Sunitinib: bridging present and future cancer treatment

Grimaldi, Antonio; Guida, Teresa; Dattino, R; Perrotta, E.; Otero, Manuela; Masala, A.; Cartenì, Giacomo

doi:10.1093/annonc/mdm221

Cited by 23 publications

(20 citation statements)

References 5 publications

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“…25 Significantly, the multi-kinase inhibitor sunitinib, which targets many of the same kinases as sorafenib (vascular endothelial growth factor receptor 1, 2, and 3; platelet-derived growth factor receptor; c-kit; FMS-like tyrosine kinase 3; and RET tyrosine kinase) but not RAF, does not result in development of SCCs or KAs. 13,26 Sorafenib is a nonselective inhibitor of wild-type and mutated forms of RAF, with poor activity against BRAF V600E tumor cells, and has been demonstrated to be an ineffective treatment for melanoma. 7,27 An estimated 6% to 7% of patients treated with sorafenib develop SCCs and KAs, which stands in contrast to 20% to 30% of patients taking vemurafenib.…”

Section: Discussionmentioning

confidence: 99%

Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study

Chu¹,

Wanat²,

Miller³

et al. 2012

Journal of the American Academy of Dermatology

161

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Background Vemurafenib, a novel selective small molecule inhibitor of BRAF, has recently been shown to be effective in the treatment of melanomas harboring the BRAF V600E mutation. Similar to the broad-spectrum RAF inhibitor sorafenib, vemurafenib induces development of squamous cell carcinomas and keratoacanthomas as a side effect of therapy. Objective We sought to detail additional cutaneous adverse effects of vemurafenib and a similar BRAF inhibitor, dabrafenib. Methods We evaluated the clinical and histologic feature of skin side effects developing on vemurafenib or dabrafenib therapy in 14 patients. Results Eight patients developed one or more squamous cell carcinomas, and 11 patients formed benign verrucous keratoses. Eight patients developed single lesions and/or widespread eruptions with histopathologic findings of acantholytic dyskeratosis, consistent with warty dyskeratomas and Darier- or Grover-like rashes, respectively. One patient developed palmoplantar hyperkeratosis, and darkening of existing nevi and new nevi within 2 months of starting vemurafenib. Side effects presented as early as 1 week after beginning therapy, with a mean time of onset of 12.6 weeks in our cohort. Limitations This study was limited by the small number of cases, all from a single institution. Conclusion Selective BRAF inhibitor therapy is associated with the development of malignant and benign growths, including keratoacanthoma-like squamous cell carcinomas, warty dyskeratomas, and verrucous keratoses, along with widespread eruptions with histologic features of acantholytic dyskeratosis. Given the potential for malignant lesions to develop on treatment, awareness of potential adverse effects of these agents is necessary, and a low threshold for biopsy of new growths is recommended.

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Section: Discussionmentioning

confidence: 99%

Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study

Chu¹,

Wanat²,

Miller³

et al. 2012

Journal of the American Academy of Dermatology

161

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“…Thus, CSF-1R blockade may be a promising therapeutic approach for some, but not all, malignant tumors. It is worth noting that Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor, that targets the CSF-1R along with many other receptor tyrosine kinases, is a first-line therapy for advanced RCC (1,48,49). Taken together, our findings clearly indicate that targeting the CSF-1R is a potential therapeutic for human RCC.…”

Section: Discussionmentioning

confidence: 99%

Autocrine CSF-1 and CSF-1 Receptor Coexpression Promotes Renal Cell Carcinoma Growth

et al. 2012

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Renal cell carcinoma is increasing in incidence but the molecular mechanisms regulating its growth remain elusive. Co-expression of the monocytic growth factor CSF-1 and its receptor CSF-1R on renal tubular epithelial cells (TEC) will promote proliferation and anti-apoptosis during regeneration of renal tubules. Here we show that a CSF-1-dependent autocrine pathway is also responsible for the growth of renal cell carcinoma (RCC). CSF-1 and CSF-1R were co-expressed in RCC and TEC proximally adjacent to RCC. CSF-1 engagement of CSF-1R promoted RCC survival and proliferation and reduced apoptosis, in support of the likelihood that CSF-1R effector signals mediate RCC growth. In vivo CSF-1R blockade using a CSF-1R tyrosine kinase inhibitor decreased RCC proliferation and macrophage infiltration in a manner associated with a dramatic reduction in tumor mass. Further mechanistic investigations linked CSF-1 and EGF signaling in RCC. Taken together, our results suggest that budding RCC stimulates the proximal adjacent microenvironment in the kidney to release mediators of CSF-1, CSF-1R and EGF expression in RCC. Further, our findings imply that targeting CSF-1/CSF-1R signaling may be therapeutically effective in RCC.

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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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Sunitinib: bridging present and future cancer treatment

Cited by 23 publications

References 5 publications

Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study

Diverse cutaneous side effects associated with BRAF inhibitor therapy: A clinicopathologic study

Autocrine CSF-1 and CSF-1 Receptor Coexpression Promotes Renal Cell Carcinoma Growth

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

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