Lab-grown pituitary tumors identify potential new Cushing’s therapy
Organoids confirm ceritinib treatment can reduce ACTH, slow tumor growth
Researchers have identified ceritinib, a cancer medication, as a promising treatment candidate for Cushing’s disease after successfully using miniature, lab-grown pituitary tumors, known as organoids, to test its effectiveness.
Ceritinib, marketed as Zykadia to treat certain lung cancers, effectively inhibited tumor growth and reduced the tumor-driven excess of adrenocorticotropic hormone (ACTH) in patient-derived organoids, with its efficacy further confirmed in mouse models.
Analysis revealed that ceritinib blocks a key signaling pathway that pituitary tumor cells use to promote their growth, survival, and hormone production.
Exploring novel therapeutic strategies
“These findings highlight a novel therapeutic strategy for [Cushing’s disease] and underscore the value of [patient-derived organoids] in preclinical drug development and mechanistic investigation,” researchers wrote.
The study, “Ceritinib inhibits growth and ACTH production of PitNETs: Insights from patient-derived organoids,” was published in the journal Pharmacological Research.
In Cushing’s disease, tumors in the brain’s pituitary gland lead to excessive production of ACTH, which in turn stimulates the adrenal glands, located atop the kidneys, to overproduce cortisol — a condition known as hypercortisolism.
In active Cushing’s disease, functioning ACTH-secreting tumors cause cortisol overproduction that leads to the characteristic Cushing’s symptoms. In contrast, silent tumors produce ACTH but do not cause clinical signs of cortisol excess, often remaining unnoticed until they grow large or are discovered incidentally.
Transsphenoidal surgery, or the surgical removal of the pituitary tumor through the nose, remains the first-line Cushing’s disease treatment; however, it carries risks of complications and variable recurrence rates.
Despite these challenges, effective pharmacological therapies that directly target the tumor — rather than merely controlling cortisol levels — are currently lacking, the researchers wrote, while adding that “drug development for [Cushing’s disease] has been limited by the absence of suitable preclinical research models.”
To address this gap, a team of researchers in China used patient-derived organoids to screen a panel of tyrosine kinase inhibitors (TKIs) — compounds widely used in targeted cancer therapy that have also shown promise in treating pituitary tumors — as a potential therapeutic strategy for Cushing’s disease.
Unlike conventional two-dimensional cell models, patient-derived organoids preserve the cellular diversity and hormone-secreting activity of pituitary gland tumors, providing a more accurate model for studying disease mechanisms and drug responses.
The organoids were developed from tissue samples collected from individuals with a pituitary tumor who underwent transsphenoidal surgery at Nanfang Hospital of Southern Medical University in China. These included six functioning tumors from people with active Cushing’s and three silent ACTH-secreting tumors.
Tumor tissue was then processed into single cells and grown under specialized conditions to produce miniature, lab replicas of each patient’s pituitary tumor.
Once validated to faithfully reproduce the structural, functional, and molecular features of the original tumors, patient-derived organoids were used to test six TKIs — pelitinib, dacomitinib, lapatinib, radotinib, nintedanib, and ceritinib — that had shown the strongest ability to inhibit tumor cell growth in an initial screening of 33 compounds using conventional cell models.
All six compounds inhibited organoid growth and reduced ACTH production to varying degrees, but ceritinib exhibited the most potent and consistent effects across organoids from different patients, including those derived from both functioning and silent tumors.
To further confirm ceritinib’s efficacy, the researchers tested the drug in mice injected with pituitary tumor cells to form small, hormone-secreting tumors mimicking Cushing’s disease. The mice received daily oral doses of ceritinib for 21 days, while control mice received a saline solution.
Compared with the controls, ceritinib-treated mice showed a marked reduction in tumor size and weight, along with significantly lower blood levels of ACTH.
Further mechanistic studies revealed that ceritinib suppresses ACTH production and tumor growth by targeting IGF1R and INSR, two receptors that activate the PI3K–Akt signaling pathway, which is well-known for promoting cell growth and survival in many types of tumors and, in ACTH-secreting pituitary tumors, also regulating hormone production.
“Ceritinib effectively suppresses tumor growth and ACTH production in [patient-derived organoids] of both functioning and silent [Cushing’s disease], positioning it as a promising therapeutic agent for [Cushing’s disease],” the researchers concluded.
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