Department of Urology Faculty Papers

Permanent URI for this collectionhttps://digital.lib.washington.edu/handle/1773/15693

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Host-derived RANKL is responsible for osteolysis in a C4-2 human prostate cancer xenograft model of experimental bone metastases
(2007) Morrissey, Colm; Kostenuik, Paul L.; Brown, Lisha G.; Vessella, Robert L.; Corey, Eva
Background: C4-2 prostate cancer (CaP) cells grown in mouse tibiae cause a mixed osteoblastic/osteolytic response with increases in osteoclast numbers and bone resorption. Administration of osteoprotegerin (OPG) blocks these increases, indicating the critical role of RANKL in osteolysis in this model. The objective of our study was to investigate whether RANKL expressed by tumor cells (human origin) directly stimulates osteolysis associated with the growth of these cells in bone or whether the increased osteolysis is caused by RANKL expressed by the host environment cells (murine origin). The relative contribution of tumor-vs. host-derived RANKL has been difficult to establish, even with human xenografts, because murine and human RANKL are both capable of stimulating osteolysis in mice, and the RANKL inhibitors used to date (OPG and RANK-Fc) inhibit human and murine RANKL. Methods: To address this question we used a neutralizing, antibody (huRANKL MAb), which specifically neutralizes the biological activities of human RANKL and thereby the contribution of C4-2 derived RANKL in this tibial injection model of experimental bone metastases. Results: Administration of huRANKL MAb did not inhibit the osteolytic response of the bone to these cells, or affect the establishment and growth of the C4-2 tumors in this environment. Conclusion: In conclusion, our results suggest that in this model, murine RANKL and not the tumor-derived human RANKL is the mediator of the osteolytic reaction associated with C4-2 growth in bone. We hypothesize that C4-2 cells express other factor/s inducing host production of RANKL, thereby driving tumor-associated osteolysis.
A phase II trial of docetaxel and erlotinib as first-line therapy for elderly patients with androgen-independent prostate cancer
(2007) Gross, Mitchell; Higano, Celestia; Pantuck, Allan; Castellanos, Olga; Green, Erica; Nguyen, Koo; Agus, David B.
Background: Docetaxel is the standard first-line agent for the treatment of androgen-independent prostate cancer (AIPC). The combination of docetaxel with molecularly targeted therapies may offer the potential to increase the efficacy and decrease the toxicity of cytotoxic chemotherapy for prostate cancer. Previous studies demonstrate activation of the human epidermal growth factor receptor (EGFR) in prostate cancer. Erlotinib is a specific inhibitor of the tyrosine-kinase activity of EGFR. The goal of this study is to determine the anti-cancer activity docetaxel combined with erlotinib for the treatment of elderly subjects with AIPC. Methods: This is a multi-institutional Phase II study in patients with histologically confirmed adenocarcinoma of the prostate and age [greater than or equal to] 65 years. Patients were requred to have progressive disease despite androgen-deprivation therapy as determined by: (1) measurable lesions on cross-sectional imaging; (2) metastatic disease by radionucleotide bone imaging; or (3) elevated prostate specific antigen (PSA). Treatment cycles consisted of docetaxel 60 mg/m2 IV on day 1 and erlotinib 150 mg PO days 1-21. Patients with responding or stable disease after 9 cycles were eligible to continue on erlotinib alone as maintenance therapy. Results: Characteristics of 22 patients enrolled included: median age 73.5 years (range, 65-80); median Karnofsky Performance Status 90 (range 70-100); median hemoglobin 12.1 g/dl (range, 10.0-14.3); median PSA 218.3 ng/ml (range, 9-5754). A median of 6 treatment cycles were delivered per patient (range 1-17). No objective responses were observed in 8 patients with measurable lesions (0%, 95% CI 0-31%). Bone scan improvement and PSA decline was seen in 1 patient (5%, 95% CI 0.1-25%). Five of 22 patients experienced [greater than or equal to] 50% decline in PSA (23%, 95% CI 8-45%). Hematologic toxicity included grade 3 neutropenia in 9 patients and neutropenic fever in 2 patients. Common non-hematologic toxicities ([greater than or equal to] grade 3) included fatigue, anorexia, and diarrhea. Conclusion: Docetaxel/erlotinib can be delivered safely in elderly patients with AIPC. Anti-cancer disease activity appears generally comparable to docetaxel when used as monotherapy. Hematologic and nonhematologic toxicity may be increased over docetaxel monotherapy. Prospective randomized studies would be required to determine if the toxicity of docetaxel and erlotinib justifies its use in this setting.
Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment
(2006) Brubaker, Kristen D.; Brown, Lisha G.; Vessella, Robert L.; Corey, Eva
Background: After development of hormone-refractory metastatic disease, prostate cancer is incurable. The recent history of chemotherapy has shown that with difficult disease targets, combinatorial therapy frequently offers the best chance of a cure. In this study we have examined the effects of a combination of zoledronic acid (ZOL), a new-generation bisphosphonate, and docetaxel on LuCaP 23.1, a prostate cancer xenograft that stimulates the osteoblastic reaction when grown in the bone environment. Methods: Intra-tibial injections of LuCaP 23.1 cells were used to generate tumors in the bone environment, and animals were treated with ZOL, docetaxel, or a combination of these. Effects on bone and tumor were evaluated by measurements of bone mineral density and histomorphometrical analysis. Results: ZOL decreased proliferation of LuCaP 23.1 in the bone environment, while docetaxel at a dose that effectively inhibited growth of subcutaneous tumors did not show any effects in the bone environment. The combination of the drugs significantly inhibited the growth of LuCaP 23.1 tumors in the bone. Conclusion: In conclusion, the use of the osteolysis-inhibitory agent ZOL in combination with docetaxel inhibits growth of prostate tumors in bone and represents a potential treatment option.
Pelvic tenderness is not limited to the prostate in chronic prostatitis/chronic pelvic pain syndrome (CPPS) type IIIA and IIIB: comparison of men with and without CP/CPPS
(2007) Berger, Richard E.; Ciol, Marcia A.; Rothman, Ivan; Turner, Judith A.
Background: We wished to determine if there were differences in pelvic and non-pelvic tenderness between men with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) Type III and men without pelvic pain. Methods: We performed the Manual Tender Point Survey (MTPS) as described by the American College of Rheumatology on 62 men with CP/CPPS Type IIIA and IIIB and 98 men without pelvic pain. We also assessed tenderness of 10 external pelvic tender points (EPTP) and of 7 internal pelvic tender points (IPTP). All study participants completed the National Institutes of Health Chronic Prostatitis Symptom Inventory (NIH CPSI). Results: We found that men with CPPS were significantly more tender in the MTPS, the EPTPS and the IPTPS. CPSI scores correlated with EPTP scale but not with IPTP scale or prostate tenderness. Prostatic tenderness was present in 75% of men with CPPS and in 50% of men without CPPS. Expressed prostatic fluid leukocytosis was not associated with prostatic tenderness. Conclusion: Men with CP/CPPS have more tenderness compared to men without CPPS. Tenderness in men with CPPS is distributed throughout the pelvis and not specific to the prostate.

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