Some of these approaches seek to exploit the normal bone turnover cycle of osteoblastic bone building and osteoclastic bone resorption, as well as the ability of prostate cancer cells to stimulate new bone formation, through mechanisms which are still not clear.
“Prostate cancer cells have a unique predilection for bone, based in part on the bidirectional growth-promoting interaction between tumor cells and cells within the marrow,” noted Howard I. Scher, MD, Chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.
“Once established, bone metastases are more resistant to therapy than prostate cancers in other sites. Uncontrolled, bone metastases can produce some of the most feared and debilitating symptoms of the disease, including pain and neurologic compromise,” he added.
But, agreed Dr. Scher, “The outlook is changing. Our increased understanding of the biology of the disease has ushered in a new era of drug development.”
Areas of Investigation
Areas now under active investigation for treating prostate cancer bone metastases include cytotoxic drugs; strategies that block specific signaling cascades; and new agents that induce differentiation, promote apoptosis, or inhibit points in the metastatic cascade.
“Many groups are now reporting response proportions in excess of 50 percent on a consistent basis using combination chemotherapy,” Dr. Scher said. “More recent studies have shown that outcomes can be improved further by the addition of specific bone-directed treatments.”
Several studies presented at the meeting showed promising results from treatment of advanced prostate cancer with zoledronic acid, a more potent third-generation bisphosphonate that is an inhibitor of osteoclastic bone resorption. Zoledronic acid, which recently joined the list of FDA-approved bisphosphonates, is indicated for the treatment of hypercalcemia of malignancy, multiple myeloma, and documented bone metastases from solid tumors, in conjunction with standard anti-cancer therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy before use of zoledronic acid.
In one multicenter study presented at the meeting, for example, in 643 patients with advanced hormone-refractory prostate cancer and at least one bone metastasis, zoledronic acid consistently reduced bone pain (as assessed by pain scores) in the treatment group at three and nine months compared with the placebo group.
The agent was well tolerated, the researchers noted, adding, “This is the first bisphosphonate to demonstrate significant palliation of bone pain compared with placebo in a randomized Phase III clinical trial in patients with metastatic prostate cancer.”
Zoledronic acid, infused at a 4 mg dose over 15 minutes, was deemed “convenient, safe, and efficacious.” Side effects included fever and myalgia.
Another speaker, Matthew Smith, MD, PhD, Assistant Professor of Medicine at Massachusetts General Hospital, said that like intravenous pamidronate—a second-generation bisphosphonate—zoledronic acid is also helpful in preserving bone density in prostate cancer patients at risk of fracture undergoing androgen-deprivation therapy.
“Many men approach androgen deprivation with osteoporosis,” he noted. And many older men who do not yet have this bone-thinning disease are still at high risk because they have male osteoporosis in the family; smoke or drink excessively; don't exercise regularly; or don't get enough calcium in their diet.
“Osteoporosis is an important complication of androgen-deprivation therapy in men with prostate cancer,” Dr. Smith emphasized. “Androgen-deprivation therapy by either bilateral orchiectomy or treatment with a gonadotropin-releasing hormone agonist decreases bone mineral density and increases fracture risk.”
Right now, he said, there is limited information about the best strategy to prevent osteoporosis in men with prostate cancer. But it appears that zoledronic acid not only prevents bone loss but increases bone mineral density during androgen-deprivation therapy,” he said. Such increased density can be noted at the hip and spine.
In addition to research on bisphosphonates, speakers presented other early promising approaches to treating osteoblastic prostate cancer metastases.
One strategy, said John T. Isaacs, PhD, Professor of Oncology & Urology at Johns Hopkins, is to use receptor-signaling inhibitors to target the apoptotic death of both prostate cancer cells and proliferative osteoblasts in bone metastases.
“Prostate cancer cells recruit and release osteoblasts—it's a feed-forward mechanism,” he explained. “Agents that can induce apoptosis of prostate cancer cells and proliferating osteoblasts would be highly advantageous.”
Dr. Isaacs is studying the indocarbazole compounds CEP-701 and CEP-751, which are potent inhibitors of tyrosine kinase receptor survival signaling, and thus selectively induce apoptosis of prostate cancer cells in various in vitro and in vivo models, he noted.
Results so far in tumor-bearing mice, he said, provide a rationale for the use of such tyrosine kinase receptor signaling inhibitors to induce apoptosis in prostate cancer cells and proliferative osteoblasts in bone metastases.
Several studies presented at the symposium highlighted the role of endothelin-1 (ET-1) in osteoblastic bone metastases. ET-1 is a 21-amino-acid peptide vasoconstrictor produced by prostate and breast cancer cells that stimulates osteoblast proliferation.
Theresa A. Guise, MD, Associate Professor in the Department of Molecular Medicine at the University of Texas Health Science Center in San Antonio, noted that plasma ET-1 is increased in men with advanced prostate cancer and bone metastases, and that results from animal studies and early clinical trials indicate that blocking ET receptors reduces osteoblastic bone metastases and the tumor burden in bone.© 2002 Lippincott Williams & Wilkins, Inc.
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