Weill Cornell Medicine researchers have identified a new role for the EZH2 enzyme in promoting the progression of aggressive, treatment-resistant prostate cancers. Their study suggests that targeting alternative functions of EZH2 could restore the effectiveness of androgen receptor inhibitors and enhance the potential of immunotherapies in these tumors, offering new hope to patients facing this difficult diagnosis.
New Perspectives on Treatment-Resistant Prostate Cancer
Scientists at Weill Cornell Medicine have discovered a surprising role for the EZH2 enzyme in promoting aggressive tumor growth in treatment-resistant prostate cancers. This discovery could pave the way for new therapies for patients with few options and marks a significant advance in understanding how advanced prostate cancer becomes resistant to treatments targeting the androgen receptor.
Prostate cancer is a leading cause of cancer-related death in men, with more than 30,000 deaths per year in the United States. While most cases initially respond to therapies that block androgen receptors, some tumors adapt and transform into a highly aggressive, treatment-resistant form called neuroendocrine prostate cancer. This variant is no longer dependent on androgen signaling, making it particularly difficult to treat. Understanding how and why this transition occurs is now a top priority for researchers and clinicians.
Unraveling a Resistance Mechanism
The new study, led by Drs. Maria Diaz-Meco and Jorge Moscat, both Professors of Oncology in Pathology at Weill Cornell Medicine, and published in Nature Communications, found that the absence of a protein called PKCι in prostate cancer cells allows to EZH2 to promote aggressive growth, even in the presence of androgen receptor inhibitors. Normally, PKCι limits the activity of EZH2.
However, in PKCι-deficient cells treated with androgen receptor inhibitors, an alternative form of EZH2 is produced that has a different function. Instead of repressing tumor suppressor genes, this form of EZH2 promotes rapid protein production and activates growth factors such as TGF-β, promoting an environment around the tumor that favors cancer progression despite androgen receptor inhibition .
Potential for New Therapies in Prostate Cancer
This study reveals a critical mechanism of treatment resistance in prostate cancer, suggesting new therapeutic approaches. By understanding the role of EZH2 in this context, we may be able to make tumors sensitive to androgen receptor inhibitors again or make cancer vulnerable again to targeted treatments, such as immunotherapies. In preclinical studies, the team targeted alternative activities of EZH2 to evaluate potential therapeutic solutions. They found that inhibiting protein synthesis or the TGF-β pathway effectively reversed resistance in PKCι-deficient tumor cells. Blocking the alternative function of EZH2 restored sensitivity to androgen receptor therapies such as enzalutamide. Furthermore, because TGF-β is associated with immune suppression in tumors, inhibiting this pathway could enhance the effectiveness of immunotherapy, a treatment with limited success against prostate cancer alone.
The researchers noted that the absence of PKCι creates a unique vulnerability in tumor cells, suggesting that combining EZH2 inhibitors with androgen receptor-targeted therapies could significantly inhibit tumor growth. However, they caution that EZH2 inhibition in tumors with high PKCι levels can sometimes counteract therapeutic effects, underscoring the need for carefully tailored treatments for patients with reduced PKCι levels. Given the complexities of the EZH2 pathway, achieving an accurate balance is essential to avoid negating the benefits of treatment.
Implications for Clinical Studies
This research lays the foundation for clinical trials combining androgen receptor inhibitors with EZH2 or TGF-β inhibitors for patients with therapy-resistant prostate cancer characterized by PKCι deficiency. Targeting these pathways offers hope not only for overcoming androgen receptor resistance, but also for broadening treatment options for this challenging form of cancer.
Dr. Moscat highlighted the collaborative efforts behind this study, based on previous findings on the role of PKCι in cancer progression. The study’s co-lead authors are postdoctoral researcher Dr. Shankha Chatterjee, instructor Dr. Juan Linares, postdoctoral researcher Dr. Tania Cid-Diaz, and research assistant professor of pathology and laboratory medicine Dr. Angeles Duran, all members of the Moscat and Diaz-Meco laboratories.
Reference: November 20, 2024, Nature Communications. The research reported in this story was supported by grants from the National Cancer Institute and the National Institute of General Medical Sciences, both part of the National Institutes of Health, under award numbers R01CA246765, R01CA277857, R01CA265892, R01CA250025, R01CA275846, R50CA283476, R50CA265332, R01CA230913, P50CA211024, R37CA230617, R01CA276308, R01GM135362.
In what ways could the absence of PKCι provide a biomarker for predicting treatment response in prostate cancer patients?
1. Can you tell us more about the role of EZH2 in the development and progression of prostate cancer?
2. What is the significance of the new discovery regarding the absence of PKCι in prostate cancer cells and its impact on EZH2 activity?
3. How does this new finding challenge our current understanding of treatment-resistant prostate cancer?
4. What are some potential therapeutic approaches suggested by the team’s research, particularly in light of the TGF-β pathway and androgen receptor inhibitors?
5. What are the challenges in developing combinatorial therapies targeting EZH2 and the TGF-β pathway?
6. How will this research impact future clinical trials for prostate cancer patients with metastatic tumors?
7. Are there any other means of identifying patients with PKCι deficiency beyond the current methods?
8. What are the next steps for the team in further exploring this area of research? And what are the long-term implications of this discovery for cancer treatment?
