Despite Preclinical Findings, ‘Much More Work’ Needed for RCC Biomarkers

Despite treatment advances for renal cell carcinoma (RCC), biomarkers are urgently needed for earlier diagnosis and treatment, and quicker assessment of treatment efficacy. Development of such tools has lagged behind biomarker research for more common cancers, and despite encouraging findings from several newly published preclinical studies, there is a long road ahead, experts caution.¹

RCC is commonly asymptomatic until tumors have progressed to advanced or metastatic disease, by which time prognosis is very poor. Most patients are diagnosed incidentally during clinical and imaging exams prompted by unrelated conditions or nonspecific symptoms like bloody urine and flank pain.² Diagnosis requires invasive tumor biopsy-and even then, differentiation between RCC subtypes, and predicting tumor behavior, can be challenging.³

Research teams around the world are working to identify and validate candidate RCC biomarkers ranging from tumor gene expression profiles and neovascularization, to point-in-time or serial monitoring of urinary microRNA or circulating DNA, immune cell ratios, enzymes and proteins.^{1, 4-8} A study of RCC cell lines, tumor immunohistochemistry, and data from The Cancer Genome Atlas (TCGA) database has tentatively identified the tetraspanin membrane protein CD9, measured alongside E-cadherin, as a biomarker that can help distinguish between RCC subtypes and potentially, predict metastasis risk.³

Developing noninvasive “liquid biopsy” approaches to early diagnosis and timely assessment of treatment efficacy is a particularly exciting area of biomarker research, and such tests for prostate cancer have made recent headlines.

Early preclinical studies of circulating VEGF-A and inflammatory cytokine biomarkers, microRNA, and tumor cells have been encouraging for RCC as well-but “much more needs to be understood about circulating biomarkers” before they can be employed clinically to predict tumor responses to immune checkpoint blockade therapies, cautioned Tian Zhang, MD, of the Duke Cancer Institute in Durham, NC, and coauthors, in a recent review of liquid RCC biomarkers for selecting antiangiogenic agents and immunotherapies.¹

“While promising, there is still much work to be done, and prospective evaluation of any potential predictive biomarker for these therapies is greatly needed,” they wrote.¹

So-called “metabolomic” markers of RCC and kidney metabolism are likely to be a focus for such research.⁹ Recently reported findings from a small, retrospective whole-genome expression study implicated upregulated tumor expression of immune system genes like BACH2 in nivolumab efficacy, and upregulated metabolic and solute transport genes in nivolumab failure, in advanced PD-L1-positive RCC.¹⁰ Those findings were based on a small sample of 13 patients and require replication.

A recent review of candidate diagnostic metabolite markers for RCC reported that serum markers might be more promising than urine markers, at least in preclinical animal models.⁹

The review’s authors concluded that no single metabolic marker has proven to be a reliable diagnostic tool, but spotlighted research tying elevated tumor tissue concentrations of creatine, glutamate, and glutamine to high-grade RCC, as evidence that amino acid metabolism and glycolysis are particularly promising areas in development of biomarkers for high-risk RCC.⁹

References:

• Zhang T, Zhu J, George DJ, Nixon AB. Metastatic clear cell renal cell carcinoma: Circulating biomarkers to guide antiangiogenic and immune therapies. Urol Oncol. 2016 Aug 4. pii: S1078-1439(16)30163-6.
• Pastore AL, Palleschi G, Silvestri L, et al. Serum and urine biomarkers for human renal cell carcinoma. Dis Markers. 2015; 2015: 251403.
• Garner JM, Herr MJ, Hodges KB, Jennings LK. The utility of tetraspanin CD9 as a biomarker for metastatic clear cell renal cell carcinoma. Biochem Biophys Res Commun. 2016 Feb 26;471(1):21-5.
• Butz H, Nofech-Mozes R, Ding Q, et al. Exosomal microRNAs are diagnostic biomarkers and can mediate cell-cell communication in renal cell carcinoma. European Urology Focus. 2016;2(2):210-218.
• Bauman TM, Huang W, Lee MH, Abel EJ. Neovascularity as a prognostic marker in renal cell carcinoma. Hum Pathol. 2016 Jul 16.
• Nientiedt M, Schmidt D, Kristiansen G, et al. YRNA expression profiles are altered in clear cell renal cell carcinoma. European Urology Focus. 2016 Aug 23.
• Templeton AJ, Knox JJ, Lin X, et al. Change in neutrophil-to-lymphocyte ratio in response to targeted therapy for metastatic renal cell carcinoma as a prognosticator and biomarker of efficacy. Eur Urol. 2016 Aug;70(2):358-64.
• Cornejo KM, Lu M, Yang P, et al. Succinate dehydrogenase B: a new prognostic biomarker in clear cell renal cell carcinoma. Hum Pathol. 2015 Jun;46(6):820-6.
• Rodrigues D, Monteiro M, Jerónimo C, et al. Renal cell carcinoma: a critical analysis of metabolomic biomarkers emerging from current model systems. Translational Research. Published online ahead of print August 2, 2016.
• Ascierto ML, McMiller TL, Berger AE, et al. The intratumoral balance between metabolic and immunologic gene expression is associated with anti-PD-1 response in patients with renal cell carcinoma. Immunology Research. 2016 Aug 4.