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Published on: January 22, 2013
Evolution of the HIF targeted therapy in clear cell renal cell carcinoma
Borivoj Golijanin1, Kamil Malshy1, Sari Khaleel1
1The Minimally Invasive Urology Institute at The Miriam Hospital, Division of Urology, Lifespan Academic Medical Center, The Legorreta Cancer Center at Brown University, Warren Alpert Medical School of Brown University, Providence, RI 02906, United States.
Abstract:
Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, affecting hundreds of thousands of people worldwide and can affect people of any age. The pathogenesis of ccRCC is most commonly due to biallelic loss of the tumor suppressor gene VHL. VHL is the recognition subunit of an E3-ubiquitin-ligase-complex essential for degradation of the hypoxia-inducible factors (HIF) 1α and 2α. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2α subunit. This leads to nuclear translocation, dimerization, and transactivation of numerous HIF-regulated genes responsible for cell survival and proliferation in ccRCC. FDA-approved therapies for RCC have primarily focused on targeting downstream effectors of HIF, then incorporated immunotherapeutics, and now, novel approaches are moving back to HIF with a focus on interfering with upstream targets. This review summarizes the role of HIF in the pathogenesis of ccRCC, novel HIF2α-focused therapeutic approaches, and opportunities for ccRCC treatment.
Insights
Clear cell renal cell carcinoma (ccRCC) pathogenesis involves VHL gene loss, leading to hypoxia-inducible factor (HIF) accumulation. Novel therapies now target HIF2α to treat this common kidney cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer globally.
- Its development is frequently linked to the loss of the VHL tumor suppressor gene.
- VHL normally facilitates the degradation of hypoxia-inducible factors (HIFs).
Purpose of the Study:
- To review the role of HIF in ccRCC pathogenesis.
- To discuss emerging therapeutic strategies targeting HIF2α.
- To explore new treatment opportunities for ccRCC.
Main Methods:
- Literature review of ccRCC pathogenesis and therapeutic strategies.
- Analysis of the VHL-HIF pathway in cancer development.
- Summary of current and novel HIF2α-targeted treatments.
Main Results:
- Loss of VHL function leads to HIF accumulation, particularly HIF2α.
- Overaccumulated HIF2α drives ccRCC cell survival and proliferation.
- Current therapies target downstream HIF effectors or use immunotherapy; novel approaches target HIF upstream.
Conclusions:
- HIF2α is a critical driver in ccRCC pathogenesis.
- Targeting HIF2α represents a promising therapeutic avenue.
- Further research into HIF-focused therapies could improve ccRCC treatment outcomes.
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