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Cancers
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Clear Cell Renal Cell Carcinoma: From Biology to Treatment
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Clear Cell Renal Cell Carcinoma: From Biology to Treatment

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (10 June 2023) | Viewed by 10780

Special Issue Editors

Dr. Scott S. Tykodi

E-Mail Website
Guest Editor
University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Interests: kidney cancer; clinical trials; immunotherapy
Special Issues, Collections and Topics in MDPI journals
Dr. Evan T. Hall

E-Mail Website
Co-Guest Editor
University of Washington and Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA
Interests: skin cancers (including melanoma); kidney cancer

Special Issue Information

Dear Colleagues,

Renal cell carcinoma is the most common primary malignancy of the kidney in adults and encompasses a family of related tumors. The clear cell subtype represents about 70% of all RCC tumors, and therefore, reflects the typical presentation of kidney cancer seen in the clinic and is the primary focus of clinical research. 

Most clear cell RCC (ccRCC) tumors have lost expression of the VHL gene that is part of the cell’s normal oxygen sensing mechanism, creating a pseudohypoxic phenotype driving constitutive overexpression of HIF transcription factors and resulting proangiogenic signals, including vascular endothelia growth factor (VEGF). Insight into this underlying biology has fostered the targeted development of inhibitors of VEGF and more recently HIF-2α for clinical use. Clear cell RCC also has a long history as a target of systemic immunotherapies, including cytokines (IFNα, IL-2), and currently immune checkpoint inhibitors that have rapidly emerged as the preferred front-line treatment for this disease, either alone or in combination with tyrosine kinase inhibitors selective for the VEGF pathway. The rapid emergence of multiple similar drugs and combination regimens involving angiogenic and immune function pathways juxtaposed with the heterogeneity of clinical outcomes encourages deeper analyses and fosters debate regarding the optimization of current and future strategies to treat ccRCC.

This Special Issue will cover aspects of preclinical modeling, biomarker development, and clinical outcomes related to both established and emerging treatments. Both original research and review articles are welcome.

Dr. Scott S. Tykodi
Dr. Evan T. Hall
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • renal cell carcinoma
  • HIF
  • angiogenesis
  • targeted therapy
  • immune checkpoint inhibitor
  • T cell
  • tumor microenvironment
  • treatment resistance
  • biomarkers

Published Papers (4 papers)

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Research

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22 pages, 7248 KiB  
Article
Targets for Renal Carcinoma Growth Control Identified by Screening FOXD1 Cell Proliferation Pathways
by Kyle H. Bond, Sunder Sims-Lucas and Leif Oxburgh
Cancers 2022, 14(16), 3958; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14163958 - 16 Aug 2022
Cited by 4 | Viewed by 1760
Abstract
Clinical association studies suggest that FOXD1 is a determinant of patient outcome in clear cell renal cell carcinoma (ccRCC), and laboratory investigations have defined a role for this transcription factor in controlling the growth of tumors through regulation of the G2/M cell cycle [...] Read more.
Clinical association studies suggest that FOXD1 is a determinant of patient outcome in clear cell renal cell carcinoma (ccRCC), and laboratory investigations have defined a role for this transcription factor in controlling the growth of tumors through regulation of the G2/M cell cycle transition. We hypothesized that the identification of pathways downstream of FOXD1 may define candidates for pharmacological modulation to suppress the G2/M transition in ccRCC. We developed an analysis pipeline that utilizes RNA sequencing, transcription factor binding site analysis, and phenotype validation to identify candidate effectors downstream from FOXD1. Compounds that modulate candidate pathways were tested for their ability to cause growth delay at G2/M. Three targets were identified: FOXM1, PME1, and TMEM167A, which were targeted by compounds FDI-6, AMZ-30, and silibinin, respectively. A 3D ccRCC tumor replica model was used to investigate the effects of these compounds on the growth of primary cells from five patients. While silibinin reduced 3D growth in a subset of tumor replicas, FDI-6 reduced growth in all. This study identifies tractable pathways to target G2/M transition and inhibit ccRCC growth, demonstrates the applicability of these strategies across patient tumor replicas, and provides a platform for individualized patient testing of compounds that inhibit tumor growth. Full article
(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma: From Biology to Treatment)
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15 pages, 2066 KiB  
Article
Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib
by Meta H. M. Diekstra, Jesse J. Swen, Loes F. M. van der Zanden, Sita H. Vermeulen, Epie Boven, Ron H. J. Mathijssen, Koya Fukunaga, Taisei Mushiroda, Fumiya Hongo, Egbert Oosterwijk, Anne Cambon-Thomsen, Daniel Castellano, Achim Fritsch, Jesus Garcia Donas, Cristina Rodriguez-Antona, Rob Ruijtenbeek, Marius T. Radu, Tim Eisen, Kerstin Junker, Max Roessler, Ulrich Jaehde, Tsuneharu Miki, Stefan Böhringer, Michiaki Kubo, Lambertus A. L. M. Kiemeney and Henk-Jan Guchelaaradd Show full author list remove Hide full author list
Cancers 2022, 14(12), 2838; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122838 - 08 Jun 2022
Cited by 1 | Viewed by 1989
Abstract
Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We [...] Read more.
Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated. Full article
(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma: From Biology to Treatment)
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Review

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15 pages, 1044 KiB  
Review
Clear Cell Renal Cell Carcinoma: From Biology to Treatment
by Adam M. Kase, Daniel J. George and Sundhar Ramalingam
Cancers 2023, 15(3), 665; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15030665 - 21 Jan 2023
Cited by 13 | Viewed by 4245
Abstract
The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over 90% of kidney tumors are renal cell carcinomas, of which, clear cell is the [...] Read more.
The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over 90% of kidney tumors are renal cell carcinomas, of which, clear cell is the most predominate histologic subtype. Von Hippel Lindau (VHL) gene alterations result in the overexpression of growth factors that are central to the pathogenesis of clear cell carcinoma. The therapeutic strategies have revolved around this tumor suppressor gene and have led to the approval of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor (VEGF) axis. The treatment paradigm shifted with the introduction of immune checkpoint inhibitors (ICI) and programed death-1 (PD-1) inhibition, leading to durable response rates and improved survival. Combinations of TKI and/or ICIs have become the standard of care for advanced clear cell renal cell carcinoma (ccRCC), changing the outlook for patients, with several new and promising therapeutic targets under development. Full article
(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma: From Biology to Treatment)
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14 pages, 407 KiB  
Review
The Role of Surgery in Spinal Intradural Metastases from Renal Cell Carcinoma: A Literature Review
by Sergio Corvino, Giuseppe Mariniello, Domenico Solari, Jacopo Berardinelli and Francesco Maiuri
Cancers 2022, 14(6), 1595; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14061595 - 21 Mar 2022
Cited by 4 | Viewed by 2049
Abstract
Background: Due to the few reported cases of spinal intradural metastases from renal cell carcinoma (RCC), there is no unanimous consensus on the best treatment strategy, including the role of surgery. Methods: A wide and accurate literature review up to January 2022 has [...] Read more.
Background: Due to the few reported cases of spinal intradural metastases from renal cell carcinoma (RCC), there is no unanimous consensus on the best treatment strategy, including the role of surgery. Methods: A wide and accurate literature review up to January 2022 has disclosed only 51 cases of spinal intradural metastases from RCC. Patients with extramedullary (19) and those with intramedullary (32) localization have been separately considered and compared. Demographics, clinical, pathological, management, and outcome features have been analyzed. Results: Extramedullary lesions more frequently showed the involvement of the lumbar spine, low back pain, and solitary metastasis at diagnosis. Conversely, the intramedullary lesions were most often detected in association with multiple localizations of disease, mainly in the brain. Surgery resulted in improvement of clinical symptoms in both groups. Conclusion: Several factors affect the prognosis of metastatic RCC. The surgical removal of spinal metastases resulted in pain relief and the arresting of neurological deficit progression, improving the quality of life and overall survival of the patient. Considering the relative radioresistant nature of the RCC, the surgical treatment of the metastasis is a valid option even if it is subtotal, with a consequent increased risk of recurrence, and/or a nerve root should be sacrificed. Full article
(This article belongs to the Special Issue Clear Cell Renal Cell Carcinoma: From Biology to Treatment)
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