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Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression

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Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression Published OnlineFirst January 19, 2016; DOI: 10.1158/1078-0432.CCR-15-2115 Personalized Medicine and Imaging Clinical Cancer Research Alternate Metabolic Programs Define Regional Variation of Relevant Biological Features in Renal Cell Carcinoma Progression Samira A. Brooks1,2, Amir H. Khandani3,4, Julia R. Fielding3, Weili Lin3, Tiffany Sills5, Yueh Lee3, Alexandra Arreola1, Mathew I. Milowsky1,5, Eric M. Wallen1,5, Michael E. Woods3, Angie B. Smith5, Mathew E. Nielsen5, Joel S. Parker1,6, David S. Lalush4,7, and W. Kimryn Rathmell1,5,6 Abstract Purpose: Clear cell renal cell carcinoma (ccRCC) has recently microvessel density, as well as for features closely linked to been redefined as a highly heterogeneous disease. In addition to metabolic processes, such as GLUT1 and FBP1. In addition, gene genetic heterogeneity, the tumor displays risk variability for signatures linked with disease risk (ccA and ccB) also demon- developing metastatic disease, therefore underscoring the urgent strated variable heterogeneity, with most tumors displaying a need for tissue-based prognostic strategies applicable to the clin- dominant panel of features across the sampled regions. Intrigu- ical setting. We have recently employed the novel PET/magnetic ingly, the ccA- and ccB-classified samples corresponded with resonance (MR) image modality to enrich our understanding of metabolic features and functional imaging levels. These correla- how tumor heterogeneity can relate to gene expression and tumor tions further linked a variety of metabolic pathways (i.e., the biology to assist in defining individualized treatment plans. pentose phosphate and mTOR pathways) with the more aggres- Experimental Design: ccRCC patients underwent PET/MR sive, and glucose avid ccB subtype. imaging, and these images subsequently used to identify areas Conclusions: Higher tumor dependency on exogenous glucose of varied intensity for sampling. Samples from 8 patients were accompanies the development of features associated with the poor subjected to histologic, immunohistochemical, and microarray risk ccB subgroup. Linking these panels of features may provide the analysis. opportunity to create functional maps to enable enhanced visu- Results: Tumor subsamples displayed a range of heterogeneity alization of the heterogeneous biologic processes of an indivi- for common features of hypoxia-inducible factor expression and dual's disease. Clin Cancer Res; 22(12); 2950–9. Ó2016 AACR. Introduction subsampled tumors. These findings reveal a core mutational signature, which likely represents early or initiating events, cou- The heterogeneous biology of most cancers challenges tools pled with variable secondary mutations, some of which are that rely on single biopsy criteria for making disease-wide assess- presumed to be associated with disease progression (1, 2). Other ments. Sporadic clear cell renal cell carcinoma (ccRCC) has recent studies have suggested that single biopsies are inadequate recently been recognized to display a high level of genetic het- to fully evaluate the molecular and genetic features of ccRCC, erogeneity, based on high-throughput sequencing studies of implying the need for multiple sampling in biomarker develop- ment, or novel alternatives to assess the disease more globally in 1UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North an individual patient (3). 2 Carolina. Curriculum in Toxicology, University of North Carolina at In addition, recent studies have implicated changes in hyp- Chapel Hill, Chapel Hill, North Carolina. 3Department of Radiology, University of North Carolina, Chapel Hill, North Carolina. 4Department oxia-regulated gene expression, and key enzymes involved in of Radiology, Nuclear Medicine, University of North Carolina at Chapel cellular metabolic programs, as potential features linked with 5 Hill, North Carolina. Department of Urology, University of North progression (4, 5). In particular, the recent finding of lost Carolina at Chapel Hill, Chapel Hill, North Carolina. 6Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North fructose 1,6 bisphosphatase 1 (FBP1) expression in renal Carolina. 7Joint Department of Biomedical Engineering, The Univer- tumors implies that metabolic diversions are central to ccRCC sity of North Carolina at Chapel Hill and North Carolina State Univer- disease progression (6). The regional variation of these and sity, Chapel Hill, Raleigh, North Carolina. other relevant protein features of ccRCC, or the associations Note: Supplementary data for this article are available at Clinical Cancer with regional metabolic variation has not been explored pre- Research Online (http://clincancerres.aacrjournals.org/). viously. Here, we use PET with fluoridated 2-deoxyglucose Corresponding Authors: W. Kimryn Rathmell, University of North Carolina, (FDG) in combination with MRI for structural and anatomic 2220 Pierce Avenue, Preston Research Building, 798C Nashville, TN 37232. Phone: resolution, gene expression, and protein marker analysis. This 615-343-0250; Fax: 615-343-0250; E-mail: [email protected]; and approach permits evaluation of the potential for metabolic Amir H. Khandani, E-mail: [email protected] imaging to provide an assessment of disease biology on region- doi: 10.1158/1078-0432.CCR-15-2115 al variation in key physiologic mechanisms driving tumorigen- Ó2016 American Association for Cancer Research. esis and tumor heterogeneity. 2950 Clin Cancer Res; 22(12) June 15, 2016 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst January 19, 2016; DOI: 10.1158/1078-0432.CCR-15-2115 Metabolic Programs Define Biological Features in RCC obtained sequentially 5 mm in thickness with a 2 mm gap and Translational Relevance precontrast and postcontrast enhanced T1-weighted images The incidence of adult renal cell carcinoma (RCC), or kidney obtained as a volume and reviewed as 3 mm contiguous images cancer, is on a steady rise in the western world. There are in multiple planes. The dose of Gadolinium chelate (Gadopen- multiple subtypes of this disease, the most frequent type, clear tetate dimeglumine) was 0.1 mg/kg over 1 minute using a cell RCC (ccRCC), is closely linked to hypoxia signaling standard delay protocol. A power injector was used to deliver through the high-frequency loss of the VHL gene. ccRCC has contrast at 2 cc/second. This sequence was repeated twice along recently been redefined as a highly heterogeneous disease. the coronal (cor) and axial orientations, respectively. The image Here, we used PET with magnetic resonance (PET/MR) imag- parameters for the coronal orientation were as follows: repeti- ing to better understand how tumor heterogeneity affects tion time, 2 seconds; echo time (TE) 94 milliseconds; slice tumor biology through variations in hypoxia signaling, metab- thickness, 8 mm for 28 slices with 20% gap; matrix size, 256 olism, vascularity, and gene expression signatures to provide  256; acceleration factor of 3 using GRAPPA; flip angle, 150- fortitude toward individual patient treatment options. Utiliz- degree; and voxel size 2  1.6  8mm3. In contrast, with the ing these tools prior to surgical resection has the potential to exception of TE ¼ 95 milliseconds, number of slices ¼ 24, reveal links between biologic correlates and imaging para- acceleration factor ¼ 2, and voxel size ¼ 1.7  1.4  8mm3, meters that can prevent unnecessary invasive procedures and images acquired during a breath hold using an axial orientation enable enhanced knowledge of the relationships of heteroge- used identical parameters as that for coronal orientation. The neity and ccRCC. HASTE images were used for the placement of ROIs throughout the tumors. In contrast to MR imaging, a 4-minute single-bed PET acquisition covering the kidneys was acquired simulta- neously with the above outlined HASTE sequence. PET images were obtained on the same table again using a breath hold to Materials and Methods reduce motion interference. Postprocedure fusion of the MR Patients and clinical samples and PET images with coregistration was performed using a All patients were enrolled to an investigator-initiated trial, dedicated workstation (Siemens Medical Solutions). LCCC1213, using a UNC Biomedical IRB-approved consent. Enrollment criteria consisted of adequate organ function, radio- Image review fi fi graphic con rmation of a renal mass of suf cient size to allow Two physicians reviewed images, one a genitourinary imaging subsampling, and a scheduled surgery date. Patients were encour- specialist with 20 years' experience and the other a nuclear aged to be fasting at the time of the scan, and blood sugar was medicine specialist with 15 years of experience. Cases were tested prior to imaging. No patients were excluded because of reviewed using a standardized hanging protocol. The high-reso- hyperglycemia. In total, 13 patients were imaged, but only ccRCC lution MR images were used to identify anatomic structures. patients were included in the primary analysis (Supplementary Location of FDG and Gd uptake were identified, focusing on the Table S1 and S2), due to the markedly differing biology of other kidney tumor and local metastases. FDG uptake was quantified subtypes such as papillary RCC (5, 7, 8). using standard uptake value (SUV). An increase of 2 SUV was Specimens were collected from October 2012 through Septem- considered increased avidity. ber 2013 at the University of North Carolina directly
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