A clinical phase II study with sorafenib in patients with progressive hormone-refractory prostate cancer: a study of the CESAR Central European Society for Anticancer Drug Research-EWIV

Sorafenib is a multi-kinase inhibitor with antiangiogenic and antiproliferative activity. The activity of sorafenib in progressive hormone-refractory prostate cancer (HRPC) patients was investigated in a phase II clinical study. Progressive HRPC patients received sorafenib 400 mg bid p.o. continuously. Only patients with no prior chemotherapy, and either one-unidimensional measurable lesion according to RECIST-criteria or increasing prostate-specific antigen (PSA) values reflecting a hormone-refractory situation, were eligible for study entry. The primary study objective was the rate of progression-free survival of ⩾12 weeks (PFS12). Secondary end points were overall response, overall survival, and toxicity. Fifty-seven patients with PC were enrolled. Two patients had to be withdrawn from the set of eligible patients. According to RECIST criteria, 4 patients out of 55 evaluable patients showed stable disease (SD). According to PSA–response, we saw 11 patients with SD PSA and 2 patients were responders at 12 weeks (PFS12=17/55=31%). Among the 257 adverse events, 15 were considered drug related of maximum CTC-grade 3. Twenty-four serious adverse events occurred in 14 patients (14/55=26%). Seven of them were determined to be drug related. No treatment-related death was observed. Sorafenib has antitumour activity in HRPCP when evaluated for RECIST- and PSA-based response. Further investigation as a component of combination regimens is necessary to evaluate its definite or overall clinical benefit for HRPCP

Novel therapies in genitourinary cancer: an update

In recent years, new treatment for renal cell carcinoma (RCC) has been a spotlight in the field of cancer therapeutics. With several emerging agents branded as 'targeted therapy' now available, both medical oncologists and urologists are progressively more hopeful for better outcomes. The new remedies may provide patients with improved survival and at the same time less toxicity when compared to traditional cytotoxic agents. This article will center on current and emerging treatment strategies for advanced RCC and other GU malignancies with updates from 2008 annual ASCO meeting

The therapeutic potential of a series of orally bioavailable anti-angiogenic microtubule disruptors as therapy for hormone-independent prostate and breast cancers

Therapies for hormone-independent prostate and breast cancer are limited, with the effectiveness of the taxanes compromised by toxicity, lack of oral bioavailability and drug resistance. This study aims to identify and characterise new microtubule disruptors, which may have improved efficacy relative to the taxanes in hormone-independent cancer. 2-Methoxy-3-O-sulphamoyl-17β-cyanomethyl-oestra-1,3,5(10)-triene (STX641), 2-methoxy-3-hydroxy-17β-cyanomethyl-oestra-1,3,5(10)-triene (STX640) and 2-methoxyoestradiol-3,17-O,O-bis-sulphamate (STX140) were all potent inhibitors of cell proliferation in a panel of prostate and breast cancer cell lines. STX641 and STX640 significantly inhibited tumour growth in the MDA-MB-231 xenograft model. STX641 inhibited both in vitro and in vivo angiogenesis. Despite good in vivo activity, STX641 was not as potent in vivo as STX140. Therefore, STX140 was evaluated in the prostate hormone-independent PC-3 xenograft model. STX140 had superior efficacy to docetaxel, 2-MeOE2 and bevacizumab. In contrast to vinorelbine, no significant toxicity was observed. Furthermore, STX140 could be dosed daily over a 60-day period leading to tumour regression and complete responses, which were maintained after the cessation of dosing. This study demonstrates that STX641 and STX140 have considerable potential for the treatment of hormone-independent breast and prostate cancer. In contrast to the taxanes, STX140 can be dosed orally, with no toxicity being observed even after prolonged daily dosing

VEGF Inhibitors and Prostate Cancer Therapy

Prostate cancer remains the most common non-cutaneous malignancy among American men. Since the advent of PSA testing, most men are diagnosed with localized disease, but a proportion of men will be diagnosed with metastatic disease, many will eventually receive chemotherapy with docetaxel and prednisone. However, responses are not durable and all men will ultimately progress on this treatment. As such, continued efforts are geared towards the discovery of new agents and mechanisms of targeting prostate cancer. Angiogenesis has been shown to play an important role in tumorigenesis, proliferation and metastasis in prostate cancer. Here we discuss the major angiogenic signaling pathway involving VEGF in prostate cancer progression and the role of various promising agents that targets this pathway. This includes bevacizumab, thalidomide and its analogues, tyrosine kinase inhibitors sorafenib and AZD2171, and other inhibitors of angiogenic signaling pathways. Results of key clinical trials associated with the use of these agents and future directions are discussed herein

Anti-angiogenesis approach to genitourinary cancer treatment

Angiogenesis plays a crucial role in the survival, proliferation, and metastatic potential of several tumors, including genitourinary (GU) cancers. Over the last decade, increasing basic science and clinical research have led to the approval of several angiogenesis inhibitors. GU tumors are unique in its pathogenesis whereby specific pathways, such as involvement of the Von Hippel-Lindau gene in clear cell renal cell cancer and aberrant overexpression of vascular endothelial growth factor in prostatic cancers and transitional cell bladder cancers, allow for potential targeting using angiogenesis inhibitors. This review discusses the biologic pathways as well as the rationale for using angiogenesis inhibitors in renal cell, prostate, and transitional cell bladder cancers. This review also focuses on pivotal trials and emerging data on the use of these inhibitors