Elucidation of the underlying mechanisms of action for Ra-223 will soon expand its clinical utility with respect to improved patient selection and integrated bone-targeted therapies.
Lewis et al provide an excellent review of current data and future prospects regarding the role of radium-223 (Ra-223) in treating prostate cancer metastasis to bone. Prostate cancer is a unique malignancy with a special affinity for bone and a remarkable capacity to develop osteoblastic metastasis. Ra-223 is an ideal drug for targeted treatment of osteoblastic metastasis, and has a favorable efficacy and toxicity profile.
A critical observation suggests that Ra-223 targets the osteoblasts but does not directly affect the malignant prostate cancer cells, leading to discordant changes in the prostate-specific antigen (PSA) and alkaline phosphatase levels. In addition, it seems that targeting of osteoblasts by Ra-223, but not osteoclasts by zoledronic acid or denosumab,[3,4] enhances survival time of patients with advanced prostate cancer. Indeed, laboratory studies using co-culture systems have shown that osteoblasts support prostate cancer growth in vitro, and tumorigenicity models show the same in vivo. By suppressing osteoblast differentiation, Ra-223 may modulate the production and expression of osteoblast-derived factors that support prostate cancer cell growth or survival within the bone metastasis (Figure).
Ra-223 is not the right treatment for all patients with bone metastasis. An improved understanding of the underlying biology of disease and mechanism of action will enable us to optimize treatment by informing patient selection and personalized care.
Tumor burden. There is strong evidence for a dose response to Ra-223 in the treatment of prostate cancer bone metastasis. However, it remains unclear whether tumor burden affects treatment benefit. The ALSYMPCA results suggest that patients with fewer bone metastases on bone scan benefit less from Ra-223. Our experience using strontium-89 (Sr-89) showed similar results. If they are confirmed, the biologic basis for these observations needs further elucidation.
Osteoblastic metastasis. Ra-223 is designed for the treatment of osteoblastic metastasis. It is unlikely to be effective for the treatment of pure osteolytic metastasis, as seen in most cases of multiple myeloma and renal cell carcinoma. It remains unknown whether Ra-223 is also beneficial for the treatment of mixed blastic/lytic bone metastasis and of lytic metastasis that becomes blastic due to healing as a result of other treatments.
Bone marrow reserve. Although Ra-223 rarely causes bone marrow suppression, because of its short half-life and low penetrance, it is prudent not to use it in the setting of low blood counts. However, if the low blood counts occur as a result of tumor infiltration into the bone marrow, and improve when treatments eliminate or reduce the tumor burden, the question of whether Ra-223 becomes an appropriate treatment after patients respond to induction therapy is of interest.
Spinal cord compression. Although Ra-223 may not reach other tissue sites due to its low penetrance, it is contraindicated in the setting of an impending spinal cord compression and base of skull syndrome, when there is a potential risk for causing myelitis and cranial nerve damage, respectively. It remains unclear whether Ra-223 can be given after the site of cord compression and nerve impingement is controlled with radiation therapy or other treatments.
The finding that Ra-223 is safe and targets a specific compartment of bone metastasis (ie, bone stroma and osteoblasts) makes it an ideal agent to combine with other agents having a different therapeutic and toxicity profile. Lessons from clinical experience with other radiopharmaceuticals suggest that combination therapy is feasible. Hence, samarium-153 (Sm-153) combined with docetaxel[10,11] or Sr-89 with weekly low-dose doxorubicin (20 mg/m2) was safe. There was an additive effect, if not a synergistic one, when Sr-89 was combined with ketoconazole. Combining Ra-223 with other proven treatments for advanced metastatic prostate cancer is currently being examined. We anticipate that combining Ra-223, which targets the tumor microenvironment, with therapies that target prostate cancer cells could lead to effective integrated therapies that improve overall clinical outcome.
Integrated therapy is not only proper but also necessary for patients with high-volume disease or anaplastic features, such as patients with androgen receptor (AR) splice variants or AR-negative tumors, who have high PSA nadirs (ie, > 4 ng/dL) on hormone ablative therapy, and who harbor visceral metastases but still have predominant osteoblastic metastases. When other components of prostate cancer are controlled, Ra-223 could enhance the clinical benefit of conventional treatments and render consolidation therapy[12,13] or maintenance treatments more practical.
When a particular treatment provides improvement in patient survival time, its mechanism of action is likely to be relevant. When the treatment has a specific cellular or molecular target, it may be possible to answer some basic biologic questions and determine how such a treatment modulates the target and affects the pathogenesis of a major cancer hallmark, namely metastasis.
Ra-223 could be useful in the laboratory for dissecting the role of the bone microenvironment in the pathogenesis of prostate cancer bone metastasis. Ra-223 is known to target and affect osteoblasts. It is of interest to identify specific osteoblast-derived factors that play an important role in homing (eg, CXCL12), colonization (eg, cadherin-11), proliferation (eg, Wnt, catenin), stem-cell niche (eg, periostin), and cancer dormancy (eg, osteopontin, TGF-beta)[19-21] in the bone microenvironment and investigate whether Ra-223 interferes with their mechanisms of action.
Several questions remain unanswered. One pertains to the reason for a survival benefit with Ra-223 but not with Sr-89 or Sm-153. Another question invokes Paget’s “seed and soil” theory. It seems that by treating the soil alone but not the seeds themselves, Ra-223 is sufficient to prolong survival time. A more mundane question concerns the causes of pain flare and intractable anemia in certain patients, who tend to experience an enhanced response to Ra-223.
In sum, this comprehensive review by Lewis et al alludes to the promising prospect that elucidation of the underlying mechanisms of action for Ra-223 will soon expand its clinical utility with respect to improved patient selection and integrated bone-targeted therapies.
Financial Disclosure:Dr. Bilen and Dr. Lin have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. Dr. Tu served as a consultant for Bayer Healthcare in February 2014.
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