Chemotherapy And Immunotherapy Of Renal Carcinomas

Renal cell carcinomas are notoriously difficult to treat by chemotherapy or radiation therapy. Several factors may contribute to this 'primary' resistance.

(1) Renal cell carcinoma are not particularly fast growing, presenting poor targets for therapies targeting highly proliferating cells (^22.2).

(2) Excretion of toxic compounds is an important functions of the normal kidney. Tumor tissues from this organ retain some of the protective systems of the kidney and in particular the excretion system involving the 'PGP glycoprotein' MDR1 (Figure 15.9). MDR1 is an ATP-dependent transport protein ('ABC' transporter) which helps to exchange lipids between the inner and outer leaflet of the cell membrane. This reaction also allows the excretion of a broad range of lipophilic cytostatic drugs from the cell. In this fashion, the protein contributes to multi-drug resistance in many human cancers. In other cancers, its expression is acquired or induced only after exposure to chemotherapy, leading to 'secondary' chemoresistance. In the kidney, in contrast, the MDR protein is normally expressed at high levels, likely to support the excretion of toxic compounds from the body. Therefore, the protein is present right from the start in RCC and this cancer type displays 'primary resistance'.

Cell membrane

Cytoplasm

Figure 15.9 Structure and function of MDR1 (PGP) The transmembrane domains (TMD1, TMD2) form a pore, through which the actual transport proceeds. It is driven by ATP bound by the nucleotide binding domains (NBD1, NBD2).

(3) A crucial change in the development of RCC is decreased apoptosis. Although the underlying mechanisms are not completey clear, they are likely to result in decreased sensitivity towards chemotherapy and radiotherapy (^22.2).

(4) In advanced renal carcinomas, loss of TP53 and PTEN functions are relatively frequent. These losses are in general associated with poor responses to chemotherapy and radiation, by diminishing apoptosis (^7.3) and enhancing tolerance to DNA strand-breaks (^3.3).

Desperation is therefore certainly part of the explanation, why RCC has become one of the favorite objects for immunotherapy. Of course, there are more strictly scientific reasons as well. Most strikingly, 'spontaneous' regression of renal

Figure 15.9 Structure and function of MDR1 (PGP) The transmembrane domains (TMD1, TMD2) form a pore, through which the actual transport proceeds. It is driven by ATP bound by the nucleotide binding domains (NBD1, NBD2).

carcinomas has been documented in individual cases. It is commonly attributed to a successful immune response. In accord with these very rare 'miracle' cures, treatment with cytokines that stimulate cytotoxic T-cells has been reported to lead to partial or complete responses (^22.1) in 15-30% of clear cell renal carcinoma patients, although not in other subtypes. Therefore, treatment with interleukin-2 (IL2) and/or interferon a (IFNa) is one of the few therapeutic options available for patients with metastatic disease. This treatment occasionally leads to spectacular responses, but it is rarely curative. Moreover, the side effects can be quite intense, comparable to those experienced in a severe case of flu. They would, perhaps, be more acceptable, if one could predict in which patient the treatment is efficacious, but this is not yet possible. So, more experimental approaches to immunotherapy of renal carcinoma are being attempted (^22.5).

In melanoma, another promising target for immunotherapy, immune responses are directed against proteins particular to melanocytes and to cancer-testis antigens ectopically expressed in the cancer (^-12.5). In renal carcinoma, oncofetal antigens, i.e. proteins normally expressed only during fetal development and down-regulated in adult kidney, may represent one type of target. More broadly, antigens recognized by immune cells in RCC are derived from proteins as part of the constitutive hypoxia response (Table 15.5), particularly in the conventional type. For instance, a promising cell membrane antigen recognized by the monoclonal antibody G250 is expressed on the surface of essentially every renal carcinoma (of various subtypes), but is not at all detectable in normal kidney. This antigen has turned out to be part of the CA9 carbonic anhydrase, which is induced several-hundred fold in clear cell RCC as a consequence of constitutive HIF1 activation.

Further reading

Ebele JN et al (eds.) Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. IARC Press, 2004

Kovacs G et al (1997) The Heidelberg classification of renal cell tumours. J. Pathol. 183, 131-133 Davies JA, Perera AD, Walker CL (1999) Mechanisms of epithelial development and neoplasia in the metanephric kidney. Int. J. Dev. Biol. 43, 473-478 Friedrich CA. (2001) Genotype-phenotype correlation in von Hippel-Lindau syndrome. Hum. Mol. Genet. 10, 763-767

Huebner K, Croce CM (2001) FRA3B and other common fragile sites: the weakest links? Nat. Rev. Cancer 1, 214-221

Meloni-Ehrig AM (2002) Renal cancer: cytogenetic and molecular genetic aspects. Am. J. Med. Genet. 115, 164-172

Bodmer D et al (2002) Understanding familial and non-familial renal cell cancer. Hum. Mol. Genet. 11, 2489-2498

Fromm MF (2002) Genetically determined differences in P-glycoprotein function: implications for disease risk. Toxicology 181-182, 299-303 Kaelin WG (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat. Rev. Cancer 2, 673-682 Pfeifer GP et al (2002) Methylation of the RASSF1A gene in human cancers. Biol. Chem. 383, 907-914 Ambudkar SV et al (2003) P-glycoprotein: from genomics to mechanism. Oncogene 22, 7468-7485 Gitlitz BJ, Figlin RA (2003) Cytokine-based therapy for metastatic renal cell cancer. Urol. Clin. North Am. 30, 589-600

Safran M, Kaelin WG (2003) HIF hydroxylation and the mammalian oxygen-sensing pathway. J. Clin. Invest. 111, 779-783

Linehan WM, Walther MM, Zbar B (2003) The genetic basis of cancer of the kidney. J. Urol. 170, 21632172

Mulders P, Bleumer I, Oosterwijk E (2003) Tumor antigens and markers in renal cell carcinoma. Urol.

Clin. North Am. 30, 455-465 Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat. Med. 9, 677-684

Vieweg J, Dannull J (2003) Tumor vaccines: from gene therapy to dendritic cells: the emerging frontier

Urol. Clin. North Am. 30, 633-643 Zbar B, Klausner R, Linehan WM (2003) Studying cancer families to identify kidney cancer genes Annu. Rev. Med. 54, 217-233

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