Targeted therapies for non-clear renal cell carcinoma

Abstract

The treatment of advanced and metastatic kidney cancer has been revolutionized by the development of targeted systemic therapies. Despite the growing number of available agents approved for use against clear cell renal cell carcinoma, patients with non-clear histologies, constituting approximately 1 in 4 cases of kidney cancer, have not received the same attention. The majority of clinical trials testing novel targeted therapies have excluded non-clear subtypes, providing limited therapeutic options for patients with these diagnoses and their oncologists. This review will focus on the use of targeted therapies against the non-clear histologic subtypes of renal cell carcinoma: papillary I and II, chromophobe, and collecting duct. The unique genetic and molecular profiles of each distinct non-clear kidney cancer subtype will be described, as these differences are integral to the development and effectiveness of the novel agents used to treat them. Trials focusing on non-clear kidney cancer, or those that treated clear cell tumors along with significant numbers of non-clear subtypes, will be discussed. The role of cytoreductive nephrectomy and the use of neoadjuvant and adjuvant targeted therapy will be reviewed. Lastly, areas of future research will be highlighted.

Fig. 1

Histopathologically distinct non-clear renal epithelial neoplasms and their incidence. Reprinted with permission from Linehan WM, Walther MM, Zbar B. (2003) The genetic basis of cancer of the kidney. J Urol 170(6 Pt 1):2163–2172 [5]

Fig. 2

Germline mutations in the tyrosine kinase domain of the protooncogene MET are found in hereditary papillary renal cancer patients, resulting in constitutive activation of the HGF/MET pathway. Reprinted with permission from Linehan WM, Walther MM, Zbar B (2003) The genetic basis of cancer of the kidney. J Urol 170(6 Pt 1):2163–2172 [5]

Fig. 3

Hypoxia-inducible factor (HIF) upregulation in FH−/− cells: Under normoxic conditions, HIF is hydroxylated by HIF prolyl hydroxylase (HPH), which allows the von Hippel-Lindau (VHL) complex to recognize and target it for ubiquitin-mediated degradation in the proteosome. In hereditary leiomyomatosis and renal cell cancer (HLRCC), the loss of FH shunts the tricarboxylic acid (TCA) cycle to produce excess fumarate. Fumarate stabilizes HIF through competitive inhibition of HIF prolyl hydroxylase (HPH), preventing HIF hydroxylation and degradation. Elevated HIF drives transcription products involved with angiogenesis (VEGF), glucose transport (GLUT-1), and growth stimulation (TGF-α, PDGF). Reproduced with permission from Pfaffenroth et al. (2008) Informa Healthcare [3]

Fig. 4

The FLCN pathway. a FLCN is the gene for the Birt-Hogg-Dubé (BHD) syndrome. Patients affected with BHD are characterized by germline mutation of the FLCN gene. The FLCN/FNIP1/FNIP2 complex binds AMPK and FLCN is phosphorylated by a rapamycin-sensitive kinase (i.e., mTORC1). b When FLCN is deficient, AKT, mTORC1 and mTORC2 are activated. Originally published in Linehan WM et al. (2010) The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol 7:277–285 [4]. Reprinted with permission