Bisphosphonates Evolve Beyond Palliative Care
In this era of targeted cancer therapies, researchers are adapting bisphosphonates - an "old workhorse" class of drugs first synthesized at the end of the 19th century and later used to treat osteoporosis and prevent complications from bone metastases - to carry anticancer drugs directly to cancer cells in the bone.
Despite its solid appearance, bone is a remarkably plastic substance, undergoing constant remodeling and replacement of old and damaged sections. Two main cell types drive this process: osteoclasts, which break down old bone, and osteoblasts, which lay down a new bone matrix.
In osteoporosis and other disorders that disrupt bone metabolism, the balance between osteoclasts and osteoblasts is disturbed, and the osteoclasts break down more bone than can be replaced, leading to a weakened skeleton.
Researchers in the 1960s developed the bisphosphonates as treatments to prevent bone breakdown. The modern bisphosphonates have an extraordinary affinity for bone cells over any other cell type, and prevent immature osteoclasts from attaching to bone, maturing, and surviving to break down the skeletal matrix.
Oncologists soon became interested in the bisphosphonates to fight the morbidities caused by cancer cells that have metastasized to bone. Aberrant signaling from these cancer cells can disrupt bone metabolism in a manner similar to osteoporosis, leading to skeletal fractures, intense bone pain, and a reduced quality of life.
Today's bisphosphonates, which are up to thousands of times more potent than the first generation, have become the standard of care for preventing skeletal complications from bone metastases.
"Bisphosphonates are really widely used in oncology," said Dr. Jennifer Eng-Wong, a breast cancer specialist at NCI's CCR. "Bone is one of the most common sites of metastasis for breast, prostate, non-small-cell lung cancer, and multiple myeloma, so for our long-term survivors, it's quite common for them to be on these agents."
Recent in vitro studies have suggested that bisphosphonates might actually possess anticancer activity. "The osteoclasts concentrate the bisphosphonates at their back end, at a much more concentrated level than you would find in the plasma," explained Dr. Patrick Mantyh, director of the Neurosystems Center at the University of Minnesota, whose research focuses on using bisphosphonates to treat bone cancer pain.
"So the tumor, which is usually sitting behind the osteoclasts, is exposed to a high concentration of the bisphosphonate, and that high concentration probably inhibits and kills endothelial cells, which would then deprive the tumor of its vascular supply," he said.
Researchers have come back to the bisphosphonates not only because of their potential antitumor activity, but because of their affinity for bone. "One idea is that you could actually use a bisphosphonate and attach another molecule to it…to deliver a drug and have it all stick to the skeleton," said Dr. Mantyh. "If you wanted to deliver a therapeutic directly to bone, this may be an attractive way to get it there."
NCI is funding investigators who are working to develop bisphosphonate conjugates - bisphosphonates chemically bound to another molecule. By attaching a cytotoxic anticancer molecule to a bisphosphonate backbone, researchers hope to turn drugs that might be too toxic if delivered alone systemically into targeted therapies.
Dr. Monica Reinholz, at the Mayo Clinic College of Medicine in Rochester, Minn., has been studying bisphosphonate conjugates for the treatment of metastatic breast cancer and multiple myeloma in collaboration with MBC Pharma, Inc., in Boulder, Colo., through a Small Business Technology Transfer grant. One exciting idea, supported by in vitro and in vivo results, she explained, is that some bisphosphonate conjugates may have more potent anticancer activity than either compound alone.
"Preliminary animal studies have shown that the conjugate reduces metastases to the bone and confers benefits to both bone quality and survival," she said. "This demonstrates efficacy beyond either the bisphosphonate or the cytotoxic drug alone or in the nonconjugated mixture."
"A lot of studies are looking at the possibility of giving bisphosphonates up front in the adjuvant setting, to maintain bone density," said Dr. Reinholz. "If you could use conjugates, you may get the benefits of the bisphosphonate and the chemotherapy all at once."
By Sharon Reynolds