Antiangiogenic Therapy in Clear Cell Renal Carcinoma (CCRC): Pharmacological Basis and Clinical Results

Angiogenesis has a direct stimulatory effect on tumor growth, duplication, invasion and metastatic development. A significant portion of conventional renal cell carcinomas are angiogenesis-dependent tumors and the pathways supporting this process have been thoroughly investigated over the last 20 years. As a consequence, many tyrosine kinase inhibitors (TKIs) (sunitinib, sorafenib, pazopanib, axitinib, and cabozantinib), one monoclonal antibody (bevacizumab), and two mammalian target of rapamycin (mTOR) inhibitors (temsirolimus and everolimus) have been investigated and approved for the treatment of advanced or metastatic clear cell renal carcinoma (metastatic CCRC) in first-line, as well as second-line, therapy, with impressive results in progression-free survival and in the objective response rate compared with previously available therapies or placebo. Recently, a new type of drug has been approved for metastatic CCRC: immunomodulatory checkpoint inhibitors (ICIs), alone or in combination with TKIs. However, many questions and areas to be explored still remain with regard to clear cell renal carcinoma (CCRC) treatment: research on predictive biomarkers, the best patient selection, how to overcome the mechanisms of resistance, and the best sequence of therapies in daily clinical practice. This review focuses on the pharmacological properties and anticancer activities of these drugs. The toxicity profile and clinical limitations of these therapies are also discussed.

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C-reactive Protein in Patients with Metastatic Clear Cell Renal Carcinoma: An Important Biomarker for Tumor-associated Inflammation

Biomarker Insights ◽

10.1177/117727190600100017 ◽

2006 ◽

Vol 1 ◽

pp. 117727190600100 ◽

Cited By ~ 2

Author(s):

Albrecht Reichle ◽

Jochen Grassinger ◽

Klaus Bross ◽

Jochen Wilke ◽

Thomas Suedhoff ◽

...

Keyword(s):

Low Dose ◽

Renal Carcinoma ◽

Tumor Response ◽

Clear Cell ◽

Objective Response ◽

Progression Free Survival ◽

Clear Cell Renal Carcinoma ◽

Phase Ii Trials ◽

Reactive Protein ◽

Cell Renal Carcinoma

Two consecutive multi-center phase II trials were designed to prove the hypothesis, whether therapeutic modeling of tumor-associated inflammatory processes could result in improved tumor response. Therapy in both trials consisted of low-dose capecitabine 1g/m2 twice daily p.o. for 14 days, every 3 weeks, day 1+, and rofecoxib 25 mg daily p.o., day 1+ (from 11/04 etoricoxib 60 mg daily instead) plus pioglitazone 60 mg daily p.o., day 1+. In study II low-dose IFN-α 4.5 MU sc. three times a week, week 1+, was added until disease progression. Eighteen, and 33 patients, respectively, with clear cell renal carcinoma and progressive disease were enrolled. Objective response (48%) was exclusively observed in study II (PR 35%, CR 13%), and paralleled by a strong CRP response after 4 weeks on treatment, p = 0.0005, in all 29 pts (100%) with elevated CRP levels. Median progression-free survival could be more than doubled from a median of 4.7 months (95% CI, 1.0 to 10.4) to 11.5 months (6.8 to 16.2) in study II, p = 0.00001. Median overall survival of population II was 26 months. Efficacious negative regulation of tumor-associated inflammation by transcription modulators may result in a steep increase of tumor response and survival.

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738P Soluble PD-1, PD-L1, pan-BTN3As, BTN3A1 and BTN2A1 as predictive biomarkers of nivolumab response in patients with metastatic clear cell renal carcinoma

Annals of Oncology ◽

10.1016/j.annonc.2020.08.810 ◽

2020 ◽

Vol 31 ◽

pp. S575

Author(s):

L. Incorvaia ◽

D. Fanale ◽

G. Badalamenti ◽

J.L. Iovanna ◽

C. Porta ◽

...

Keyword(s):

Renal Carcinoma ◽

Clear Cell ◽

Predictive Biomarkers ◽

Clear Cell Renal Carcinoma ◽

Cell Renal Carcinoma

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Tissue Based Biomarkers for Metastatic Clear Cell Renal Carcinoma: A Systematic Review

Kidney Cancer ◽

10.3233/kca-200103 ◽

2020 ◽

Vol 4 (4) ◽

pp. 197-210

Author(s):

Andrew L. Schmidt ◽

Paul A. Bain ◽

Bradley A. McGregor

Keyword(s):

Full Text ◽

Renal Carcinoma ◽

Clear Cell ◽

Immune Therapy ◽

Predictive Biomarkers ◽

Clear Cell Renal Carcinoma ◽

Hand Search ◽

Cell Renal Carcinoma ◽

Full Text Review

Background: Treatments for metastatic clear cell renal carcinoma (mccRCC) are evolving with multiple targeted and immune therapy drugs currently approved by regulatory agencies as single agents or in combination. Developing predictive biomarkers to determine which patients derive a differential benefit from a particular treatment is an area of ongoing clinical research. Objective: We sought to systematically evaluate the role of tumour tissue-based biomarkers that assist in selection of therapy for mccRCC. Methods: Literature addressing the role of biomarkers in mccRCC was identified through a search of the electronic databases MEDLINE, Embase, and the Web of Science and a hand search of major conference abstracts (from Jan 2010 –Sep 2020). Abstracts were screened to identify papers meriting full-text review. Studies with a comparison arm were included to assess biomarker relevance. A narrative review of studies was performed. Results: The literature search yielded 6784 potentially relevant articles. 133 articles met criteria for full text review, and 10 articles were identified by scanning bibliographies of relevant studies. A total of 33 articles (involving 13 studies) were selected for data extraction and subsequent review. Conclusions: Predictive biomarkers for immediate use in the clinic are lacking, and embedding their evaluation and validation in future clinical trials is needed to refine practice and patient selection.

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1651: Molecular Prognostic Modeling Using Protein Expression Profile in Clear Cell Renal Carcinoma

The Journal of Urology ◽

10.1016/s0022-5347(18)38859-1 ◽

2004 ◽

Vol 171 (4S) ◽

pp. 436-436 ◽

Cited By ~ 3

Author(s):

Hyung L. Kim ◽

David B. Seligson ◽

Nicolette Janzen ◽

Matthew H. Bui ◽

Robert A. Figlin ◽

...

Keyword(s):

Protein Expression ◽

Expression Profile ◽

Renal Carcinoma ◽

Clear Cell ◽

Clear Cell Renal Carcinoma ◽

Protein Expression Profile ◽

Cell Renal Carcinoma ◽

Prognostic Modeling

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The VHL tumor suppressor inhibits expression of the IGF1R and its loss induces IGF1R upregulation in human clear cell renal carcinoma

Oncogene ◽

10.1038/sj.onc.1210474 ◽

2007 ◽

Vol 26 (45) ◽

pp. 6499-6508 ◽

Cited By ~ 68

Author(s):

J S P Yuen ◽

M E Cockman ◽

M Sullivan ◽

A Protheroe ◽

G D H Turner ◽

...

Keyword(s):

Tumor Suppressor ◽

Renal Carcinoma ◽

Clear Cell ◽

Clear Cell Renal Carcinoma ◽

Cell Renal Carcinoma

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The Influence of the Extremely Low Frequency Electromagnetic Field on Clear Cell Renal Carcinoma

International Journal of Molecular Sciences ◽

10.3390/ijms22031342 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1342

Author(s):

Aleksandra Cios ◽

Martyna Ciepielak ◽

Wanda Stankiewicz ◽

Łukasz Szymański

Keyword(s):

Electromagnetic Field ◽

Cancer Cells ◽

Cell Lines ◽

Renal Carcinoma ◽

Clear Cell ◽

Low Frequency ◽

Inhibitory Effect ◽

Hek293 Cells ◽

Clear Cell Renal Carcinoma ◽

Cell Renal Carcinoma

The development of new technologies and industry is conducive to the increase in the number and variety of electromagnetic field (EMF) sources in our environment. The main sources of EMF are high-voltage lines, household appliances, audio/video devices, mobile phones, radio stations, and radar devices. In the growing use of electronic devices, scientists are increasingly interested in the effects of EMF on human health. Even though many studies on the effects of EMF have already been carried out, none of them has shown a significant effect on mammals, including humans. Moreover, it is not entirely clear how EMF influences cell behavior. The International Agency for Research on Cancer on 31 May 2011, classified PEM as a possible carcinogenic factor. This study aimed to investigate the effect of the electromagnetic field on morphological and functional changes in clear cell renal carcinoma. The research was carried out on in vitro cultures of four cell lines: HEK293, 786-O 769-P, and Caki1. The results of the research showed that the EMF of low frequency had a slight effect on the viability of cells. EMF, which induced cell arrest in the G1 phase, increased the number of early apoptotic cells and decreased the number of viable cells in the 786-O line. EMF did not affect the proliferation and viability of HEK293 cells. Extreme low-frequency EMF (ELF-EMF) also showed an inhibitory effect on the migration and metastatic properties of clear cell kidney cancer cells. Moreover, shortly after the end of ELF-EMF exposure, significant increases in ROS levels were observed in all tested cell lines. As part of the work, it was shown that low-frequency EMF shows an inhibitory effect on the proliferation of primary cancer cells, diminishing their migratory, invasive, and metastatic abilities. It also increases the apoptosis of cancer cells and the amount of reactive oxygen species. Based on the results of our research, we want to point up that the effect of ELF-EMF depends on a specific metabolic state or at a specific stage in the cell cycle of the cells under study.

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