A phase II trial of imatinib mesylate in patients with prostate specific antigen progression after local therapy for prostate cancer

Rao, Kamakshi V.; Goodin, Susan; Levitt, Michael; Davé, Nisha; Shih, Weichung Joe; Lin, Yong; Capanna, Terry; Doyle-Lindrud, Susan; Juvidian, Parisa; DiPaola, Robert S.

doi:10.1002/pros.20130

Cited by 63 publications

(28 citation statements)

References 17 publications

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“…Recent clinical trials using imatinib mesylate (STI571, Gleevec), a small-molecule inhibitor of PDGFRseither alone (Mathew et al, 2004;Rao et al, 2005;Lin et al, 2006;Bajaj et al, 2007) or in combination with docetaxel (Mathew et al, 2007)-have been disappointing, showing significant adverse toxic effects combined with lack of efficacy in counteracting bone metastatic progression and/or improving overall survival. However, it should be considered that, although in the adult organism both PDGFRa and PDGFRb cooperate in modulating largely overlapping physiological processincluding angiogenesis, wound healing and tissue homeostasis (Heldin and Westermark, 1999;Betsholtz, 2004)-PDGFRb plays an overall predominant role (Andrae, Gallini and Betsholtz, 2008).…”

Section: Resultsmentioning

confidence: 99%

The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

et al. 2008

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Bone resorption by osteoclasts is thought to promote the proliferation of prostate cancer cells disseminated to the skeleton (Mundy, 2002). Using a mouse model of experimental metastasis, we found that although latestage metastatic tumors were indeed surrounded by osteoclasts, these cells were spatially unrelated to the small foci of cancer cells in early-stage metastases. This is the first evidence that survival and growth of disseminated prostate cancer cells immediately after their extravasation may not depend on osteoclast involvement. Interestingly, prostate cancer cells expressing the a-receptor for platelet-derived growth factor (PDGFRa) progress during early-stages of skeletal dissemination, whereas cells expressing lower levels or lacking this receptor fail to survive after extravasation in the bone marrow. However, non-metastatic cells acquire bone-metastatic potential upon ectopic overexpression of PDGFRa. Finally, functional blockade of human PDGFRa on prostate cancer cells utilizing a novel humanized monoclonal antibodysoon to undergo phase-II clinical trials-significantly impairs the establishment of early skeletal metastases. In conclusion, our results strongly implicate PDGFRa in prostate cancer bone tropism through its promotion of survival and progression of early-metastatic foci, providing ground for therapeutic strategies aimed at preventing or containing the initial progression of skeletal metastases in patients affected by prostate adenocarcinoma.

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Section: Resultsmentioning

confidence: 99%

The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

et al. 2008

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“…For example, Rao et al performed a phase II study with imatinib, 20 which is used as a treatment for chronic myelogenous leukemia due to its ability to inhibit the fusion kinase bcr-abl. 21 Based on its ability to also inhibit the PDGF receptor is being tested in patients with prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…This study was terminated early when five of 21 patients exhibited an inordinately fast rise in PSA. 20 In a similar study, Mathew et al evaluated the combination of imatinib and docetaxel in a phase II study. 22 This study incorporated a lead in period in which patients were treated with imatinib alone for 30 days to assess response.…”

Section: Discussionmentioning

confidence: 99%

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Collins

Carducci

Eisenberger

et al. 2007

Cancer Biology & Therapy

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Purpose-CEP-701 is a potent inhibitor of trk receptors that causes cell death in prostate cancer (PC) models. CEP-701 binds to serum proteins and a preprostatectomy study was performed to assess prostate tissue penetration and clinical response to CEP-701.Methods-Growth assays and Western blot analyses were performed to evaluate CEP-701 kinase inhibition. In a preprostatectomy study, patients received CEP-701 for five days prior to prostatectomy and prostate tissue analyzed for CEP-701 levels. A phase II dose escalation study was performed in patients with hormone refractory PC with rising PSA and no metastases. Endpoints included PSA response and safety.Results-CEP-701 binds to serum proteins limiting tissue penetration. An oral dose of 40 mg bid of CEP-701 for five days produced levels of 219 ± 38 nM in prostate at time of prostatectomy. No patients in the Phase II study met the primary response criteria of >50% PSA decline. Seven/9 patients had increase in PSA slope on CEP-701 compared to PSA slope prestudy. Five/9 patients had a decrease in PSA levels after stopping CEP-701. Laboratory studies showed increased PSA production by CEP-701 growth arrested human PC cells in vitro and in vivo.Conclusions-Evaluation of PSA response is an inadequate indicator of response in CEP-701 treated PC patients. Therefore, the effectiveness of CEP-701 as treatment for prostate cancer has not been adequately tested. Based on a strong preclinical rationale, further clinical studies with CEP-701 using alternative endpoints are indicated.

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“…Of the 17 patients evaluable for response, there were no patients with a PSA decline of ≥ 50% and there was significant toxicity as six patients were removed from study due to Grade 3 and 4 toxicities. 57 A phase II trial looking at the combination of imatinib and zoledronic acid is currently underway. Preliminary results of 11 evaluable patients show no significant responses in any of the major endpoints.…”

Section: Other Novel Agentsmentioning

confidence: 99%

Novel Therapeutic Strategies in Prostate Cancer

Retter

Gulley²,

Dahut³

2004

Cancer Biology & Therapy

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A phase II trial of imatinib mesylate in patients with prostate specific antigen progression after local therapy for prostate cancer

Abstract: This first study evaluated the efficacy and safety of imatinib in patients with early androgen sensitive prostate cancer following local therapy. As a single agent at this dosing, imatinib had limited biochemical activity.

Cited by 63 publications

References 17 publications

The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

The α-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells

Preclinical and clinical studies with the multi-kinase inhibitor CEP-701 as treatment for prostate cancer demonstrate the inadequacy of PSA response as a primary endpoint

Novel Therapeutic Strategies in Prostate Cancer

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