Researchers from Rice University and Baylor College of Medicine are hoping a first-of-its-kind "glyco-immune" checkpoint inhibitor could be the key to stopping bone cancer metastasis for breast cancer survivors.
Breast cancer often migrates to other organs. As many as 40% of breast cancer survivors are diagnosed with metastatic cancer, sometimes years after their initial treatment. Bone metastasis is involved in more than two-thirds of those cases, and bone metastatic lesions are known to "seed" metastatic cancer in other organs of the body.
Rice chemist Han Xiao and Baylor biologist Xiang Zhang have identified a new way to train patients' immune systems to specifically target and kill bone metastatic cancer. Thanks to a $2.3 million Breakthrough II award from the Breast Cancer Research Program of the Department of Defense's Congressionally Directed Medical Research Programs, they'll be able to further test the technology and see if it warrants development for human clinical trials.
Xiao said metastatic bone cancer eats away at patients' skeletons, leaving them prone to fractures that often require surgery.
"For bone metastasis right now, unfortunately there's no cure," said Xiao, who joined Rice in 2017 with funding from the Cancer Prevention and Research Institute of Texas (CPRIT). "It is a terribly painful disease. Patients endure many fractures and surgeries. Better and more effective treatments are badly needed."
The therapy Xiao and Zhang are developing is an innovative new checkpoint inhibitor, a type of immunotherapy drug that was pioneered by James Allison at the University of Texas MD Anderson Cancer Center in Houston.
Cancer often evades attack by the body's immune system by co-opting regulatory systems that dampen immune response. Checkpoint inhibitors are drugs that block this evasion. They target immune-damping proteins on the surface of cancer cells, allowing the immune system to recognize cancer and mark it for destruction by immune T-cells.
Checkpoint inhibitors have been a game-changer for the treatment of some cancers, including some forms of breast cancer. But currently approved checkpoint inhibitors have so far proven ineffective at treating metastatic bone cancer, Xiao said.
"Bone is a really immunosuppressive environment," he said. "T-cell proliferation is lower, and it is very hard to stimulate the T-cells. That's why we needed to find a marker, an immune checkpoint marker, that was specific to the bone."
Unlike other checkpoint inhibitors, which target immune-suppressing proteins, Xiao and Zhang's therapy targets a specific glycoprotein, a molecule that's part protein and part sugar.
Glycoprotein conjugates are abundant in nature, and they are one of Xiao's specialties. A chemical biologist, his research group focuses on both cancer immunology and glycobiology to understand the interface between cancer and immunity.
Xiao and Zhang previously identified the glycoprotein as a glyco-immune checkpoint target that was prevalent in metastatic bone cancer cells. They developed a drug that binds with the glycoprotein, and it proved remarkably effective in preliminary tests. In the first animal tests on a small sample of rodents, for example, the treatment eradicated cancer from some animals.
"Our study will, for the first time, reveal how a blockade of the glyco-immune checkpoint in bone may impede bone metastasis and subsequent multiorgan metastases," said Zhang, interim director of Baylor's Lester and Sue Smith Breast Center and a member of the Dan L Duncan Comprehensive Cancer Center.
Xiao is a Norman Hackerman-Welch Young Investigator, a CPRIT Scholar in Cancer Research and an assistant professor of chemistry, bioengineering and biosciences at Rice. Zhang is a William T. Butler Endowed Chair for Distinguished Faculty at Baylor, a McNair Scholar and a professor of molecular and cellular biology.
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CAPTION: From left, Baylor College of Medicine biologist Xiang Zhang and Rice University chemist Han Xiao have received $2.3 million from the Department of Defense to continue development of a promising new "glyco-immune" checkpoint inhibitor, a drug that would train the immune systems of breast cancer survivors to target and kill metastatic bone cancer. (Photo by Jeff Fitlow/Rice University)
