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Cell Signaling in Kidney Cancer
Cell Signaling in Kidney Cancer KIDNEY cancer comprises several distinct neoplasms, the most common of which is renal cell carcinoma (RCC). By the end of 2009 approximately 58,000 new cases of kidney cancer will have been diagnosed in the United States, with approximately 13,000 people dying of the disease. Although the prognosis for localized disease is excellent with a 5-year survival rate of more than 70%, dissemination of tumors beyond the kidney is associated with a dramatic reduction in survival. Patients with metastatic RCC have 5-year survival rates of approximately 10%. The most common treatment for renal cancer involves nephrectomy when tumors are organ confined. For tumors that are no longer localized additional strategies are required. Renal tumors are highly resistant to conventional chemotherapy, and while immunotherapy based on interferon-␣ and/or interleukin-2 has shown some efficacy in a subset of patients, this approach is associated with significant toxicity. Given these challenges much effort has gone into identifying the biochemical and molecular basis of renal cancer biology, and exploiting this knowledge to develop treatments that affect longterm management and cure. Thus, kidney cancer has become the poster child for the promise and the challenges associated with targeted therapy of malignancies. In this issue of The Journal Porta and Figlin (page 2569) review the literature on the potential for targeting the phosphoinositide-3=-kinase (PI3K)/Akt pathway for the treatment of kidney cancer. The PI3K/Akt pathway is a major mediator of cell survival and displays aberrant activation in multiple tumor types. Analysis of human renal cancer specimens has shown that the expression and activity of pathway constituents including the phosphatase PTEN and the kinases PI3K, Akt and mTOR are altered in RCC, and that up-regulation of PI3K/Akt signaling is associated with reduced survival.1 Thus, it appears that PI3K/Akt dependent signals contribute to renal cancer pathogenesis and, therefore, represent a viable therapeutic target. Among the pathways that drive renal cancer biology those stimulated by vascular endothelial growth factor (VEGF) and its effectors have been most ex-
0022-5347/09/1826-2555/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
tensively characterized. Expression of VEGF is regulated at the transcriptional level by hypoxia inducible factor-1, which itself integrates multiple inputs. These include positive regulators such as hypoxia and the PI3K/Akt/mTOR and Raf/MEK/Erk cascades, as well as negative regulators such as ubiquitin mediated degradation. Of particular relevance to kidney cancer, hypoxia inducible factor-1 ubiquitination is mediated by the E3 ubiquitin ligase encoded by the von Hippel-Lindau gene, a tumor suppressor that is functionally inactivated in a high proportion of renal tumors.2 Targeted therapies for renal cancer exploit the central role of the VEGF-VEGF receptor axis in this disease by inhibiting the pathway at discrete nodes including ligand binding, receptor activation and effector stimulation. Targeted agents currently approved for the treatment of metastatic RCC include bevacizumab (Avastin®), a function blocking monoclonal antibody to VEGF that is used in combination with interferon-␣, sunitinib (Sutent®, SU11248) and sorafenib (Nexavar®), tyrosine kinase inhibitors that inhibit activation of receptor tyrosine kinases including VEGF receptor family members, the platelet derived growth factor receptor c-Kit and in the case of sorafenib the Raf/MEK/Erk cascade, and the rapamycin analogues everolimus (RAD-001) and temsirolimus (Torisel®, CCI-779) that inhibit mTOR. Each of these agents has shown promising clinical activity alone, or combined with conventional chemotherapy, radiation or cytokine treatment.3 Additional agents also under consideration for RCC treatment are those that target the PI3K/Akt/ mTOR signaling module. As noted by Porta and Figlin, agents of particular interest are the dual PI3K/mTOR inhibitors NVP-BEZ-235 and NVPBGT-226, and the alkylphospholipid perifosine, all of which are currently undergoing clinical evaluation. Because of their ability to inhibit PI3K and mTOR, BEZ-235 and BGT-226, in theory, achieve vertical pathway blockade with a single agent. Indeed the preclinical data on these agents indicate potent antitumor activity when used alone or with other anticancer drugs. Perifosine, an alkylphosphocholine, has garnered considerable attention in the Vol. 182, 2555-2556, December 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.09.032
www.jurology.com
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CELL SIGNALING IN KIDNEY CANCER
context of Akt pathway inhibition. Perifosine acts by binding to the Akt pleckstrin homology domain and preventing its membrane recruitment, a critical step in Akt phosphorylation and subsequent activation. Perifosine induces apoptosis and decreases cell survival in an Akt dependent manner in lung cancer cells.4 In addition, it inhibits endothelial tube formation in vitro,5 suggesting the potential for antiangiogenic as well as antiproliferative activities in vivo. Initial clinical trials with perifosine have shown moderate activity as first line monotherapy. Additional studies are ongoing to determine the efficacy of perifosine in patients with RCC in whom sunitinib or sorafenib has failed.6 Despite the encouraging data to date, there are still challenges to be addressed. Key among these are identification of patients likely to benefit most from targeted therapy, improved understanding of mechanisms leading to the development of resistance to targeted agents and how best to minimize toxicity arising from the drug combination that inhibits activities required for normal cell metabolism. Although vertical blockade may minimize the emergence of tumor cells that are refractory to a given
treatment, this approach can also lead to unacceptable toxicity in patients as observed with combinations of sunitinib and temsirolimus or bevacizumab. Efforts are under way to ameliorate drug induced toxicity by careful attention to sequencing and dosing of agents.7 Of equal concern is the possibility of tumor adaptation to treatment as demonstrated in 2 recent preclinical evaluations of antiangiogenic therapy.8 In those studies systemic inhibition of VEGF receptor function in mice inhibited growth of primary tumors but led to the emergence of highly aggressive metastatic lesions and reduced survival. Similarly the use of mTOR inhibitors in patients has been linked to increased phosphorylation as well as activation of Akt9 and Erk,10 both of which are potent stimulators of tumor cell growth and survival. Therefore, it will be necessary to proceed with caution in the use of targeted therapy in renal carcinoma. Rosalyn Adam Department of Urology Childrens Hospital Boston Boston, Massachusetts
REFERENCES 1. Park JY, Lin PY and Weiss RH: Targeting the PI3K-Akt pathway in kidney cancer. Expert Rev Anticancer Ther 2007; 7: 863.
vation of the extrinsic apoptotic pathway. Mol Cancer Ther 2007; 6: 2029.
2. Clark PE: The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy. Kidney Int 2009; Epub ahead of print.
5. Zerp SF, Vink SR, Ruiter GA et al: Alkylphospholipids inhibit capillary-like endothelial tube formation in vitro: antiangiogenic properties of a new class of antitumor agents. Anticancer Drugs 2008; 19: 65.
3. Bellmunt J: Future developments in renal cell carcinoma. Ann Oncol 2009; 20: i13.
6. Hutson TE and Figlin RA: Novel therapeutics for metastatic renal cell carcinoma. Cancer 2009; 115: 2361.
4. Elrod HA, Lin YD, Yue P et al: The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and acti-
7. Sosman J and Puzanov I: Combination targeted therapy in advanced renal cell carcinoma. Cancer 2009; 115: 2368.
8. Loges S, Mazzone M, Hohensinner P et al: Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009; 15: 167. 9. O’Reilly KE, Rojo F, She QB et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500. 10. Carracedo A, Ma L, Teruya-Feldstein J et al: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118: 3065.
0022-5347/09/1826-2555/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
tensively characterized. Expression of VEGF is regulated at the transcriptional level by hypoxia inducible factor-1, which itself integrates multiple inputs. These include positive regulators such as hypoxia and the PI3K/Akt/mTOR and Raf/MEK/Erk cascades, as well as negative regulators such as ubiquitin mediated degradation. Of particular relevance to kidney cancer, hypoxia inducible factor-1 ubiquitination is mediated by the E3 ubiquitin ligase encoded by the von Hippel-Lindau gene, a tumor suppressor that is functionally inactivated in a high proportion of renal tumors.2 Targeted therapies for renal cancer exploit the central role of the VEGF-VEGF receptor axis in this disease by inhibiting the pathway at discrete nodes including ligand binding, receptor activation and effector stimulation. Targeted agents currently approved for the treatment of metastatic RCC include bevacizumab (Avastin®), a function blocking monoclonal antibody to VEGF that is used in combination with interferon-␣, sunitinib (Sutent®, SU11248) and sorafenib (Nexavar®), tyrosine kinase inhibitors that inhibit activation of receptor tyrosine kinases including VEGF receptor family members, the platelet derived growth factor receptor c-Kit and in the case of sorafenib the Raf/MEK/Erk cascade, and the rapamycin analogues everolimus (RAD-001) and temsirolimus (Torisel®, CCI-779) that inhibit mTOR. Each of these agents has shown promising clinical activity alone, or combined with conventional chemotherapy, radiation or cytokine treatment.3 Additional agents also under consideration for RCC treatment are those that target the PI3K/Akt/ mTOR signaling module. As noted by Porta and Figlin, agents of particular interest are the dual PI3K/mTOR inhibitors NVP-BEZ-235 and NVPBGT-226, and the alkylphospholipid perifosine, all of which are currently undergoing clinical evaluation. Because of their ability to inhibit PI3K and mTOR, BEZ-235 and BGT-226, in theory, achieve vertical pathway blockade with a single agent. Indeed the preclinical data on these agents indicate potent antitumor activity when used alone or with other anticancer drugs. Perifosine, an alkylphosphocholine, has garnered considerable attention in the Vol. 182, 2555-2556, December 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.09.032
www.jurology.com
2555
2556
CELL SIGNALING IN KIDNEY CANCER
context of Akt pathway inhibition. Perifosine acts by binding to the Akt pleckstrin homology domain and preventing its membrane recruitment, a critical step in Akt phosphorylation and subsequent activation. Perifosine induces apoptosis and decreases cell survival in an Akt dependent manner in lung cancer cells.4 In addition, it inhibits endothelial tube formation in vitro,5 suggesting the potential for antiangiogenic as well as antiproliferative activities in vivo. Initial clinical trials with perifosine have shown moderate activity as first line monotherapy. Additional studies are ongoing to determine the efficacy of perifosine in patients with RCC in whom sunitinib or sorafenib has failed.6 Despite the encouraging data to date, there are still challenges to be addressed. Key among these are identification of patients likely to benefit most from targeted therapy, improved understanding of mechanisms leading to the development of resistance to targeted agents and how best to minimize toxicity arising from the drug combination that inhibits activities required for normal cell metabolism. Although vertical blockade may minimize the emergence of tumor cells that are refractory to a given
treatment, this approach can also lead to unacceptable toxicity in patients as observed with combinations of sunitinib and temsirolimus or bevacizumab. Efforts are under way to ameliorate drug induced toxicity by careful attention to sequencing and dosing of agents.7 Of equal concern is the possibility of tumor adaptation to treatment as demonstrated in 2 recent preclinical evaluations of antiangiogenic therapy.8 In those studies systemic inhibition of VEGF receptor function in mice inhibited growth of primary tumors but led to the emergence of highly aggressive metastatic lesions and reduced survival. Similarly the use of mTOR inhibitors in patients has been linked to increased phosphorylation as well as activation of Akt9 and Erk,10 both of which are potent stimulators of tumor cell growth and survival. Therefore, it will be necessary to proceed with caution in the use of targeted therapy in renal carcinoma. Rosalyn Adam Department of Urology Childrens Hospital Boston Boston, Massachusetts
REFERENCES 1. Park JY, Lin PY and Weiss RH: Targeting the PI3K-Akt pathway in kidney cancer. Expert Rev Anticancer Ther 2007; 7: 863.
vation of the extrinsic apoptotic pathway. Mol Cancer Ther 2007; 6: 2029.
2. Clark PE: The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy. Kidney Int 2009; Epub ahead of print.
5. Zerp SF, Vink SR, Ruiter GA et al: Alkylphospholipids inhibit capillary-like endothelial tube formation in vitro: antiangiogenic properties of a new class of antitumor agents. Anticancer Drugs 2008; 19: 65.
3. Bellmunt J: Future developments in renal cell carcinoma. Ann Oncol 2009; 20: i13.
6. Hutson TE and Figlin RA: Novel therapeutics for metastatic renal cell carcinoma. Cancer 2009; 115: 2361.
4. Elrod HA, Lin YD, Yue P et al: The alkylphospholipid perifosine induces apoptosis of human lung cancer cells requiring inhibition of Akt and acti-
7. Sosman J and Puzanov I: Combination targeted therapy in advanced renal cell carcinoma. Cancer 2009; 115: 2368.
8. Loges S, Mazzone M, Hohensinner P et al: Silencing or fueling metastasis with VEGF inhibitors: antiangiogenesis revisited. Cancer Cell 2009; 15: 167. 9. O’Reilly KE, Rojo F, She QB et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006; 66: 1500. 10. Carracedo A, Ma L, Teruya-Feldstein J et al: Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 2008; 118: 3065.