These new organoids suggest that the extracellular matrix of tumours may be more important in regulating therapeutic response and efficacy of anti-cancer drugs than initially thought.
With an estimated 1.4 million new cases and 375,000 deaths in 2020, prostate cancer has become the second most commonly diagnosed cancer and the fifth leading cause of cancer death among men worldwide. While some prostate cancers grow slowly and are confined to the prostate gland, where they may not cause serious harm, other types can be aggressive and metastasise quickly.
To treat prostate cancers, clinicians prescribe androgen receptor pathway inhibitors as they have been shown to prolong survival in patients with advanced prostate cancer. However, about 1 in 5 patients have been reported to develop more advanced-stage neuroendocrine prostate cancer as a result of this type of hormone therapy. At present, targeted therapies to treat neuroendocrine prostate cancer remain unavailable as clinicians have not been able to fully understand the progression of these cancers.
“These patients lose their dependency on hormone-driven processes, and conventional treatments don’t work for them,” said Ankur Singh, associate professor in both the Wallace H. Coulter Department of Biomedical Engineering at Emory University and Georgia Tech and the George W. Woodruff School of Mechanical Engineering at Tech.
“There are no targeted therapies, so there is a clear clinical need,” he added. “But a major challenge is, we don’t fully understand what these tumours entail, the kind of tumour microenvironment it has, or the factors that induce resistance to therapeutics. There are no models to effectively study this cancer.”
To fill these gaps of knowledge, a multi-institutional team of scientists, spearheaded by Singh, has developed a prostate cancer organoid that allows them to model patient-specific microenvironments. Using novel research tools, their findings are expected to clarify our understanding of a virtually untreatable form of prostate cancer and guide the development of effective therapeutics.
Grown from a patient’s own cells, organoids are tiny, three-dimensional tissue cultures that can be engineered to replicate different organs of the human body or to model diseases. They are produced entirely in vitro and are generally grown in a gel that acts as the extracellular matrix. Organoids are considered to be valuable tools for exploring targeted treatments as researchers can perform studies and evaluate therapeutic efficiency in authentic human micro-anatomies without posing any harm to patients.
Previously, Singh’s collaborators developed Matrigel organoid models of neuroendocrine prostate cancer. Using these organoids, they identified a new therapeutic target called EZH2, a histone-modifying protein that promotes tumour growth. While EZH2 inhibitors were found to slow down tumour growth, Singh revealed that EZH2 inhibitors may require high doses and does not eliminate the tumour in its entirety in certain patients. Moreover, because their experiments were performed using organoids grown in Matrigel that is naturally derived from mouse tumour cells and is not identical to the human tumour microenvironment, the scientists believed that it may have failed to capture the full therapeutic effects of EZH2 inhibitors.
In their current study, Singh and colleagues designed a synthetic, Maleimide-polyethyleneglycol-based hydrogel that accurately mimics the extracellular matrix of a patient-specific tumour. They achieved this by analysing 111 patient biopsies and thoroughly profiling aggressive tumour samples using a multi-omics approach and microscopy techniques.
By growing the organoids in this new hydrogel, the researchers were able to evaluate how the matrix affects tumour development and how certain changes could turn an initially treatable prostate cancer tumour untreatable. Their analyses revealed that the extracellular matrix regulates EZH2 activity and the efficacy of EZH2 inhibitors. Through their experiments, they also identified a new molecule, called DRD2, that could potentially be used as a therapeutic target. Although DRD2 inhibitors are being investigated in clinical trials for gliomas, they have never been tested for treating neuroendocrine prostate tumours.
Although certain extracellular matrices found in patients could potentially render neuroendocrine tumours resistant to DRD2 inhibitors, Singh’s team believes that this resistance could be solved through a combination therapy of EZH2 and DRD2 inhibitors, with the former being used to reprogramme the cells and make them more susceptible to DRD2 inhibition.
With these cutting-edge tools, we could be looking at a new standard of precision medicine. “We could take a biopsy sample, profile the patient’s microenvironment, take that specific information and create an organoid model that you can treat with drugs and develop a personalised treatment regime. Tailoring this towards precision oncology would be pretty huge for us. That was original idea. That is the ultimate goal,” said Singh. [APBN]
Source: Mosquera et al. (2021). Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors. Advanced Materials, 2100096.