” said Singh, associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Tech and the George W. School. from Woodruff Mechanical Engineering to Tech.

“There are no targeted therapies, so there is a clear clinical need,” he added. “But a major challenge is that we don’t fully understand what these tumors involve, the type of tumor microenvironment they have, or the factors that induce resistance to treatments. There is no model to effectively study this cancer.”

“To begin to answer these questions, Singh and his team developed a prostate cancer organoid that can help them model the patient-specific microenvironment. It could offer an important step forward in precision medicine, and they described it in the November issue of the journal Advanced Materials.

Organoids are tiny three-dimensional tissue cultures grown from a patient’s cells. They can be designed to mimic different organs in the human body or to model diseases. Produced entirely in vitro, organoids are valuable tools for researchers, who can explore targeted treatments in authentic human microanatomies without harming a patient.

Scientists grow organoids in a gel that acts as the extracellular matrix -; the protein-rich molecular network that surrounds and supports cells in the body, helping them attach and communicate with each other and playing a key role in multiple cellular functions.

Singh’s collaborators in this study had previously developed Matrigel organoid models of neuroendocrine cancer of the prostate -; that is, they grew cells in Matrigel, a solution naturally derived from mouse tumor cells. Using these organoids, the researchers discovered a new therapeutic target called EZH2, a histone-modifying protein that promotes tumor growth. By using an EZH2 inhibitor, they were able to slow tumor growth.

“EZH2 inhibitors may require high doses, and we are only just beginning to understand the factors that control EZH2 activity. And, in some patients, EZH2 inhibitors may not completely eliminate the tumor,” Singh said.

Reasoning that the EZH2 inhibitor would reach its full potential in the right kind of tumor microenvironment, something they might design -; ie not Matrigel -; they analyzed 111 patient biopsies using a multi-omics approach and microscopy techniques to deeply profile these aggressive tumors.

Their findings helped them design and develop a synthetic maleimide-polyethylene glycol hydrogel that precisely mimics the extracellular matrix of a patient-specific tumor. Using these organoids, the researchers were able to study the impact of the matrix on tumor development -; in particular the changes associated with the transformation of a treatable prostate cancer tumor into an incurable tumor.

With the new organoids, they discovered that the extracellular matrix regulates EZH2 activity and the efficacy of EZH2 inhibitors, a phenomenon previously less understood. They also discovered a potential new therapeutic target, a molecule called DRD2. Currently, DRD2 inhibitors are being tested in clinical trials for gliomas, but they have never been tested in neuroendocrine tumors of the prostate.

Singh’s team found that certain extracellular matrices found in patients could make neuroendocrine tumors resistant to DRD2 inhibitors, but the resistance could be overcome with combination therapy: first, an EZH2 inhibitor to reprogram cells and cells. make them more susceptible to inhibition of DRD2.

“As a single agent targeted therapy, DRD2 is very exciting,” said Singh, whose collaborators included co-principal investigator Oliver Elemento, director of the England Institute for Precision Medicine at Weill Cornell Medicine, the unit of biomedical research and Cornell Medical School. University. The lead author was Matthew Mosquera, a former Ph.D. student in Singh’s lab.

Singh believes this work could evolve into a new standard in precision medicine.

“Every patient’s tumor microenvironment is not the same,” Singh said. “We could take a biopsy sample, profile the patient’s microenvironment, take that specific information, and create an organoid model that you can drug-treat and develop a personalized treatment regimen. us. It was original. idea. It was the ultimate goal.

Source:

Georgia Institute of Technology

Journal reference:

Mosque, MJ, et al. (2021) The extracellular matrix in synthetic hydrogel-based prostate cancer organoids regulates the therapeutic response to EZH2 and DRD2 inhibitors. Advanced materials. doi.org/10.1002/adma.202100096.


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