In a significant stride toward improving colorectal cancer treatment, scientists at the Van Andel Institute in Grand Rapids, Michigan, have discovered a novel approach that leverages the unique properties of two medications, traditionally used to treat blood cancers, to combat solid tumors more effectively. Published in the journal Science Advances, this preclinical study illuminates the synergistic potential of DNMT and EZH2 inhibitors, setting the stage for a pioneering clinical trial aimed at evaluating this combination therapy in colorectal cancer and other solid tumor patients.
Epigenetic Modulation as a Therapeutic Strategy
At the core of this innovative treatment strategy is the manipulation of epigenetic processes, which are crucial in regulating gene expression. Aberrations in these processes allow cancer cells to thrive and proliferate. DNMT inhibitors, known for inducing a state of viral mimicry in cancer cells, make them more vulnerable to the body's immune system. EZH2 inhibitors, on the other hand, modulate gene expression by acting on the epigenetic level. "DNMT inhibitors are approved to treat blood cancer while EZH2 inhibitors are approved to treat blood cancer and a rare type of sarcoma. To date, they’ve had limited individual success in solid tumors like colorectal cancer," explained Scott Rothbart, Ph.D., Van Andel Institute Professor and the study's corresponding author.
The Synergistic Effect of DNMT and EZH2 Inhibition
The research team demonstrated that the combination of low doses of a DNMT inhibitor with an EZH2 inhibitor results in a potent anti-cancer effect, superior to the use of either drug alone. This synergistic interaction primes cancer cells in a way that enhances their sensitivity to the EZH2 inhibitor, effectively activating the viral mimicry process more robustly. "Our findings highlight the promise of combination cancer therapies by revealing how these two medications interact," Rothbart stated, underscoring the potential of this approach to significantly improve treatment outcomes.
Upcoming Clinical Trials and Future Directions
The promising results of this study serve as the foundation for an upcoming Phase I clinical trial, marking the first instance of these two types of medication being combined to target solid tumors. With colorectal cancer positioned as the second leading cause of cancer death worldwide, and with rates notably increasing among younger populations, the urgency for more effective treatment modalities is clear. "Although it is not clear why colorectal cancer cases are rising among young people, it is clear that we need more effective treatment strategies," Rothbart remarked, highlighting the critical need addressed by this research.
The trial will benefit from the support of the Van Andel Institute–Stand Up To Cancer© (SU2C) Epigenetics Dream Team and a National Cancer Institute Specialized Programs of Research Excellence (SPORE) award. These collaborations underscore the multidisciplinary effort to enhance cancer treatment through epigenetic therapies. Additionally, the study hints at the potential of epigenetic drugs to sensitize tumors to immunotherapy, offering another promising avenue for treatment enhancement.
Original Publication:
Chomiak, A. A., Tiedemann, R. L., Liu, Y., Kong, X., Cui, Y., Wiseman, A. K., Thurlow, K. E., Cornett, E. M., Topper, M. J., Baylin, S. B., & Rothbart, S. B. (2024). Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling. Science Advances, 10(13), eadk4423. https://www.science.org/doi/abs/10.1126/sciadv.adk4423
Epigenetic Modulation as a Therapeutic Strategy
At the core of this innovative treatment strategy is the manipulation of epigenetic processes, which are crucial in regulating gene expression. Aberrations in these processes allow cancer cells to thrive and proliferate. DNMT inhibitors, known for inducing a state of viral mimicry in cancer cells, make them more vulnerable to the body's immune system. EZH2 inhibitors, on the other hand, modulate gene expression by acting on the epigenetic level. "DNMT inhibitors are approved to treat blood cancer while EZH2 inhibitors are approved to treat blood cancer and a rare type of sarcoma. To date, they’ve had limited individual success in solid tumors like colorectal cancer," explained Scott Rothbart, Ph.D., Van Andel Institute Professor and the study's corresponding author.
The Synergistic Effect of DNMT and EZH2 Inhibition
The research team demonstrated that the combination of low doses of a DNMT inhibitor with an EZH2 inhibitor results in a potent anti-cancer effect, superior to the use of either drug alone. This synergistic interaction primes cancer cells in a way that enhances their sensitivity to the EZH2 inhibitor, effectively activating the viral mimicry process more robustly. "Our findings highlight the promise of combination cancer therapies by revealing how these two medications interact," Rothbart stated, underscoring the potential of this approach to significantly improve treatment outcomes.
Upcoming Clinical Trials and Future Directions
The promising results of this study serve as the foundation for an upcoming Phase I clinical trial, marking the first instance of these two types of medication being combined to target solid tumors. With colorectal cancer positioned as the second leading cause of cancer death worldwide, and with rates notably increasing among younger populations, the urgency for more effective treatment modalities is clear. "Although it is not clear why colorectal cancer cases are rising among young people, it is clear that we need more effective treatment strategies," Rothbart remarked, highlighting the critical need addressed by this research.
The trial will benefit from the support of the Van Andel Institute–Stand Up To Cancer© (SU2C) Epigenetics Dream Team and a National Cancer Institute Specialized Programs of Research Excellence (SPORE) award. These collaborations underscore the multidisciplinary effort to enhance cancer treatment through epigenetic therapies. Additionally, the study hints at the potential of epigenetic drugs to sensitize tumors to immunotherapy, offering another promising avenue for treatment enhancement.
Original Publication:
Chomiak, A. A., Tiedemann, R. L., Liu, Y., Kong, X., Cui, Y., Wiseman, A. K., Thurlow, K. E., Cornett, E. M., Topper, M. J., Baylin, S. B., & Rothbart, S. B. (2024). Select EZH2 inhibitors enhance viral mimicry effects of DNMT inhibition through a mechanism involving NFAT:AP-1 signaling. Science Advances, 10(13), eadk4423. https://www.science.org/doi/abs/10.1126/sciadv.adk4423