J O U R N A L C L U B
Essential Peer-Reviewed Reading in Kidney Cancer
The peer-reviewed articles summarized in this section were selected by the
Editor-in-Chief, Robert A. Figlin, MD, for their timeliness, importance, relevance,
and potential impact on clinical practice or translational research
Adjuvant therapy in renal cell carcinoma: does higher
risk for recurrence improve the chance for success?
Figlin RA, Leibovich BC, Stewart GD, et al. Ann Oncol.
2017 Nov 24; doi: 10.1093/annonc/mdx743.
Summary: The success of targeted therapies, including inhibitors
of the vascular endothelial growth factor pathway
or the mammalian target of rapamycin, in the treatment
of metastatic renal cell carcinoma (RCC) led to interest in
testing their efficacy in the adjuvant setting. Results from
the first trials are now available with other studies due to
report imminently. This review provides an overview
of adjuvant targeted therapy in RCC, including interpretation
of currently available conflicting data and future direction
of research. It discusses the key differences between
the completed targeted therapy adjuvant trials, and highlight
the importance of accurately identifying patients
who are likely to benefit from adjuvant treatment. Also
considered are reasons why blinded independent radiology
review and treatment dose may prove critical for adjuvant
treatment success. The implications of using diseasefree
survival as a surrogate endpoint for overall survival
from the patient perspective and measurement of health
benefit have recently been brought into focus and are
discussed. Finally, the paper discusses how the ongoing
adjuvant trials with targeted therapies and checkpoint
inhibitors may improve our understanding and ability to
prevent tumor recurrence after nephrectomy in the future.
Insights into Epigenetic Remodeling in VHL-Deficient
Clear Cell Renal Cell Carcinoma. Ricketts CJ, Linehan
WM. Cancer Discov. 2017 Nov; 7(11):1221-1223. doi:
10.1158/2159-8290.
Summary: Clear cell renal cell carcinoma (ccRCC) is
characterized by loss of the von Hippel-Lindau tumor suppressor
gene (VHL), and the functional tumorigenic consequences
of this loss have been used to develop therapies
for advanced ccRCC, such as targeting activation of the
HIF pathway. Yao and colleagues elucidate how VHL loss
contributes to chromatin alteration at both gene promoters
and enhancers/superenhancers, in both an HIF-dependent
as well as independent manner, and how this
may provide additional targets for therapeutic intervention
in advanced ccRCC.
HIF2 targeted RNAi therapeutic inhibits clear cell renal
cell carcinoma. Wong SC, Cheng W, Hamilton H, et al.
Mol Cancer Ther. 2017 Oct 27; pii: molcanther.
0471.2017. doi: 10.1158/1535-7163.
Summary: Targeted therapy against VEGF and mTOR
pathways has been established as the standard-of-care for
metastatic clear cell renal cell carcinoma (ccRCC); however,
these treatments frequently fail and most patients
become refractory requiring subsequent alternative therapeutic
options. Therefore, development of innovative and
effective treatments is imperative. About 80-90% of ccRCC
tumors express an inactive mutant form of the von Hippel-
Lindau protein (pVHL), an E3 ubiquitin ligase that
promotes target protein degradation. Strong genetic and
experimental evidence supports the correlate that pVHL
functional loss leads to the accumulation of the transcription
factor hypoxia-inducible factor 2 (HIF2 ) and that an
over-abundance of HIF2 functions as a tumorigenic driver
of ccRCC.
Conclusion: In this report, we describe an RNAi therapeutic
for HIF2 that utilizes a targeting ligand that selectively
binds to integrins v 3 and v 5 frequently over-expressed
in ccRCC. We demonstrate that functional delivery of a
HIF2 specific RNAi trigger resulted in HIF2 gene silencing
and subsequent tumor growth inhibition and degeneration
in an established orthotopic ccRCC xenograft model.
Tumor Microvessel Density as a Prognostic Marker in
High-Risk Renal Cell Carcinoma Patients Treated on
ECOG-ACRIN E2805. Jilaveanu LB, Puligandla MA,
Weiss SA, et al. Clin Cancer Res. 2017 Oct 24; doi:
10.1158/1078-0432.
Summary: Increased vascularity is a hallmark of renal cell
carcinoma (RCC). Microvessel density (MVD) is one measurement
of tumorangiogenesis; however, its utility as a
biomarker of outcome is unknown. ECOG-ACRIN 2805
(E2805) enrolled 1,943 resected high-risk RCC patients
randomized to adjuvant sunitinib, sorafenib, or placebo.
We aimed to determine the prognostic and predictive role
of MVD in RCC. We obtained pretreatment primary RCC
nephrectomy tissues from 822 patients on E2805 and
constructed tissue microarrays. Using quantitative
immunofluorescence, we measured tumor MVD as the area
of CD34- expressing cells. We determined the association
with disease-free survival (DFS), overall survival (OS), treatment
arm, and clinicopathologic variables. High MVD
(above the median) was associated with prolonged OS for
the entire cohort (P = 0.021) and for patients treated with
placebo (P = 0.028). The association between high MVD
and OS was weaker in patients treated with sunitinib or
sorafenib (P = 0.060). MVD was not associated with DFS
(P = 1.00). On multivariable analysis, MVD remained independently
associated with improved OS (P = 0.013). High
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