Investigating Drug Resistance, Recurrence in Advanced Prostate Cancer

The Giancotti Lab

We’re studying the origin of metastatic cancer cells; the biological basis of dormant metastatic cells and their reactivation; and the pathways that link treatment resistance to metastasis.

The research

“Thyroid Hormone Receptor Signaling Promotes Antiandrogen Resistance and Bone Metastasis in Prostate Cancer,” presented at the 2022 AACR Annual Meeting

The cancer problem we are solving 

Androgen receptor (AR) blockers, commonly used to treat prostate cancer, delay, but don’t stop, progression of metastatic castration-resistant prostate cancer, an advanced form of the disease. About 30% of patients are resistant to treatment with AR blockers, and while the remaining 70% respond initially, resistance ultimately develops. To develop novel therapies for advanced prostate cancer, it is important to identify the factors that sustain prostate cancer cells that have become insensitive to androgen and so resistant to AR blockade.

Our project and approach

We have recently reported that treatment of prostate cancer cells with the anti-androgen enzalutamide, a common drug used to treat prostate cancer, drives their reprogramming to an alternative “mesenchymal and stem cell-like” state; a hallmark of cancer progression. These reprogammed cells are resistant to AR blockade and clinically aggressive. We want to understand how the reprogramming happens so that we can design new treatments to stop progression to advanced disease. We examined the regions of chromatin, the structural packaging for DNA in cells, that “open up” and become accessible to transcription factors (TFs) in prostate cancer cells treated with enzalutamide. TFs are proteins that are critical in the process of gene regulation and are commonly involved in cancer progression. They regulate gene expression by binding simultaneously to two key parts of the DNA--the enhancer and the promoter of the gene--whose jobs are to increase the likelihood that transcription of a particular gene will occur or ‘turn on’. 

Utilizing sophisticated chromatin sequencing techniques and bioinformatic analysis, we uncovered that the Thyroid Hormone Receptor Beta gene (THRB), which is involved in thyroid hormone signaling, plays a key role in both resistance to AR therapy and metastasis of prostate cancer. 

Our discovery in a nutshell

By examining the changes in chromatin and transcription factor activity in enzalutamide treated prostate cancer cells, we discovered that Thyroid Hormone Receptor Beta is a novel mediator of resistance to AR therapy and bone metastasis in prostate cancer cells. This is very interesting because we know from epidemiologic studies that there is a higher incidence of prostate cancer in men with elevated thyroid hormone levels and our studies suggest a direct link between thyroid hormone and aggressive prostate cancer.

Next steps

The findings from this research will help us further investigate and evaluate potential targeted therapies for metastatic prostate cancer.