Groundbreaking Work on Connexins Leads to Potential Breast Cancer Drug
Mays Cancer Center Annual Report
Our cells “talk” to one another through an information superhighway known as gap junctions. These junctions, formed by proteins called connexins, help law-abiding cells share important biological news and even small molecules directly with their neighbors without having to go through the extracellular fluid surrounding them.
Gap junctions help good neighbors stay on the same page when it comes to coordinating activities in healthy tissue. But they are conspicuously absent when it comes to cancer tumor cells — until they try to metastasize. When that happens, connexin in healthy cells can form an emergency response system to communicate outside their walls and post a strong warning to keep intruders out.
“Connexins and intracellular communication are essential for healthy cell function and homeostasis,” says Jean Jiang, PhD, professor of biochemistry and structural biology and holder of the Zachry Distinguished University Chair at UT Health San Antonio.
“Typically, primary cancer cells don’t have gap junction communication, and there was a time that we thought gap junctions played the role in suppressing cancer, but the last decade of research revealed the picture is much more complicated.”
While cancer cells don’t talk to each other through gap junctions, they do form gap junctions when they metastasize to healthy tissue in an effort to hijack their systems, and such is the case with metastatic breast cancer. Dr. Jiang discovered that when breast cancer cells try to spread to skeletal tissue, specialized bone cells called osteocytes have an innate defense system that kicks in when they are under stress.
Their connexins form tunnels, called hemichannels, which allow bone cells to release small molecules, such as adenosine triphosphate (ATP) to the micro-environment outside the cell. ATP alarms the immune system and inhibits cancer cell growth. “We found if we can open these channels in bone cells, they can release these factors that can inhibit tumor growth to the bone.”
Breast cancer is a leading cancer in Latino women in South Texas and is more often diagnosed at a later stage in this population when it is more advanced. Bone metastasis occurs in approximately 70 percent of metastatic breast cancers, which according to the American Cancer Society, drops five-year survival rates to 27 percent.
Dr. Jiang’s interest in gap junctions began in 1991 after reading in The New York Times about their possible role as a tumor suppressor. She joined the gap junction lab at Harvard before coming to UT Health in 1997 where her basic research has been continually funded by the National Institutes of Health.
Uncovering the function of hemichannels, Dr. Jiang developed custom antibodies to stimulate the opening of these channels in bone cells to further protect skeletal tissue from invasion of breast cancer cells.
Exercise has much the same effect in opening these hemichannels. “Mechanical loading exercise is not only good for preventing metastasis, but for overall well-being,” Dr. Jiang says, “but for people who already have some bone metastasis and bone pain, it makes it very difficult to exercise, and they need a therapeutic intervention.”
Live cell lab work has shown the antibody is effective. Although the COVID-19 crisis has slowed development, the antibody is currently in research and development studies with AlaMab Therapeutics in collaboration with UT Health. AlaMab bought licensing rights for the potential first-in-class breast cancer drug that may be worth as much as $114 million for UT Health depending on it reaching successful milestones, Dr. Jiang says. “The research and development preclinical data are looking good and approved for the Phase 1 clinical trial. The Phase 1 clinical trial was initiated last year and is currently ongoing.”
Even so, the potential for targeting connexin hemichannels with therapeutics is a game changer. Dr. Jiang also developed a second antibody that reduces inflammation in spinal cord injuries, in this case, by closing hemichannels.
While the basic research is funded by the NIH, translational drug development is funded by the U.S. Department of Defense.
Dr. Jiang was honored as a Fellow of the American Association for the Advancement of Science for her groundbreaking work uncovering the mechanics of connexin channels and awarded a Presidential Distinguished Senior Research Scholar Award at UT Health.
“Doing the basic research for 30 years now, I really think if this research pays off in a translational drug to benefit all of humanity, that would be the greatest reward I could ever receive,” she added.