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In Reply:

Departments of Genitourinary Medical Oncology and Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX

Drs Hofer and Rubin have referred to their work on characterizing the prevalence of platelet-derived growth factor receptor beta (PDGFR-ß) expression in localized and hormone-refractory prostate cancers obtained from radical prostatectomies and warm autopsies.¹ We agree that variations in estimates of the prevalence of expression of PDGFR-ß may arise from the variable performance of different antibodies from different sources under different conditions, and may explain the differences between their results and previously published estimates.^2,3 We have found that cross-reactivity to PDGFR- and PDGFR-ß as well as the epidermal growth factor receptor and the performance of phospho-specific antibodies in formalin-fixed tissues are challenges to be addressed during optimization of these antibodies. However, organ-specific variations in PDGFR expression in metastatic sites offer an additional variable to be dealt with, and this is not well described in Dr Hofer and Dr Rubin's paper.

Our work has focused on the molecular mechanisms of bone metastases given its importance in the biology of prostate cancer. Our goals are to target mechanisms of disease progression in bone to modulate favorably the natural history of the disease. Our preclinical data have consistently demonstrated the upregulation of PDGFR expression in prostate cancer cells in the bone microenvironment as well as in endothelial cells in tumor vasculature, and we have suggested that this may be a target for therapy.⁴ Our results thus far on informative bone marrow biopsies from patients with metastatic androgen-independent prostate cancer are consistent with the estimates previously published.^2,3 Our ongoing clinical studies on a larger study set (n = 144) are likely to illuminate this further.

Imatinib mesylate is an inhibitor of both PDGFR- and PDGFR-ß, and it would seem that the absence of a significant response to imatinib during the short lead-in period in our modular phase I trial⁵ is indicative of the fact that the biology of the disease is not singularly dependent on this signaling pathway, such as it may be in diseases in which the PDGFR receptor is translocated or constitutionally activated by mutation. The weight of evidence from our preclinical studies⁴ pointed toward a benefit for combination therapy rather than single-agent imatinib or taxane. The principal goals of our phase I study were to establish the feasibility of combining a PDGFR inhibitor with taxane chemotherapy, but also, through the modular design, to obtain a preliminary glimpse of activity of the single-agent imatinib and the combination with docetaxel. We were intrigued by the long-term responses with combination therapy (median freedom from progression, 23 months) observed in a fraction of these patients belonging to a heavily pretreated cohort. As we have noted in the article, the results of combination therapy were not directly comparable with other phase II designs in patients with minimal or no prior chemotherapy, and in our judgment, these findings deserved better evaluation in the phase II setting. It is premature to state that the overall results represent a modest improvement.

Authors' Disclosures of Potential Conflicts of Interest

The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant: Paul Mathew, Aventis, Novartis. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.

REFERENCES

1. Hofer MD, Fecko A, Shen R, et al: Expression of the platelet-derived growth factor receptor in prostate cancer and treatment implications for tyrosine kinase inhibitors. Neoplasia 6:503-512, 2004[CrossRef][Medline]

2. Ko YJ, Small EJ, Kabbinavar F, et al: A multi-institutional study of SU101, a platelet-derived growth factor receptor inhibitor, for patients with hormone-refractory prostate cancer. Clin Cancer Res 7:800-805, 2001[Abstract/Free Full Text]

3. Chott A, Sun Z, Morganstern D, et al: Tyrosine kinases expressed in vivo by human prostate cancer bone marrow metastases and loss of the type 1 insulin-like growth factor receptor. Am J Pathol 155:1271-1279, 1999[Abstract/Free Full Text]

4. Uehara H, Kim SJ, Karashima T, et al: Effects of blocking platelet-derived growth factor-receptor signaling in a mouse model of experimental prostate cancer bone metastases. J Natl Cancer Inst 95:558-570, 2003

5. Mathew P, Thall P, Jones D, et al: Platelet-derived growth factor receptor inhibitor imatinib mesylate and docetaxel: A modular phase I trial in androgen-independent prostate cancer. J Clin Oncol 22:3323-3329, 2004[Abstract/Free Full Text]

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Related Correspondence

• Platelet-Derived Growth Factor Receptor Inhibitor Imatinib Mesylate and Docetaxel: A Modular Phase I Trial in Androgen-Independent Prostate Cancer
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  JCO 2005 23: 1332-1333 [Full Text]

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