Chung-Han Lee

An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma

Dysregulated metabolism is a hallmark of cancer, manifested through alterations in metabolites. We performed metabolomic profiling on 138 matched clear cell renal cell carcinoma (ccRCC)/normal tissue pairs and found that ccRCC is characterized by broad shifts in central carbon metabolism, one-carbon metabolism, and antioxidant response. Tumor progression and metastasis were associated with metabolite increases in glutathione and cysteine/methionine metabolism pathways. We develop an analytic pipeline and visualization tool (metabolograms) to bridge the gap between TCGA transcriptomic profiling and our metabolomic data, which enables us to assemble an integrated pathway-level metabolic atlas and to demonstrate discordance between transcriptome and metabolome. Lastly, expression profiling was performed on a high-glutathione cluster, which corresponds to a poor-survival subgroup in the ccRCC TCGA cohort.

A systematic review of predictive and prognostic biomarkers for VEGF-targeted therapy in renal cell carcinoma

BACKGROUND Vascular endothelial growth factor (VEGF)-targeted therapy is the currently standard treatment for advanced and metastatic renal cell carcinoma (RCC). Multiple candidate predictive and prognostic biomarkers have been evaluated. We performed a systematic review and graded the available evidence on the biomarkers for VEGF-targeted therapy in RCC. METHODS We conducted an independent review of PubMed and ASCO databases up to August 2013. Studies were included if biomarkers obtained from metastatic clear-cell RCC patients treated with the FDA-approved VEGF-targeted therapy were assessed for their correlation with clinical outcomes. We graded the studies and determined the Level-of-evidence for each biomarker using a previously published framework. RESULTS A total of 50 articles were selected for this review. Seven studies assessed the predictive value of biomarkers using the archived specimens from randomized controlled trials. Five predictive biomarkers, such as VEGF, interleukin (IL)-6, hepatocyte growth factor (HGF), osteopontin, single nucleotide polymorphisms in IL-8, satisfied Level II evidence. IL-6 is the most corroborated predictive biomarker based on its consistent predictive value in two different trials. The prognostic value of biomarkers was assessed in 48 studies using the archived specimens from clinical trials, prospective and retrospective observational registries. Three biomarkers, including IL-8, HGF and osteopontin, satisfied Level I evidence for PFS. CONCLUSION Though several promising predictive biomarkers for VEGF-targeted therapy have been found, none of them has satisfied the determination of Level I evidence. A more focused development of biomarkers with prospective assessment in clinical trials and clear intent of use in clinical practice is needed.

Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Genomic studies have linked mTORC1 pathway-activating mutations with exceptional response to treatment with allosteric inhibitors of mTORC1 called rapalogs. Rapalogs are approved for selected cancer types, including kidney and breast cancers. Here, we used sequencing data from 22 human kidney cancer cases to identify the activating mechanisms conferred by mTOR mutations observed in human cancers and advance precision therapeutics. mTOR mutations that clustered in focal adhesion kinase targeting domain (FAT) and kinase domains enhanced mTORC1 kinase activity, decreased nutrient reliance, and increased cell size. We identified 3 distinct mechanisms of hyperactivation, including reduced binding to DEP domain-containing MTOR-interacting protein (DEPTOR), resistance to regulatory associated protein of mTOR-mediated (RAPTOR-mediated) suppression, and altered kinase kinetics. Of the 28 mTOR double mutants, activating mutations could be divided into 6 complementation groups, resulting in synergistic Rag- and Ras homolog enriched in brain-independent (RHEB-independent) mTORC1 activation. mTOR mutants were resistant to DNA damage-inducible transcript 1-mediated (REDD1-mediated) inhibition, confirming that activating mutations can bypass the negative feedback pathway formed between HIF1 and mTORC1 in the absence of von Hippel-Lindau (VHL) tumor suppressor expression. Moreover, VHL-deficient cells that expressed activating mTOR mutants grew tumors that were sensitive to rapamycin treatment. These data may explain the high incidence of mTOR mutations observed in clear cell kidney cancer, where VHL loss and HIF activation is pathognomonic. Our study provides mechanistic and therapeutic insights concerning mTOR mutations in human diseases.

A Phase Ib Study of BEZ235, a Dual Inhibitor of Phosphatidylinositol 3-Kinase (PI3K) and Mammalian Target of Rapamycin (mTOR), in Patients With Advanced Renal Cell Carcinoma

Lessons Learned Our results highlight additional toxicities of dual PI3K/mTOR inhibition in the clinical setting that were unforeseen from preclinical models. Because of toxicity and lack of efficacy, BEZ235 should not be further developed in the current formulation for patients with renal cell carcinoma. Background. Allosteric inhibitors of the mammalian target of rapamycin complex 1 (mTORC1) are approved for advanced renal cell carcinoma (RCC). Preclinical models have suggested that dual inhibition of phosphatidylinositol 3-kinase (PI3K) and mTOR kinase may establish superior anticancer effect. We aimed to establish safety for BEZ235, a potent inhibitor of both PI3K and mTOR, in advanced RCC. Methods. Patients with advanced RCC who had previously failed standard therapy received escalating doses of BEZ235 in sachet formulation twice daily until progression or unacceptable toxicity. Primary endpoints were to identify the maximally tolerated dose (MTD) and to determine the recommended dose for the phase II study. Results. The study was terminated early because of high incidence of dose-limiting toxicities (DLTs) across all dose levels tested. Ten patients were treated with BEZ235—six with clear cell and four with non-clear cell subtypes. Five of these patients suffered DLTs: 2 of 2 patients in the original 400 mg b.i.d. cohort, 1 of 6 in the 200 mg b.i.d. cohort, and 2 of 2 in the 300 mg b.i.d. cohort. DLTs included fatigue, rash, nausea and vomiting, diarrhea, mucositis, anorexia, and dysgeusia. Five patients were evaluable for response: Two had stable disease as best response, and three had progressive disease. Conclusion. BEZ235 twice daily resulted in significant toxicity without objective responses; further development of this compound will not be pursued in this disease.

Phase II Trial and Correlative Genomic Analysis of Everolimus Plus Bevacizumab in Advanced Non–Clear Cell Renal Cell Carcinoma

Purpose The decreased effectiveness of single-agent targeted therapies in advanced non-clear cell renal cell carcinoma (ncRCC) compared with clear cell renal cell carcinoma (RCC) supports the study of combination regimens. We evaluated the efficacy of everolimus plus bevacizumab in patients with metastatic ncRCC. Patients and Methods In this single-center phase II trial, treatment-naive patients received everolimus 10 mg oral once per day plus bevacizumab 10 mg/kg intravenously every 2 weeks. The primary end point was progression-free survival (PFS) at 6 months. Correlative analyses explored candidate tissue biomarkers through next-generation sequencing. Results Thirty-five patients were enrolled with the following histologic subtypes: chromophobe (n = 5), papillary (n = 5), and medullary (n = 2) RCC and unclassified RCC (uRCC, n = 23). The majority of patients had papillary growth as a major component (n = 14). For 34 evaluable patients, median PFS, overall survival, and objective response rate (ORR) were 11.0 months, 18.5 months, and 29%, respectively. PFS varied by histology ( P < .001), and ORR was higher in patients with significant papillary (seven of 18) or chromophobe (two of five) elements than for others (one of 11). Presence of papillary features were associated with benefit, including uRCC, where it correlated with ORR (43% v 11%), median PFS (12.9 v 1.9 months), and overall survival (28.2 v 9.3 months; P < .001). Several genetic alterations seemed to segregate by histology. In particular, somatic mutations in ARID1A were seen in five of 14 patients with papillary features but not in other RCC variants. All five patients achieved treatment benefit. Conclusion The study suggests efficacy for this combination in patients with ncRCC characterized by papillary features. Distinct mutational profiles among ncRCCs vary according to specific histology.

Circulating biomarkers and outcome from a randomised phase II trial of sunitinib vs everolimus for patients with metastatic renal cell carcinoma

Background:RECORD-3 assessed non-inferiority of progression-free survival (PFS) with everolimus vs sunitinib in previously untreated patients with metastatic renal cell carcinoma. Baseline plasma sample collection and randomised design enabled correlation of circulating biomarkers with efficacy.Methods:Samples were analysed for 121 cancer-related biomarkers. Analyses of biomarkers categorised patients as high or low (vs median) to assess association with first-line PFS (PFS1L) for each treatment arm. A composite biomarker score (CBS) incorporated biomarkers potentially predictive of PFS1L with everolimus.Results:Plasma samples from 442 of the 471 randomised patients were analysed. Biomarkers were associated with PFS1L for everolimus alone (29), sunitinib alone (9) or both (12). Everolimus-specific biomarkers (CSF1, ICAM1, IL-18BP, KIM1, TNFRII) with hazard ratio ⩾1.8 were integrated into a CBS (range 0–5). For CBS low (0–3, n=291) vs high (4–5, n=151), PFS1L differed significantly for everolimus but not for sunitinib. There was no significant difference in PFS1L between everolimus and sunitinib in the high CBS patient cohort.Conclusions:Baseline levels of multiple soluble biomarkers correlated with benefit from everolimus and/or sunitinib, independent of clinical risk factors. A similar PFS1L was observed for both treatments among patients with high CBS score.

Immune Checkpoint Therapy in Renal Cell Carcinoma.

AbstractRenal cell carcinoma (RCC) is a largely chemotherapy-resistant disease that is commonly treated with molecularly targeted therapies. Evidence suggests that RCC is also an immune-responsive disease, and checkpoint inhibitors are in active development as agents for the treatment of systemic disease. Programmed cell death 1 (PD-1) is an inhibitory immune checkpoint, and blockade of the PD-1 cascade is an attractive target in RCC. Expression of the ligand for PD-1 in RCC has been shown to be a negative prognostic factor; however, response to PD-1 blockade is not restricted to tumors expressing the ligand for PD-1. Nivolumab is the most completely characterized anti–PD-1 agent in RCC and has been shown to be efficacious as monotherapy. Currently, there are multiple ongoing clinical trials exploring the use of combination therapy with PD-1 blockade.

Genomic Characterization of Renal Medullary Carcinoma and Treatment Outcomes

Micro‐Abstract Renal medullary carcinoma (RMC) is a rare kidney cancer with poor outcomes. We analyzed treatment outcomes in patients with RMC and performed targeted sequencing of tumors to identify unique molecular features. Although responses to platinum‐based therapy were found, these were short‐lived. There was uniform loss of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through translocations and deletions, and further research should go into targeting this pathway. Background: Renal medullary carcinoma (RMC) is a rare and aggressive type of kidney cancer that primarily affects young adults with sickle cell trait; outcomes are poor despite treatment. Identifying molecular features of this tumor could provide biologic rationale for novel targeted therapies. The objective was to report on clinical outcomes with systemic therapy and characterize molecular features. Patients and Methods: This was a retrospective analysis on 36 patients given a pathologic diagnosis of RMC at one institution from 1995 to 2015. Tumors were analyzed for expression of SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily B, Member 1 (SMARCB1) through immunohistochemistry and for genomic alterations with fluorescence in situ hybridization for SMARCB1, and targeted next‐generation sequencing. Time from initiation of therapy to progression of disease and overall survival were calculated using the Kaplan–Meier method. Results: The median age in the cohort was 28 (range, 12‐72) years, and all patients tested had sickle cell trait. Overall survival was 5.8 months (95% confidence interval [CI], 4.1‐10.9) and for 12 patients who received platinum‐based therapy, median progression‐free survival was 2.5 months (95% CI, 1.2‐not reached). A total of 10 available tumors underwent analysis with fluorescence in situ hybridization for SMARCB1; this revealed loss of heterozygosity with concurrent translocation in 8, and biallelic loss in 2. Next‐generation targeted sequencing showed no recurring mutations. Conclusions: Outcome was generally poor in this cohort of patients with RMC. Uniform loss of SMARCB1 is a key molecular feature in this tumor and mechanism of loss appears to be mostly through translocations and deletions.

Prevalence of Germline Mutations in Cancer Susceptibility Genes in Patients With Advanced Renal Cell Carcinoma

Importance Identification of patients with hereditary renal cell carcinoma (RCC) is important for cancer screening and, in patients with advanced disease, for guiding treatment. The prevalence of cancer-related germline mutations in patients with advanced RCC and the phenotypes associated with some rare mutations are unknown. Objectives To examine the prevalence of germline mutations in both known RCC predisposition genes and other cancer-associated genes and to identify clinical and pathologic factors associated with germline mutations. Design, Setting, and Participants In this cohort study conducted from October 1, 2015, to July 31, 2017, 254 of 267 patients with advanced (American Joint Committee on Cancer stage III or IV) RCC who were seen in medical oncology or urology clinics agreed to germline sequencing and disclosure of results under an institutional protocol of matched tumor-germline DNA sequencing. Main Outcomes and Measures Mutation prevalence and spectrum in patients with advanced RCC were determined. Clinical characteristics were assessed by mutation status. Results Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB). The most frequent mutations were CHEK2 (n = 9) and FH (n = 7). Of genes not previously associated with RCC risk, CHEK2 was overrepresented in patients compared with the general population, with an odds ratio of RCC of 3.0 (95% CI, 1.3-5.8; P = .003). Patients with non–clear cell RCC were significantly more likely to have an RCC-associated gene mutation (9 [11.7%] of 74 vs 3 [1.7%] of 177; P = .001), and 8 (10.0%) had a mutation in a gene that could guide therapy. Of patients with mutations in RCC-associated genes, 5 (35.7%) failed to meet current clinical guidelines for genetic testing. Conclusions and Relevance Of patients with non–clear cell RCC, more than 20% had a germline mutation, of which half had the potential to direct systemic therapy. Current referral criteria for genetic testing did not identify a substantial portion of patients with mutations, supporting the role of a more inclusive sequencing approach.

Persistent Severe Hyperlactatemia and Metabolic Derangement in Lethal SDHB-Mutated Metastatic Kidney Cancer: Clinical Challenges and Examples of Extreme Warburg Effect

PurposeTo describe the unique clinical features, determine the genomics, and investigate the metabolic derangement of an extremely rare form of a hereditary lethal kidney cancer syndrome.Patients and MethodsThree patients with lethal kidney cancer (age 19, 20, and 37 years) exhibiting persistent (1 to 3 months) extremely high levels of blood lactate (> 5 mM) despite normal oxygen perfusion, highly avid tumors on [18F]fluorodeoxyglucose positron emission tomography (PET), and pleomorphic histopathologic features were identified and treated in a single institute. Integrated studies including whole-genome sequencing (WGS), targeted sequencing, immunohistochemistry, cell-based assays, and 18F-glutamine PET imaging were performed to investigate this rare kidney cancer syndrome.ResultsAll three patients with kidney cancer were initially given various diagnoses as a result of diverse tumor histopathology and atypical clinical presentations. The correct diagnoses of these SDHB-mutated renal cell carcinomas were f...