Targeting SPOP with small molecules provides a novel strategy for kidney cancer therapy

Abstract

Renal cell carcinoma (RCC), accounting for 4% of all cancers, is the second most common cancer in urology. The most common form of RCC is clear cell RCC (ccRCC), with a ratio over 70%. Early-phase kidney diseases usually show rare symptoms in clinic; unfortunately, most patients are diagnosed with kidney cancer at the end stage, at which point the cancer is both resistant to chemotherapy and metastatic, thus leading to high mortality. Understanding cancer biology enables manipulation of disease targets by using small-molecule modulators, which eventually drive the development of novel therapeutic agents for ccRCC. In this insight, we would like to briefly outline several promising and revolutionizing targets and the target-based design of therapeutic agents for ccRCC.Interleukin-2 (Aldesleukin) and interferon are common immunotherapy for patients with metastatic RCC, while their effectiveness is still controversial. In 2015, the first checkpoint inhibitor nivolumab (Opdivo, BMS) with improved overall survival for the RCC therapy was approved by the FDA (Food and Drug Administration) as a single agent in the second-line setting, which is a monoclonal antibody targeting PD-1 in order to suppress the growth of ccRCC cells. Comparing checkpoint-inhibitor based combinations with other anti-tumor agents in the first-line setting are ongoing in phase III for *Corresponding author (email: yangcg@simm.ac.cn) ccRCC therapy. With several checkpoint inhibitors alone or in combination, this field is promising and evolving rapidly (Curtis et al., 2016).Hereditary or sporadic ccRCC always demonstrates correlation with the inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL), lowing ubiquitination level of the down-stream protein hypoxic stress and hypoxia-inducible factor α (HIFα), and bringing about its stabilization and accumulation in ccRCC cells. Cellular stimuli activate the phosphoinositide 3-kinase (PI3K)/Akt (protein kinase) pathway and mammalian target of rapamycin (mTOR), which can also raise the HIFα protein level in ccRCC cells. Consequently, the activated transcription factor HIF increases the transcription level of hypoxia-related genes, including vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), and results in tumor-inclined cell proliferation, migration, and permeation. There is considerable pharmaceutical research into drug discovery by targeting protein phosphorylation signaling pathways. Indeed, the FDA has approved several agents targeting ccRCC-closely related proteins for the metastatic RCC therapy. Temsirolimus (Torisel, Wyeth), an inhibitor of mTOR conplex1 (mTORC1), shows good antitumor activity in patients with metastatic RCC. VEGF receptor (VEGFR) and PDGF receptor (PDGRF) tyrosine kinases inhibitors sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer) are released to the market for the treatment of RCC.

Construction and validation of an autophagy‐related long noncoding RNA signature for prognosis prediction in kidney renal clear cell carcinoma patients

“…3 It has been reported that about 30% of patients with KIRC has already developed metastases at first diagnosis. 5 Therefore, to construct an effective prognostic prediction signature was of significant importance for the management of patients with KIRC.…”

“…Moreover, KIRC was resistant to radiotherapy and chemotherapy, 4 and surgery was the primary effective treatment method for localized KIRC, but had limited efficacy in advanced KIRC 3 . It has been reported that about 30% of patients with KIRC has already developed metastases at first diagnosis 5 . Therefore, to construct an effective prognostic prediction signature was of significant importance for the management of patients with KIRC.…”

Downregulation of lncRNA SDPR-AS is associated with poor prognosis in renal cell carcinoma

“…Because kidney diseases are mostly asymptomatic during the early stages, many RCC patients are diagnosed with advanced stage metastatic diseases that are often resistant to chemotherapy, and therefore this is associated with high mortality 3. Despite the great advances made in the diagnosis and treatment of RCC, therapeutic options are limited and prognosis remains unfavorable 4.…”

Clear Cell Renal Carcinoma: MicroRNAs With Efficacy in PreclinicalIn VivoModels

“…SPOP expression correlates with a bad prognosis in ccRCC (163). Small molecules have been identified which inhibit SPOP-substrate protein interaction and suppress oncogenic SPOP signaling pathways in ccRCC (164).…”