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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2009  |  Volume : 20  |  Issue : 3  |  Page : 355-361
Prognostic markers and new, innovative treatments in renal cell carcinoma


Department of Urologic Surgery, University of Medicine and Pharmacy, Timisoara, Romania

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   Abstract 

We reviewed the current medical literature to present the prognostic markers and current treatments of Renal Cell Carcinoma (RCC) and to propose new and innovative treatments for RCC. A PubMed search (http://www.ncbi.nlm.nih.gov/PubMed/) was performed and prognostic markers in RCC were reviewed and presented here. We hypothesize our own innovative theoretical research in new treatments for RCC. This includes a combination formed of an anticancer vaccine (VAX-x), which prevents the emergence of drug-resistance to (DRUG-x), with its corresponding anticancer drug (DRUG-x), administrated after immunological response to (VAX-x), can be employed to successfully treat and cure RCC in its various stages. We therefore propose that new treatment options of RCC are possibly VAX-x with either of the tyrosine kinase inhibitors-sunitinib or sorafenib.

Keywords: Anticancer vaccine, Renal Cell Carcinoma, Sunitinib, Sorafenib

How to cite this article:
Secasan CC. Prognostic markers and new, innovative treatments in renal cell carcinoma. Saudi J Kidney Dis Transpl 2009;20:355-61

How to cite this URL:
Secasan CC. Prognostic markers and new, innovative treatments in renal cell carcinoma. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2020 Nov 27];20:355-61. Available from: https://www.sjkdt.org/text.asp?2009/20/3/355/50756

   Introduction Top


The tumor, node, metastasis (TNM) staging system is currently the most extensively used tool for providing prognostic information for RCC. However, further revisions are needed in the current staging system and improvements can be made with the introduction of new, more accurate and predictive prognostic factors. An optimized reverse transcription PCR (RT-PCR) assay can accurately measure expression of most prognostic tumor markers in renal cell carcino­ma (RCC). [1] Useful biomarkers may have also the potential as therapeutic targets. Renal cell cancer is a disease in which cancer cells form in tubules of the kidney. There are 6 types of treatment options for RCC: Surgery, Radiation Therapy, Chemotherapy, Immunotherapy, Tar­geted Therapy and Stem Cell Transplant. Tar­geted Therapy uses drugs that can find and kill cancer cells. Antiangiogenic agents keep blood vessels from forming in a tumor, causing the tumor to stop growing and even shrink.


   Design and Methods Top


A PubMed search (http://www.ncbi.nlm.nih.gov/PubMed/) was performed and prognostic markers in RCC were reviewed for prognostic markers and treatment options available to date. Surgery is considered curative treatment for localized RCC and Nephron Sparing Surgery (NSS) cures most of the early-stage small re­sectable RCCs and open radical nephrectomy is mainly performed in patients with large tumor size, locally advanced tumors and tumor throm­bus extending into the vena cava. [2] Survival and progression of RCC depends on multiple fac­tors that may also help in decision making for chemotherapy. A long list of valuable markers have accumulated and several studies have tried to correlate them with disease activity, response to treatment and survival [Table 1]. [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],[36] Type of the tumor may also predicit the expression of these tumor markers [37],[38] along with other inde­pendent predictors of long-term survival in pre­viously untreated metastatic RCC include base­line hemoglobin level, number of involved sites, involved kidney, and Eastern Cooperative On­cology Group performance status (ECOG PS). [39] Other considerations include metastasectomy in the management of patients with metastatic renal cell cancer undergoing either immunothe­ 40 rapy or targeted treatment is strongly suggested


   Treatment Options Top


Renal cell carcinoma (RCC) is the most lethal of the common urologic malignancies, with approximately 40% of patients eventually dying of cancer progression. One third of patients present with metastatic disease, and up to 40% treated for localized disease have a recurrence. [41] Historically, treatment options for metastatic RCC have been limited because of inherent tumor resistance to chemotherapy and radiothe­rapy. The only approved drug for RCC in the past 30 years has been high-dose interleukin-2. Its benefit is observed in 20%-25% of highly selected good performance status RCC patients. [42] Renal cell carcinoma (RCC) presents as loca­ lized disease in 54% of the cases. For these patients, surgery is the primary curative treat­ment. Unfortunately, up to 65% of all patients show recurrent disease. The TNM (tumor, nodes, metastasis) staging system is currently the most extensively used staging system for RCC, but it has undergone systematic revisions as a result of emerging data. Antiangiogenic therapeutic agents Sunitinib and sorafenib are a potent inhibitors of VEGF-R, FMS-like tyrosine kinase 3 (FLT3), c-KIT, and PDGF, give the drug its direct antitumor and antiangiogenic properties. [43],[44] Specific inhibitor of the mammalian target of rapamycin (mTOR) kinase, has also shown a survival advantage over interferon in advanced, poor-prognosis RCC patients. [45] Other agents Bevacizumab (Avastin(R)), a monoclonal anti­body (mAb) inhibiting VEGF, increases prog­ression-free survival as second-line treatment. [46] Pazopanib (GW-786034) is a second-generation multitargeted tyrosine kinase inhibitor against VEGFR-1, 2 and 3, PDGFR-alpha, PDGFR-beta and c-kit. A placebo-controlled Phase III trial is ongoing in untreated or cytokine-treated pa­tients with RCC. [47] Other multitargeted tyrosine kinase inhibitors (lapatinib, axitinib) and anti­angiogenic agents (lenalidomide) have also de­monstrated activity in early studies. Combina­tions of these agents and development of vac­ cine are being evaluated. [48],[49] Tumor stage, which describes the anatomic extent of disease, is a powerful determinant of prognosis and survival for patients with renal cell carcinoma RCC. The treatment of advanced RCC has evolved signi­ficantly following the identification of the von Hippel-Lindau (VHL) gene and the function of its protein, and subsequent development of antiangiogenic therapies. There is substantial evidence of an association between mutation on VHL gene and the earliest stages of tumori­genesis of RCC. The main consequence of VHL loss is the upregulation of downstream pro­angiogenic factors leading to highly vascular tumors. Over expression of hypoxia inducible factor (HIF) is also caused by the mTOR, a key component of signaling pathways inside the cell, involved in cell proliferation. The inhibi­tion of proangiogenic factors and mTOR was the main idea behind the development of new targeted agents in advanced RCC. [50] Since De­cember 2005, 3 targeted agents have been ap­proved by the U.S. Food and Drug Adminis­tration (FDA) for the treatment of advanced RCC: sorafenib, sunitinib and temsirolimus. Sora­fenib and sunitinib are synthetic, orally active agents shown to directly inhibit vascular endo­thelial growth factor receptors -2 and -3 (VEGFR­2, VEGFR-3) and platelet-derived growth factor receptor beta (PDGFR-beta), while temsirolimus is an mTOR inhibitor. [50] Recent clinical studies form the basis for new guidelines for the treat­ment of advanced RCC: sorafenib should be used as a second-line treatment, sunitinib as the first-line therapy for good and intermediate-risk patients, and temsirolimus should be considered as first-line treatment for poor-risk patients. Future approaches to targeted therapy should focus on optimizing the use of current active drugs, exploring their combinations or investi­gating their sequential use. In addition, it is im­portant to define the mechanisms of resistance on their use and to further investigate bio­markers and enhance treatment efficacy for the individual patients. The development of these targeted therapies represents an exciting step forward in the treatment of advanced RCC. [50] TG4010 (MVA-MUC1-IL2).is a vaccine which incorporates the MUC1 antigen, which is over expressed in the majority of cancers and inter­leukin-2 (as an immune stimulus). The vaccine has been tested in breast, kidney, prostate and lung cancers with encouraging results. [51] In our opinion, IL2 should not be incorporated into anticancer vaccines, since it represents a treat­ment per se. Moreover, we suggest that anti­cancer vaccines should be personalized and ad­ministrated to each patient in function of the various antigens which appear over expressed in that respective patients' tumor. Personalized medicine should be our ultimate goal. A Phase I/II study of vaccination with electrofused allo­geneic dendritic cells /autologous tumor-derived cells in patients with stage IV renal cell carci­noma confirmed that vaccination was feasible, well tolerated, and resulted in immunologic and clinical responses in a subset of patients (10/21 evaluable patients). [52] Dendritic cell (DC) vaccines are an important experimental immunotherapy for renal cell carcinomas. DC vaccines have proven safe, but only minimal clinical efficacy has been observed to date. [53] (CAIX) is a RCC­specific tumor protein that is targeted using heat shock protein 110 (hsp110). The chaperoning ability of hsp110 can be utilized to form a complex with CAIX (hsp110 + CAIX) in vitro, which can be administered as a highly con­centrated tumor vaccine. [54] Recombinant hsp110 complexed to CAIX should be evaluated for treatment of RCC. [54] Interestingly, in patients responding to vaccination with peptide-pulsed dendritic cells, T-cell responses to antigens not used for vaccinations, such as adipophilin, telo­merase, or oncofetal antigen, could be detected, indicating that epitope spreading might occur. [55] Simultaneous presentation of tumor antigens by both MHC class I and II molecules generates a robust and long-lasting anti-tumor immune res­ponse. [56] MHC class II+/Ii- tumor cells are po­tent tumor cell vaccines and also cure a signi­ficant number of animals with renal and pros­tate tumors. Analogous human gene vectors that are suitable for most patients and cancers have also been developed by researchers at Antigen Express, Inc. [56] Stimulation of the patient's immune system through vaccination with tumor cells has long been at the vanguard of cancer thera­peutic vaccines, and several have been demons­trated to be safe and to have efficacy in early clinical trials for a range of cancers including melanoma, renal cell carcinoma, prostate and colorectal cancers. [57] Renal Cancer Vaccines have been excellently presented and described. [58] On the other hand, Cancer Drug Resistance has been presented in detail. [59] Combining informations from the two sources [58],[59] leads us to the idea that vaccines should be used to overcome drug resistance, by prevention. Between 1998 and 2007 we have searched concomitantly for a cure for infectious diseases (HIV/AIDS, mala­ria, TB) and for cancers. [60],[61],[62] The combination of immunotherapy (vaccines) with multitarget­oriented drugs can function synergistically and lead to cures for both "incurable" infectious di­ seases and cancers. [61],[62] An almost complete Lis­ting of (FDA) Approved Oncology Drugs with "Approved Indications" can be found at: [63] (. htm ); Cancer therapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumor cells. [64],[65] MDR can be in­ trinsic or acquired, depending on the time of its occurrence, either at diagnosis or during che­motherapy. Renal cancers often have intrinsic form of MDR because of de novo expression of P-glycoprotein (P-gp) in renal cells. [65] Molecu­lar investigations on MDR during the past two decades have led to the isolation and charac­terization of genes coding for P-gp, multidrug resistance-associated protein (MRP), lung resis­tance-related protein (LRP), breast cancer resis­tance protein (BCRP/MXR), drug resistance­associated protein (DRP), and ATP-binding cassette protein (ABCP). [65] Because of the re­cent developments in microarray technology, DNA and protein arrays against drug resistant genes are available commercially now. [65] MS­209, a quinolone-derived sphingomyelin synthase inhibitor that blocks P-glycoprotein and multi­drug resistance-associated protein-1, is under development by Schering for the potential treat­ment of multidrug resistant tumors. [66] Protein kinase C inhibitors (PKCI) have been found to be able to reverse multidrug resistance in renal carcinoma cells in vitro via changes of expre­ssion of MDR1. [67] Vaccines are a promising treatment of RCC intended to stimulate a specific antineoplasic response both in an adjuvant and in a metastatic setting. However, we are proposing here the use of anticancer vaccines (VAX-x), as prevention for emergence of Anti­cancer Drug (DRUG-x)-resistance. [62] A vaccine which prevents the emergence of Sorafenib­resistant tumor cells (VAX-sorafenib) or Sunitinib­resistant tumor cells (VAX-sunitinib) should be administrated before onset of therapy with either agent. The vaccine should be made of inactivated tumour cells which are resistant to Sorafenib or Sunitinib, or of the genes or DNA­segments which confer this resistance. (VAX-x, DRUG-x) -couples could prove to be superior to the respective anticancer drug (DRUG-x) since they actively involve the immune system in the battle against cancer cells. [61],[62]


   Conclusions Top


The potential of molecular markers suggested by clinical research is encouraging. Knowledge of various immune pathways and biomarkers may have potential as therapeutic targets. A combination formed of an anticancer vaccine (VAX-x), which prevents the emergence of drug-resistance to (DRUG-x), with its corres­ponding anticancer drug (DRUG-x), adminis­trated after immunological response to (VAX­x) may be a model for research in the future with sorafenib and sunitinib. Complementary anticancer vaccines (VAX-x) could also be created for other chemotherapeutic agents. In this way drug resistance can be avoided, and high cure rates may be possible.

 
   References Top

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Correspondence Address:
Ciprian C Secasan
Department of Urologic Surgery, P-ta Eftimie Murgu, Nr 2, 300041, Timisoara
Romania
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