Phase II study of sunitinib in men with advanced prostate cancer

Michaelson, M. Dror; Regan, Meredith M.; Oh, William K.; Kaufman, Donald S.; Olivier, Kara; Michaelson, Simon; Spicer, Beverly; Gurski, Carol; Kantoff, Philip W.; Smith, Matthew R.

doi:10.1093/annonc/mdp111

Cited by 138 publications

(106 citation statements)

References 27 publications

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“…Within the renal cell carcinoma population, there is probably a higher incidence of osteonecrosis of the jaw when IVBP therapy for bone metastases is combined with sunitinib (or sorafenib) than when IVBP is used alone; the mechanism for the increased risk remains unclear (Beuselinck et al 2012). Possible etiologies for osteonecrosis of the jaw as a side effect in this population relate to the anti-angiogenic effects of sunitinib or antiresorptive activity, the latter which has been demonstrated by Sahi et al in a small number of patients with RCC metastatic to bone and in a study of prostate cancer patients metastatic to bone (Dror Michaelson et al 2009, Sahi et al 2009, Agrillo et al 2012, Baldazzi et al 2012, Beuselinck et al 2012.…”

Section: Vegf Inhibitorsmentioning

confidence: 99%

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Alemán¹,

Farooki²,

Girotra³

2014

Endocrine-Related Cancer

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Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment. Key Words" bone " calcium " metastasis " parathyroid hormone " tyrosine kinase inhibitor

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Section: Vegf Inhibitorsmentioning

confidence: 99%

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Alemán¹,

Farooki²,

Girotra³

2014

Endocrine-Related Cancer

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“…In colorectal cancer patients with metastatic disease, PlGF levels increased following the administration of bevacizumab in combination with chemotherapy and/or radiation (26,27). VEGF-A and PlGF levels increased following sunitinib treatment in patients with bevacizumab-refractory metastatic RCC and in men with advanced prostate cancer who were treated with sunitinib (28,29). It has been proposed that PlGF plays a role in resistance to antiangiogenic therapies and that an antibody against PlGF may help overcome resistance to VEGF receptor inhibitors (30).…”

Section: Introductionmentioning

confidence: 99%

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

Ren¹,

Weber²,

Yao³

et al. 2011

Clinical Cancer Research

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Purpose: Placental growth factor (PlGF) is an angiogenic protein. Upregulation of PlGF has been observed in the clinic following antiangiogenic regimens targeting the VEGF pathway. PlGF has been proposed as a therapeutic target for oncology. sFLT01 is a novel fusion protein that neutralizes mouse and human PlGF (mPlGF, hPlGF) and mouse and human VEGF-A (mVEGF-A, hVEGF-A). It was tested in syngeneic and xenograft tumor models to evaluate the effects of simultaneously neutralizing PlGF and VEGF-A and to investigate changes observed in the clinic in preclinical models. Experimental Design: Production of PlGF and VEGF-A by B16F10 and A673 cancer cells in vitro was assessed. Mice with subcutaneous B16F10 melanoma or A673 sarcoma tumors were treated with sFLT01. Tumor volumes and microvessel density (MVD) were measured to assess efficacy. Serum levels of hVEGF-A, hPlGF, and mPlGF at early and late time points were determined by ELISA. Results: Exposure of cancer cell lines to sFLT01 caused a decrease in VEGF secretion. sFLT01 inhibited tumor growth, prolonged survival, and decreased MVD. Analysis of serum collected from treated mice showed that sFLT01 administration caused a marked increase in circulating mPlGF but not hPlGF or hVEGF. sFLT01 treatment also increased circulating mPlGF levels in non–tumor-bearing mice. Conclusion: With the tumor cell lines and mouse models we used, antiangiogenic therapies that target both PlGF and VEGF may elicit a host response rather than, or in addition to, a malignant cell response that contribute to therapeutic resistance and tumor escape as suggested by others. Clin Cancer Res; 17(5); 976–88. ©2011 AACR.

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“…Serum PlGF levels increased in colorectal cancer patients following bevacizumab therapy (22,23). Similar observations have been made in patients with metastatic RCC who no longer responded to bevacizumab or in patients with prostate cancer who were treated with sunitinib (24,25). The administration of sFLT01 to patients with elevated serum PlGF levels could offer a novel approach to neutralize PlGF that may be contributing to drug resistance and tumor escape.…”

Section: Discussionmentioning

confidence: 52%

“…In colorectal cancer patients with metastatic disease, serum PlGF levels increased following the administration of bevacizumab in combination with chemotherapy and/or radiation (22,23). VEGF-A and PlGF levels increased following sunitinib treatment in patients with bevacizumab-refractory metastatic RCC and in men with advanced prostate cancer who were treated with sunitinib (24,25). Thus, PlGF may have a role in resistance to certain antiangiogenic therapies and its neutralization may overcome resistance to VEGF receptor inhibitors (26).…”

Section: Introductionmentioning

confidence: 99%

sFLT01: A Novel Fusion Protein with Antiangiogenic Activity

Kurtzberg¹,

Weber²,

Nguyen³

et al. 2011

Molecular Cancer Therapeutics

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AbstractsFLT01 is a novel fusion protein that consists of the VEGF/PlGF (placental growth factor) binding domain of human VEGFR1/Flt-1 (hVEGFR1) fused to the Fc portion of human IgG 1 through a polyglycine linker. It binds to both human VEGF (hVEGF) and human PlGF (hPlGF) and to mouse VEGF (mVEGF) and mouse PlGF (mPlGF). In vitro, sFLT01 inhibited the proliferation of human umbilical vein endothelial cells and pericytes stimulated by either hVEGF or hPlGF. In vivo, sFLT01 had robust and significant antitumor activity in numerous preclinical subcutaneous tumor models including H460 non-small cell lung carcinoma, HT29 colon carcinoma, Karpas 299 lymphoma, MOLM-13 AML (acute myeloid leukemia), 786-O, and RENCA renal cell carcinoma (RCC). sFLT01 also increased median survival in the orthotopic RENCA RCC model. sFLT01 had strong antiangiogenic activity and altered intratumoral microvessel density, blood vessel lumen size and perimeter, and vascular and vessel areas in RCC models. sFLT01 treatment resulted in fewer endothelial cells and pericytes within the tumor microenvironment. sFLT01 in combination with cyclophosphamide resulted in greater inhibition of tumor growth than either agent used alone as a monotherapy in the A673 Ewing's sarcoma model. Gene expression profiling indicated that the molecular changes in the A673 sarcoma tumors are similar to changes observed under hypoxic conditions. sFLT01 is an innovative fusion protein that possessed robust antitumor and antiangiogenic activities in preclinical cancer models. It is a dual targeting agent that neutralizes both VEGF and PlGF and, therefore, has potential as a next generation antiangiogenic therapeutic for oncology. Mol Cancer Ther; 10(3); 404-15. Ó2011 AACR.

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Phase II study of sunitinib in men with advanced prostate cancer

Cited by 138 publications

References 27 publications

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Placental Growth Factor Upregulation Is a Host Response to Antiangiogenic Therapy

sFLT01: A Novel Fusion Protein with Antiangiogenic Activity

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