Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Motzer, Robert J.; Rini, Brian I.; Bukowski, Ronald M.; Curti, Brendan D.; George, Daniel J.; Hudes, Gary R.; Redman, Bruce G.; Margolin, Kim; Merchan, Jaime R.; Wilding, George; Ginsberg, Michelle S.; Bacik, Jennifer; Kim, Sindy T.; Baum, Charles M.; Michaelson, M. Dror

doi:10.1001/jama.295.21.2516

Cited by 1,138 publications

(732 citation statements)

References 23 publications

(29 reference statements)

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“…34,35 Sunitinib targets selectively VEGF, KIT, FLT3, RET, PDGFRA, and PDGFRB 36,37 and the fact that CSF1R shares structural and organizational homology with those receptor tyrosine kinases suggests a relevant role of CSF1R as a target of sunitinib in renal cell carcinoma patients. Furthermore, recent studies using hematopoietic colony assays demonstrated that imatinib targets CSF1R at therapeutic concentrations, 38,39 further indicating that CSF1R may represent a future valuable therapeutic target of receptor tyrosine kinase drug inhibitors in renal cell carcinoma patients.…”

Section: Discussionmentioning

confidence: 99%

CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

et al. 2009

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Renal cell carcinomas comprise a heterogeneous group of tumors. Of these, 80% are clear cell renal cell carcinomas, which are characterized by loss of 3p, often with concomitant gain of 5q22qter. Although VHL is considered the main target gene of the 3p deletions, none has been identified as the relevant target gene for the 5q gain. We have studied 75 consecutive kidney tumors and paired normal kidney samples to evaluate at the genomic and expression levels the tyrosine kinase genes CSF1R and PDGFRB as potential targets in this region. Our findings show that RNA expression of CSF1R, but not of PDGFRB, was significantly higher in clear cell renal cell carcinomas than in normal tissue samples, something that was corroborated at the protein level by immunohistochemistry. The CSF1R staining pattern in clear cell renal cell carcinomas was clearly different from that observed in other renal cell carcinomas, suggesting its potential usefulness in differential diagnosis. FISH analysis demonstrated whole chromosomal gain and relative CSF1R/PDGFRB copy number gain in clear cell renal cell carcinomas, which might contribute to CSF1R overexpression. Finally, one polymorphism and two novel mutations were identified in CSF1R in clear cell renal cell carcinoma patients. Our data allow us to conclude that CSF1R plays a relevant role in clear cell renal cell carcinoma carcinogenesis and raise the possibility that CSF1R may represent a future valuable therapeutic target in these patients. Keywords: renal cell carcinoma; CSF1R oncogene; mutation; overexpression Renal cell carcinomas comprise a heterogeneous group of tumors that represent about 3% of all malignancies in adults in the Western countries. 1 Clear cell renal cell carcinomas, which represent about 80% of all kidney tumors, are characterized by the loss of the short arm of chromosome 3 (3p), often with a concomitant gain of 5q22qter as the result of an unbalanced 3p;5q translocation. 2 Several genes have been presented as the targets of the 3p deletions seen in this tumor type, with emphasis for VHL (3p25Bp26). In fact, germline mutations of VHL underlie the von Hippel-Lindau syndrome (which includes clear cell renal cell carcinoma as one of its features), whereas somatic inactivation of this gene has been demonstrated in the great majority of sporadic clear cell renal cell carcinomas. 3,4 On the other hand, no target genes have been identified for the 5q22qter gain, the second most common copy number change in clear cell renal cell carcinomas. 2,5 The colony-stimulating factor-1 receptor (CSF1R) gene located in 5q33 is a potential target for this chromosomal gain in clear cell renal cell carcinomas. CSF1R is a transmembrane tyrosine kinase receptor and the CSF1R/CSF1 receptor/ligand complex has essential physiological functions in monocyte and macrophage differentiation, embryonic implantation, placental development, and lactogenic differentiation of the human breast. 6 Codons 301 and 969 located in CSF1R exons 7 and 22, respectively, have been shown to be mutated in he...

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Section: Discussionmentioning

confidence: 99%

CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

et al. 2009

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“…[18][19] The utility of these agents including Sunitinib and Sorafenib in a neoadjuvant setting has yet to be explored. Patients at higher risk of developing metastatic disease may be counseled about the potential for metastases and the potential need for adjuvant therapy after surgery.…”

Section: Discussionmentioning

confidence: 99%

Preoperative Nomogram Predicting 12-Year Probability of Metastatic Renal Cancer

et al. 2008

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Purpose-For patients with renal masses localized to the kidney, there is currently no preoperative tool to predict the likelihood of metastatic recurrence following surgical intervention. The primary goal of this study was to develop a predictive model that could be used in the preoperative setting.Methods-We pooled institutional databases from Memorial Sloan-Kettering and Mayo Clinic and identified 2,517 patients with renal masses and no concurrent evidence of metatases, who underwent radical or partial nephrectomy and with complete data. Cox proportional hazard regression analyses were used to model pre-operative clinical and radiographic characteristics as predictors for development of metastases following nephrectomy. Internal validation was performed with a statistical bootstrapping technique.Results-Metastatic recurrence developed in 340 of the 2517 patients. Median follow-up for patients without metastatic recurrence was 4.7 years. A nomogram was developed using preoperative characteristics to predict the 12-year likelihood of post-operative metastatic recurrence, with a concordance index (CI) of 0.80. In contrast, the concordance index of pre-operative TNM staging was 0.71. Size of the primary renal mass, evidence of lymphadenopathy or necrosis on pre-operative imaging and the mode of presentation were important predictors for the subsequent development of metastases.Conclusions-We present a pre-operative nomogram that accurately predicts the development of metastatic recurrence following nephrectomy. This nomogram may be potentially useful to identify high-risk patients for clinical trials in neoadjuvant setting.

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“…Therefore, their treatment may be more difficult, and it is possible that combination with other antitumor approaches might be useful. For renal cell cancer, antiangiogenic approaches are appealing due to universal von Hippel Lindau pathway defects, which result in high expression of vascular endothelial growth factor and subsequent strong angiogenic signaling, as corroborated in recent human trials (45,46). Despite obvious efficacy, complete responses have been rare, a survival benefit has not yet been shown, and few or no patients are cured.…”

Section: Discussionmentioning

confidence: 99%

Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses

Guse

Ranki

Ala‐Opas

et al. 2007

Molecular Cancer Therapeutics

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Renal cancer is a common and deadly disease that lacks curative treatments when metastatic. Here, we have used oncolytic adenoviruses, a promising developmental approach whose safety has recently been validated in clinical trials. Although preliminary clinical efficacy data exist for selected tumor types, potency has generally been less than impressive. One important reason may be that expression of the primary receptor, coxsackie-adenovirus receptor, is often low on many or most advanced tumors, although not evaluated in detail with renal cancer. Here, we tested if fluorescence-assisted cell sorting could be used to predict efficacy of a panel of infectivity-enhanced capsid-modified marker gene expressing adenoviruses in renal cancer cell lines, clinical specimens, and subcutaneous and orthotopic murine models of peritoneally metastatic renal cell cancer. The respective selectively oncolytic adenoviruses were tested for killing of tumor cells in these models, and biodistribution after locoregional delivery was evaluated. In vivo replication was analyzed with noninvasive imaging. Ad5/3-#24, Ad5-#24RGD, and Ad5.pK7-#24 significantly increased survival of mice compared with mock or wild-type virus and 50% of Ad5/3-#24 treated mice were alive at 320 days. Because renal tumors are often highly vascularized, we investigated if results could be further improved by adding bevacizumab, a humanized antivascular endothelial growth factor antibody. The combination was well tolerated but did not improve survival, suggesting that the agents may be best used in sequence instead of together. These results set the stage for clinical testing of oncolytic adenoviruses for treatment of metastatic renal cancer currently lacking other treatment options. [Mol Cancer Ther 2007;6(10):2728 -36]

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Sunitinib in Patients With Metastatic Renal Cell Carcinoma

Abstract: clinicaltrials.gov Identifier: NCT00077974.

Cited by 1,138 publications

References 23 publications

CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

CSF1R copy number changes, point mutations, and RNA and protein overexpression in renal cell carcinomas

Preoperative Nomogram Predicting 12-Year Probability of Metastatic Renal Cancer

Treatment of metastatic renal cancer with capsid-modified oncolytic adenoviruses

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