Targeting bone metastasis and hypercalcemia
Most cancer patients are not killed by their primary tumors but succumb to metastatic disease. The most common human cancers–lung, breast, and prostate–frequently spread to bone, causing suffering and morbidity through pain, fractures, and nerve compression syndromes.
Tumor cells enter bones through blood and lymphatic vessels. In order to establish bone metastases, they have to influence bone metabolism. Most breast cancers that spread to bone express high levels of parathyroid hormone related protein, or PTHrP, a molecule that promotes bone breakdown. Scientists believe that the bone breakdown caused by PTHrP starts a vicious cycle: cross-talk between the tumor cells and the osteoclasts, cells that specialize in breaking down bone, ultimately leads to more and more bone loss and more and more aggressive growth of the tumor.
Consistent with this scenario, inhibition of osteoclast activity not only decreases bone lesions but also reduces tumor burden in animals. Preliminary results from human patients treated with bisphosphonates, a group of drugs also used to prevent and treat osteoporosis, suggest that the same might be true in humans.
An article in the November 18 issue of the Journal of Clinical Investigation focuses on direct inhibition of PTHrP, the molecule that is believed to play a critical role in starting the vicious cycle in most breast cancers that metastasize to bone.
Wolfgang Gallwitz and colleagues (of Osteoscreen Ltd in San Antonio, Texas) identified two compounds that inhibit PTHrP production in human breast cancer cells. In animal models, the compounds did reduce metastatic bone breakdown, and compared favorably with bisphoshonates. The mode of action of the two classes of drugs is different–the new compounds inhibit PTHrP production and secretion by the tumor cells whereas bisphosphonates inhibit osteoclasts–which suggests that the two drugs might have synergistic effects when used in combination.
In an accompanying Commentary, T. John Martin, of St. Vincents Institute of Medical Research in Melbourne, Australia, discusses the findings in the context of our understanding of bone metabolism and comments on potential therapeutic benefits and risks of PTHrP inhibitors in cancer.
PTHrP secretion by tumor cells frequently causes another complication in cancer patients, namely elevated calcium levels. The excess calcium comes on the one hand from increased breakdown of bone, and on the other from increased retention of calcium by the kidney. Hypercalcemia occurs in an estimated 10-20% of cancer patients and is the most common life-threatening metabolic abnormality associated with neoplastic disease. Mouse studies performed by Gallwitz and colleagues suggest that their PTHrP inhibitors have potential in the treatment of hypercalcemia as well.
Wolfgang E. Gallwitz
2040 Babcock Road
San Antonio, TX 78229
Phone 1: 210-614-0770
Fax 1: 210-614-0797
Manipulating the environment of cancer cells in bone: a novel therapeutic approach
T. John Martin
St. Vincents Institute of Medical Research
9 Princes Street
Fitzroy, Melbourne, Victoria 3065
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