sciencecodex | Researchers from Case Western Reserve University School of Medicine
and the Dana-Farber Cancer Institute have made a fundamental discovery
relevant to the understanding and treatment of heart failure – a leading
cause of death worldwide. The team discovered a new molecular pathway
responsible for causing heart failure and showed that a first-in-class
prototype drug, JQ1, blocks this pathway to protect the heart from
damage.
In contrast to standard therapies for heart failure, JQ1 works
directly within the cell's command center, or nucleus, to prevent
damaging stress responses. This groundbreaking research lays the
foundation for an entirely new way of treating a diseased heart. The
study is published in the August 1 issue of Cell.
"As a practicing cardiologist, it is clear that current heart failure
drugs fall alarmingly short for countless patients. Our discovery
heralds a brand new class of drugs which work within the cell nucleus
and offers promise to millions suffering from this common and lethal
disease," said Saptarsi Haldar, MD, senior author on the paper,
assistant professor of medicine at Case Western Reserve and cardiologist
at University Hospitals Case Medical Center.
Heart failure occurs when the organ's pumping capacity cannot meet
the body's needs. Existing drugs, most of which block hormones such as
adrenaline at the cell's outer surface, have improved patient survival.
Unfortunately, several clinical studies have demonstrated that heart
failure patients taking these hormone-blocking drugs still succumb to
high rates of hospitalization and death. Leveraging a new approach, the
research team turned their attention from the cell's periphery to the
nucleus – the very place that unleashes sweeping damage-control
responses which, if left unchecked, ultimately destroy the heart.
The team found that a new family of genes, called BET bromodomains,
cause heart failure because they drive hyperactive stress responses in
the nucleus. Prior research linking BET bromodomains to cancer prompted
the laboratory of James Bradner, MD, the paper's senior author and a
researcher at the Dana-Farber, to develop a direct-acting BET inhibitor,
called JQ1. In models of cancer, JQ1 functions to turn off key
cancer-causing genes occasionally prompting cancer cells to "forget"
they are cancer. In models of heart failure, JQ1 silences genetic
actions causing enlargement of and damage to the heart – even in the
face of overwhelming stress.
"While it's been known for many years that the nucleus goes awry in
heart failure, potential therapeutic targets residing in this part of
the cell are often dubbed as 'undruggable' given their lack of
pharmacological accessibility," said Jonathan Brown, MD, cardiologist at
Brigham and Women's Hospital and co-first author on the paper. "Our
work with JQ1 in pre-clinical models shows that this can be achieved
successfully and safely." Fist tap Dale.
