Bevacizumab treatment of prostate cancer

Small, Alexander; Oh, William K.

doi:10.1517/14712598.2012.704015

Cited by 21 publications

(18 citation statements)

References 47 publications

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“…As a result of CTLA-4 blockade, granulocytes and lymphocytes infiltrate the endothelia resulting in its destruction and tumor necrosis. The clinical efficacy of targeting VEGF-A, and this effect on pathologic angiogenesis has been extensively studied with the use of bevacizumab ( 7-13 ), and suggests a role in counteracting the immunosuppressive actions of VEGF. Given the effects on tumor vasculature witnessed in melanoma patients being treated with ipilimumab and the known activity of bevacizumab, we conducted a phase I study to investigate the potential synergies of this combination in patients with metastatic melanoma.…”

Section: Introductionmentioning

confidence: 99%

Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

Hodi¹,

Lawrence

Lezcano

et al. 2014

Cancer Immunology Research

519

400

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Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA-4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (1), hepatitis (2), and uveitis (2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8+ and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7+/−/CD45RO+ cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 stable disease, and a disease-control rate (DCR) of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. This provides a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation as well as future combinations of anti-angiogenesis agents and immune checkpoint blockade.

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Section: Introductionmentioning

confidence: 99%

Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

Hodi¹,

Lawrence

Lezcano

et al. 2014

Cancer Immunology Research

519

400

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“…A clinical trial of bevacizumab, a recombinant anti-VEGF monoclonal antibody, combined with chemotherapy showed increased progression-free survival compared to placebo plus chemotherapy. However, this treatment combination did not significantly improve overall survival compared to the control arm [25]. The limited responses and acquired resistance to anti-VEGF therapy suggest that while angiogenesis through VEGF is an important target for cancer therapies, the development of successful new drugs will require a deeper understanding of factors that facilitate escape from anti-angiogenic therapy and allow for continued tumor survival and vascularization.…”

Section: Introductionmentioning

confidence: 99%

Cabozantinib Inhibits Growth of Androgen-Sensitive and Castration-Resistant Prostate Cancer and Affects Bone Remodeling

et al. 2013

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Cabozantinib is an inhibitor of multiple receptor tyrosine kinases, including MET and VEGFR2. In a phase II clinical trial in advanced prostate cancer (PCa), cabozantinib treatment improved bone scans in 68% of evaluable patients. Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone-sensitive and castration-resistant PCa in preclinical models while delineating its effects on tumor and bone. Using immunohistochemistry and tissue microarrays containing normal prostate, primary PCa, and soft tissue and bone metastases, our data show that levels of MET, P-MET, and VEGFR2 are increasing during PCa progression. Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases. To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen-sensitive LuCaP 23.1 and castration-resistant C4-2B PCa tumors. In vivo, cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors. Furthermore, cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume. In summary, the expression pattern of cabozantinib targets in primary and castration-resistant metastatic PCa, and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease.

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“…The use of anti-VEGF therapies in preclinical and clinical studies has been associated with increased side effects, including hypertension, gastrointestinal bleeding, intestinal perforation, and pulmonary embolism (Mangoni et al 2012, Ogita et al 2012. Although bevacizumab has shown some promise with improved progression-free survival, no significant improvement in overall survival has been achieved even in combination therapies (reviewed by Small & Oh (2012) and Armstrong et al (2013)). A newer anti-angiogenesis agent derived from the extracellular domains of the VEGFR (aflibercept) in combination with docetaxel and prednisone also offered no improvement in overall survival (Tannock et al 2013).…”

Section: Anti-vegf Signaling Therapies In the Clinical Management Of Pcamentioning

confidence: 99%

Regulation of vascular endothelial growth factor in prostate cancer

Brot¹,

Ntekim²,

Cardenas³

et al. 2015

Endocrine-Related Cancer

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Prostate cancer (PCa) is the most common malignancy affecting men in the western world. Although radical prostatectomy and radiation therapy can successfully treat PCa in the majority of patients, up to w30% will experience local recurrence or metastatic disease. Prostate carcinogenesis and progression is typically an androgen-dependent process. For this reason, therapies for recurrent PCa target androgen biosynthesis and androgen receptor function. Such androgen deprivation therapies (ADT) are effective initially, but the duration of response is typically %24 months. Although ADT and taxane-based chemotherapy have delivered survival benefits, metastatic PCa remains incurable. Therefore, it is essential to establish the cellular and molecular mechanisms that enable localized PCas to invade and disseminate. It has long been accepted that metastases require angiogenesis. In the present review, we examine the essential role for angiogenesis in PCa metastases, and we focus in particular on the current understanding of the regulation of vascular endothelial growth factor (VEGF) in localized and metastatic PCa. We highlight recent advances in understanding the role of VEGF in regulating the interaction of cancer cells with tumor-associated immune cells during the metastatic process of PCa. We summarize the established mechanisms of transcriptional and post-transcriptional regulation of VEGF in PCa cells and outline the molecular insights obtained from preclinical animal models of PCa. Finally, we summarize the current state of anti-angiogenesis therapies for PCa and consider how existing therapies impact VEGF signaling.

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Bevacizumab treatment of prostate cancer

Cited by 21 publications

References 47 publications

Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma

Cabozantinib Inhibits Growth of Androgen-Sensitive and Castration-Resistant Prostate Cancer and Affects Bone Remodeling

Regulation of vascular endothelial growth factor in prostate cancer

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