Novel drugs for renal cell carcinoma

Vakkalanka, Bhanu; Bukowski, Ronald M.

doi:10.1517/13543784.17.10.1501

Cited by 5 publications

(9 citation statements)

References 71 publications

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“…Although surgery is often curative, 30% of patients will present with metastases at the time of initial diagnosis (1). The 5-year survival rate is only 5% in metastatic RCC as advanced RCC is resistant to chemotherapy and radiotherapy (2,3). Previous studies indicated immunotherapy is relatively effective against RCC (2,3).…”

Section: Introductionmentioning

confidence: 99%

“…The 5-year survival rate is only 5% in metastatic RCC as advanced RCC is resistant to chemotherapy and radiotherapy (2,3). Previous studies indicated immunotherapy is relatively effective against RCC (2,3). However, the response rate is only 15% to 20% (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies indicated immunotherapy is relatively effective against RCC (2,3). However, the response rate is only 15% to 20% (1)(2)(3). Therefore, defining the factors involved in disease progression and metastasis will provide novel molecular targets for the development of effective therapies.…”

Section: Introductionmentioning

confidence: 99%

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TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Tang

Chuang

et al. 2012

Molecular Cancer Research

107

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TNF-a is a cytokine with antitumorigenic property. In contrast, low dose, chronic TNF-a production by tumor cells or stromal cells may promote tumor growth and metastasis. Serum levels of TNF-a are significantly elevated in renal cell carcinoma (RCC) patients. Here, we showed that TNF-a induced epithelial-mesenchymal transition (EMT) and promoted tumorigenicity of RCC by repressing E-cadherin, upregulating vimentin, activating MMP9, and invasion activities. In addition, TNF-a treatment inhibited glycogen synthase kinase 3b (GSK-3b) activity through serine-9 phosphorylation mediated by the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway in RCC cells. Inhibition of PI3K/AKT by LY294002 reactivated GSK-3b and suppressed the TNFa-induced EMT of RCC cells. Inactivation of GSK-3b by LiCl significantly increased MMP9 activity and EMT of RCC cells. Activation of GSK-3b by transduction of constitutively active GSK-3b into RCC cells suppressed TNFa-mediated anchorage-independent growth in soft agar and tumorigenicity in nude mice. Overexpression of a kinase-deficient GSK-3b, in contrast, potentiated EMT, anchorage-independent growth and drastically enhanced tumorigenicity in vivo. Most importantly, a 15-fold inactivation of GSK-3b activity, 3-fold decrease of E-cadherin, and 2-fold increase of vimentin were observed in human RCC tumor tissues. These results indicated that inactivation of GSK-3b plays a pivotal role in the TNF-a-mediated tumorigenesis of RCC. Mol Cancer Res; 10(8); 1109-19. Ó2012 AACR. IntroductionRenal cell carcinoma (RCC) is the tenth most common cause of cancer-related deaths worldwide (1). Although surgery is often curative, 30% of patients will present with metastases at the time of initial diagnosis (1). The 5-year survival rate is only 5% in metastatic RCC as advanced RCC is resistant to chemotherapy and radiotherapy (2, 3). Previous studies indicated immunotherapy is relatively effective against RCC (2, 3). However, the response rate is only 15% to 20% (1-3). Therefore, defining the factors involved in disease progression and metastasis will provide novel molecular targets for the development of effective therapies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Tang

Chuang

et al. 2012

Molecular Cancer Research

107

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“…2). Whereas nelfinavir is an investigational anti-cancer drug not yet approved for cancer treatment, sorafenib has already been approved for the treatment of renal cell carcinoma [29,30] and hepatocellular carcinoma [31]. It has the further advantage of being a multi-kinase inhibitor with additional anti-angiogenic functions by inhibiting tyrosine kinases [32] and to cooperate with other cytostatic drugs [33].…”

Section: Discussionmentioning

confidence: 99%

Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

et al. 2009

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The HIV protease inhibitor nelfinavir is an investigational drug for cancer treatment. We have previously demonstrated induction of apoptosis by nelfinavir even in chemo-resistant ovarian cancer cells. In contrast to the pro-apoptotic effect of nelfinavir on human cancer cells, we noticed a significant upregulation of the anti-apoptotic mitochondrial membrane protein mcl-1 by nelfinavir, resulting in a mitochondria-independent induction of apoptosis. Upregulation of mcl-1 was associated with enhanced phosphorylation of both mcl-1 and of ERK1/2 (extracellular signal-regulated kinases 1/2). ERK1/2 enhanced stability of mcl-1 protein expression by serine-163 phosphorylation. The combination of nelfinavir with sorafenib, a clinically applied inhibitor of the RAS/RAF/ ERK1/2 pathway, inhibited nelfinavir-induced ERK1/2 activation and mcl-1 protein upregulation. Further, the combination of nelfinavir with sorafenib induced mitochondrial membrane potential disruption and resulted in an improved activity of nelfinavir on ovarian cancer cells. Thus, a combination of these two investigational anticancer drugs could be of interest especially because of their unique mechanism of apoptosis induction even in otherwise chemo-resistant human cancer cells.

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“…Fatigue, asthenia, and proteinuria were the most common grade 3 toxicities (11, 26). FDA approved bevacizumab in 2009 at 10 mg/kg IV every 2 weeks in combination with IFN-α.…”

Section: Evidence Synthesismentioning

confidence: 99%

Targeted Therapy for Metastatic Renal Carcinoma: an Update

Silva

Gustafson

Nogueira

et al. 2014

jkcvhl

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Conventional chemotherapy is associated with poor outcomes in metastatic renal cell carcinoma (RCC). Advances in the understanding of tumor molecular biology and the implementation of new drugs that target these molecular pathways have increased the arsenal against advanced RCC and improved outcomes in these patients. Herein, we briefly describe the latest data on targeted therapies used in the treatment of advanced renal cell carcinoma. Search strategy was performed according to PRISMA guidelines. Abstracts of relevant studies published in PubMed between 2000 and 2014 were analyzed by two authors. Abstracts were selected if they were published in English, data reported was of phase II or III clinical trials, and outcomes followed FDA approval. If consensus between the two authors was achieved, they were included in the review. Key words used were “target therapy” and “metastatic renal cell carcinoma”. The results of the studies analyzed in this review support the benefits of targeted therapy in metastatic RCC. These include improved progression-free survival, overall survival, and quality of life as well as reduced toxicities compared to immunotherapy. The improvement in outcomes in metastatic RCC makes these drugs a preferred option as a primary treatment for these patients.

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Novel drugs for renal cell carcinoma

Cited by 5 publications

References 71 publications

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

TNF-α Induces Epithelial–Mesenchymal Transition of Renal Cell Carcinoma Cells via a GSK3β-Dependent Mechanism

Nelfinavir induces mitochondria protection by ERK1/2-mediated mcl-1 stabilization that can be overcome by sorafenib

Targeted Therapy for Metastatic Renal Carcinoma: an Update

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