Androgen receptor pathway
inhibitors can prolong survival for patients with advanced prostate cancer.
However, about 20 percent of patients develop more advanced-stage
neuroendocrine prostate cancer in response to this type of hormone therapy, and
so far, researchers have not had effective ways to study this progression.
“These patients lose their dependency on hormone-driven processes, and
conventional treatments do not work for them,” elaborated associate professor
Ankur Singh who led the study.
“There are no targeted
therapies, so there is a clear clinical need,” Singh added. “But a major
challenge is we do not 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.”
The team developed a
prostate cancer organoid that can help them model the patient-specific
microenvironment. They had previously developed organoid models of
neuroendocrine prostate cancer using Matrigel, a naturally derived solution
from mouse tumour cells . Using these organoids, described in Advanced Materials,
the researchers discovered a new therapeutic target called EZH2, a
histone-modifying protein that promotes tumour growth. Using an EZH2 inhibitor,
they were able to slow tumour growth.
“EZH2 inhibitors may
require high doses, and we are just beginning to understand factors that
control EZH2 activity. And, in some patients, EZH2 inhibitors may not eliminate
the tumour in its entirety,” Singh added.
The team subsequently
analysed 111 patient biopsies using a multi-omics approach and microscopy
techniques to thoroughly profile these aggressive tumours. Their findings
helped them design and develop a synthetic, Maleimide-polyethyleneglycol-based
hydrogel that accurately mimics the extracellular matrix of a patient-specific
tumour.
The researchers used the
organoids to study the impact of the matrix on tumour development, particularly
the changes associated with transforming a treatable prostate cancer tumour
into an untreatable one. They then discovered that extracellular matrix
regulates EZH2 activity and the efficacy of EZH2 inhibitors.”
The team also revealed 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 prostate tumours.
Finally, the team found
that certain extracellular matrices found in patients could render
neuroendocrine tumours resistant to DRD2 inhibitors, but the resistance could
be overcome with a combination therapy: an EZH2 inhibitor to reprogramme the
cells and make them more susceptible to DRD2 inhibition.
Singh believes this work
could evolve into a new standard of precision medicine. “Not every patient’s
tumour microenvironment is the same,” Singh concluded. “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.
European Journal of Case Reports and Clinical Images is an international open-access journal publi
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