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Combining epigenetic
cancer
medications may have benefit for
colorectal cancers
and other
tumor
types
2024-03-27
·
Science Daily
免疫疗法
临床1期
A pair of medications that make malignant cells act as if they have a virus could hold new promise for treating
colorectal cancers
and other
solid tumors
, reports a new study. The preclinical research determined how low doses of a
DNMT
inhibitor sensitize
cancer
cells to an
EZH2
inhibitor, resulting in a one-two punch that combats
cancer
cells better than either drug alone. The findings are the foundation for an upcoming Phase I clinical trial to evaluate this combination in people with
colorectal cancer
or other
solid tumors
. A pair of medications that make malignant cells act as if they have a virus could hold new promise for treating
colorectal cancers
and other
solid tumors
, reports a study published today in Science Advances. The preclinical research, led by
Van Andel Institute
scientists, determined how low doses of a
DNMT
inhibitor sensitize
cancer
cells to an
EZH2
inhibitor, resulting in a one-two punch that combats
cancer
cells better than either drug alone. The findings are the foundation for an upcoming Phase I clinical trial to evaluate this combination in people with
colorectal cancer
or other
solid tumors
. "
DNMT inhibitors
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
," said
Van Andel Institute
Professor Scott Rothbart, Ph.D., the study's corresponding author. "Our findings highlight the promise of combination
cancer
therapies by revealing how these two medications interact, with the
DNMT
inhibitor priming
cancer
cells in a way that makes the
EZH2
inhibitor more effective."
DNMT
and
EZH2
inhibitors
work by controlling the epigenetic processes that regulate gene expression. In
cancer
, epigenetic errors enable malignant cells to survive and proliferate -- and offer critical targets for treatment. Previous studies show that
DNMT inhibitors
DNMT
inhibitors cause
cancer
cells to behave as if infected by a virus, which makes the cells more susceptible to attack by one's own immune system. In their new study, Rothbart and colleagues demonstrated that combining DNMT and
EZH2
inhibitors activate this viral mimicry process more effectively than either drug on its own. The upcoming trial will be the first time these two medication types will be combined to enhance the activities of these inhibitors in
solid tumors
.
Colorectal cancers
are the second leading cause of
cancer
death globally, according to the World Health Organization. More than 1.9 million cases were diagnosed in 2020, with incidence expected to rise to 3.2 million cases by 2040. Although screening and early detection have driven down
colorectal cancer
rates among older people in the U.S., rates are rising in younger people. "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 said. "Combining medications may be a powerful way to simultaneously target multiple drivers of
cancer
. In addition to revealing how DNMT and
EZH2
inhibitors
work together, our findings suggest that epigenetic drugs also may sensitize
tumors
to immunotherapy, which offers another important opportunity to enhance
cancer
treatment." The upcoming trial will be supported by the
Van Andel Institute
-Stand Up To
Cancer
© (SU2C) Epigenetics Dream Team, a multi-institutional collaboration that evaluates promising potential combination therapies for
cancer
, and a National
Cancer
Institute Specialized Programs of Research Excellence (SPORE) award, a prestigious five-year grant that supports a team of scientists seeking to improve epigenetic
cancer
therapies. Today's findings were made possible in part by a SPORE-supported subproject on DNMT and EZH2 inhibitors led by Rothbart and Stephen Baylin, M.D., of
Johns Hopkins University
and
Van Andel Institute
. Baylin also serves as co-leader of the VAI-SU2C Epigenetics Dream Team and is an author on today's study. The study's first authors are Alison A. Chomiak, Ph.D., and Rochelle L. Tiedemann, Ph.D., of VAI. Other authors include Yanqing Liu, M.D., Ashley K. Wiseman, M.S., and Kate E. Thurlow, M.Sc., of VAI; Xiangqian Kong, Ph.D., Ying Cui, Ph.D., and Michael E. Topper, Ph.D., of
Johns Hopkins University
; and Evan M. Cornett, Ph.D., of
Indiana University
.
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机构
Van Andel Institute
The Johns Hopkins University
Indiana University
适应症
肿瘤
结直肠癌
实体瘤
[+2]
靶点
DNMT1
EZH2
药物
DNMT/HDAC inhibitors(Shenzhen University)
CaMKII inhibitors(Academia Sinica)
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