Advanced ccRCC Research Articles

First-in-human clinical trial design of a first-in-class theranostic approach with a peptide-based radioligand targeting CA IX-expressing tumors.

TPS3160 Background: Expression of carbonic anhydrase IX (CA IX), a cell surface glycoprotein, can be induced by a state of hypoxia or by mutation of the Von Hippel-Lindau tumor suppressor gene. CAIX expression in tumors is often associated with progressive disease and overall poor outcomes in various solid cancers. Notably, high CA IX expression has been observed in 83%, 40%, and 29% of clear cell renal cell carcinoma (ccRCC), pancreatic ductal adenocarcinoma (PDAC), and colorectal cancer (CRC) specimens, respectively1. CA IX may therefore represent a valuable therapeutic target. DPI-4452 is a first-in-class cyclic peptide that binds with high affinity to CA IX. Radiolabeling DPI-4452 with gallium-68 ([68Ga]Ga-DPI-4452) or lutetium-177 ([177Lu]Lu-DPI-4452) is an innovative theranostic approach for identifying and treating patients (pts) with CA IX-expressing tumors. Pre-clinical data has shown that [177Lu]Lu-DPI-4452 is taken up by tumors and induces dose-dependent growth inhibition in ccRCC and CRC xenograft mouse models1,2. Methods: We present the design of a Phase I/II study (NCT05706129) of [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452 in pts with unresectable locally advanced or metastatic ccRCC, CRC or PDAC. The study is comprised of three phases: imaging (Part A), dose-escalation (Part B), and expansion (Part C). In Part A, pts will receive a single intravenous (IV) 185 MBq dose of [68Ga]Ga-DPI-4452. Safety, tolerability, pharmacokinetics (PK), dosimetry and imaging characteristics of [68Ga]Ga-DPI-4452 will be evaluated using positron emission tomography/computed tomography (CT) at four timepoints on Day 1. All pts will be followed for seven days post-injection for safety observations. In Part B, based on [68Ga]Ga-DPI-4452 uptake, pts will receive sequential, escalating doses of IV [177Lu]Lu-DPI-4452 on Day 1 of each 28-day cycle for up to eight cycles. During Cycle 1, each pt will undergo up to four whole-body planar imaging and single photon emission CT/CT analyses for dosimetry over seven days. In Part B, the recommended Phase 2 dose of [177Lu]Lu-DPI-4452 will be determined, guided by a Bayesian Logistic Regression model. Safety, PK, and dosimetry will be assessed to minimize any radiation-induced toxicity and to optimize absorbed radiation dose in the tumor. Upon completion of Part B, Part C will enroll up to three cohorts of pts with CA IX-positive ccRCC, CRC or PDAC to assess preliminary efficacy of [177Lu]Lu-DPI-4452, with a primary endpoint of objective response rate, as measured by RECIST v1.1. References Wiedemann N et al. J Nucl Med 2022;63(Suppl 2):4048. Attinger A et al. Eur J Nucl Med Mol Imaging 2022;49(Suppl 1):S1–S751. Clinical trial information: NCT05706129 .

Prognostic prediction and immunotherapy response analysis of the fatty acid metabolism-related genes in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (ccRCC) is a common urinary cancer. Although diagnostic and therapeutic approaches for ccRCC have been improved, the survival outcomes of patients with advanced ccRCC remain unsatisfactory. Fatty acid metabolism (FAM) has been increasingly recognized as a critical modulator of cancer development. However, the significance of the FAM in ccRCC remains unclear. Herein, we explored the function of a FAM-related risk score in the stratification and prediction of treatment responses in patients with ccRCC. MethodsFirst, we applied an unsupervised clustering method to categorize patients from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets into subtypes and retrieved FAM-related genes from the MSigDB database. We discern differentially expressed genes (DEGs) among different subtypes. Then, we applied univariate Cox regression analysis followed by least absolute shrinkage and selection operator (LASSO) linear regression based on DEGs expression to establish a FAM-related risk score for ccRCC. ResultsWe stratified the three ccRCC subtypes based on FAM-related genes with distinct overall survival (OS), clinical features, immune infiltration patterns, and treatment sensitivities. We screened nine genes from the FAM-related DEGs in the three subtypes to establish a risk prediction model for ccRCC. Nine FAM-related genes were differentially expressed in the ccRCC cell line ACHN compared to the normal kidney cell line HK2. High-risk patients had worse OS, higher genomic heterogeneity, a more complex tumor microenvironment (TME), and elevated expression of immune checkpoints. This phenomenon was validated in the ICGC cohort. ConclusionWe constructed a FAM-related risk score that predicts the prognosis and therapeutic response of ccRCC. The close association between FAM and ccRCC progression lays a foundation for further exploring FAM-related functions in ccRCC.

Excavation of diagnostic biomarkers and construction of prognostic model for clear cell renal cell carcinoma based on urine proteomics.

Clear cell renal cell carcinoma (ccRCC) is the most common pathology type in kidney cancer. However, the prognosis of advanced ccRCC is unsatisfactory. Thus, early diagnosis becomes one of the most important research priorities of ccRCC. However, currently available studies about ccRCC lack urine-related further studies. In this study, we applied proteomics to search urinary biomarkers to assist early diagnosis of ccRCC. In addition, we constructed a prognostic model to assist judge patients' prognosis. Urine which was used to perform 4D label-free quantitative proteomics was collected from 12 ccRCC patients and 11 non-tumor patients with no urinary system diseases. The urine of 12 patients with ccRCC confirmed by pathological examination after surgery was collected before operatoin. Bioinformatics analysis was used to describe the urinary proteomics landscape of these patients with ccRCC. The top ten proteins with the highest expression content were selected as the basis for subsequent validation. Urine from 46 ccRCC patients and 45 control patients were collected to use for verification by enzyme linked immunosorbent assay (ELISA). In order to assess the prognostic value of urine proteomics, a prognostic model was constructed by COX regression analysis on the intersection of RNA-sequencing data in The Cancer Genome Atlas (TCGA) database and our urine proteomic data. 133 proteins differentially expressed in the urinary samples were found and 85 proteins (Fold Change, FC>1.5) were identified up-regulated while 48 down-regulated (FC<0.5). Top 10 proteins including S100A14, PKHD1L1, FABP4, ITIH2, C3, C8G, C2, ATF6, ANGPTL6, F13B were performed ELISA to verify. The results showed that PKHD1L1, ANGPTL6, FABP4 and C3 were statistically significant (P<0.05). We performed multivariate logistic regression analysis and plotted a nomogram. Receiver operating characteristic (ROC) curve indicted that the diagnostic efficiency of combined indicators is satisfactory (Aare under curve, AUC=0.835). Furthermore, the prognostic value of the urine proteomics was explored through the intersection between urine proteomics and TCGA RNA-seq data. Thus, COX regression analysis showed that VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 were statistically significant (P<0.05). Our study indicated that the application of urine proteomics to explore diagnostic biomarkers and to construct prognostic models of renal clear cell carcinoma is of certain clinical value. PKHD1L1, ANGPTL6, FABP4 and C3 can assist to diagnose ccRCC. The prognostic model constituted of VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 can significantly predict the prognosis of ccRCC patients, but this still needs more clinical trials to verify.

Identification and validation of fatty acid metabolism-related lncRNA signatures as a novel prognostic model for clear cell renal cell carcinoma

Clear cell renal cell carcinoma (ccRCC) is a main subtype of renal cancer, and advanced ccRCC frequently has poor prognosis. Many studies have found that lipid metabolism influences tumor development and treatment. This study was to examine the prognostic and functional significance of genes associated with lipid metabolism in individuals with ccRCC. Using the database TCGA, differentially expressed genes (DEGs) associated with fatty acid metabolism (FAM) were identified. Prognostic risk score models for genes related to FAM were created using univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses. Our findings demonstrate that the prognosis of patients with ccRCC correlate highly with the profiles of FAM-related lncRNAs (AC009166.1, LINC00605, LINC01615, HOXA-AS2, AC103706.1, AC009686.2, AL590094.1, AC093278.2). The prognostic signature can serve as an independent predictive predictor for patients with ccRCC. The predictive signature's diagnostic effectiveness was superior to individual clinicopathological factors. Between the low- and high-risk groups, immunity research revealed a startling difference in terms of cells, function, and checkpoint scores. Chemotherapeutic medications such lapatinib, AZD8055, and WIKI4 had better outcomes for patients in the high-risk group. Overall, the predictive signature can help with clinical selection of immunotherapeutic regimens and chemotherapeutic drugs, improving prognosis prediction for ccRCC patients.

Abstract CT011: A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC)

Abstract Background: While doublet therapies provide important first-line treatment options in metastatic renal cell carcinoma (mRCC), novel and mechanistically distinct agents are needed for pts who are not cured by/intolerant of such therapies. Due to the high incidence (~80%) of CD70 antigen expression in primary and mRCC, yet limited expression in normal tissue, ccRCC is an attractive proof-of-concept tumor for CD70 directed allogeneic CAR T. TRAVERSE (NCT04696731), a first-in-human trial, seeks to identify a maximum tolerated dose (MTD) of ALLO-316 after conditioning with fludarabine/cyclophosphamide with/without ALLO-647 in pts with advanced or metastatic ccRCC. ALLO-316 is an anti-CD70 allogeneic CAR T cell product that utilizes TALEN® gene editing to knock out TCRα constant gene to reduce the risk of graft-versus-host disease (GvHD) and knock out CD52 gene to permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells without affecting allogeneic CAR T cells. Methods: This multicenter, single-arm, open-label, 3+3 dose-escalation trial enrolls adults with advanced or metastatic ccRCC and ≥1 measurable lesion and ECOG Performance Status 0 or 1. Prior treatment with an immune checkpoint inhibitor and a vascular endothelial growth-factor targeted therapy was required, with evidence of progression on/after treatment or discontinuation due to toxicity. ALLO-316 is administered at escalating doses (40 - 240 × 106 allogeneic CAR+ cells IV) on Day 0 after conditioning. The primary endpoint is a target incidence rate for dose-limiting toxicities (DLTs) &amp;lt;33% in the first 28 days after infusion of ALLO-316. Results: By 12/3/2022, 18 pts with ccRCC (median age: 63 yrs; 82% male) were enrolled; all (100%) 17 pts who received ALLO-316, had metastatic disease with 3 lines (median) of prior therapy. Eleven (65%) of these pts experienced CRS, all low Gr except one (6%) Gr 3. No ICANS or GVHD was observed. One (6%) DLT (elevated LFT) was observed and required dose expansion. MTD has not yet been reached. Three pts achieved best overall response of PR at all time points with two PRs confirmed at subsequent visits; ORR = 12% and disease control rate (DCR) = 71%. In pts with confirmed CD70+ tumors (n=9), confirmed ORR = 22% (unconfirmed ORR = 33%) and DCR = 100%. High CAR T cell expansion was observed in peripheral blood (median Cmax &amp;gt; 35,000 copies/μg) and high VCN in available tumor aspirates (n=3). Conclusions: ALLO-316, an allogeneic CAR T cell product targeting CD70 in advanced mRCC, is demonstrating encouraging antitumor activity and a manageable safety profile. A single administration of ALLO-316 could be an effective treatment for pts with CD70+ solid tumors, including RCC, and hematologic malignancies. The MTD for ALLO-316 in TRAVERSE will support Phase 2 trial design. Enrollment of pts with CD70+ tumors is ongoing. Citation Format: Samer Srour, Ritesh Kotecha, Brendan Curti, Jad Chahoud, Alexandra Drakaki, Lily Tang, Lovely Goyal, Sacha Prashad, Victoria Szenes, Kevin Norwood, Sumanta Pal. A phase 1 multicenter study (TRAVERSE) evaluating the safety and efficacy of ALLO-316 following conditioning regimen in pts with advanced or metastatic clear cell renal cell carcinoma (ccRCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT011.

BAP1-related signature predicts benefits from immunotherapy over VEGFR/mTOR inhibitors in ccRCC: a retrospective analysis of JAVELIN Renal 101 and checkmate-009/010/025 trials.

In patients with advanced clear cell renal cell carcinoma, despite the undoubted benefits from immune checkpoint inhibitor (ICI)-based therapies over monotherapies of angiogenic/mTOR inhibitors in the intention-to-treat population, approximately a quarter of the patients can scarcely gain advantage from ICIs, prompting the search for predictive biomarkers for patient selection. Clinical and multi-omic data of 2428 ccRCC patients were obtained from The Cancer Genome Atlas (TCGA, n = 537), JAVELIN Renal 101 (avelumab plus axitinib vs. sunitinib, n = 885), and CheckMate-009/010/025 (nivolumab vs. everolimus, n = 1006). BAP1 mutations were associated with large progression-free survival (PFS) benefits from ICI-based immunotherapies over sunitinib/everolimus (pooled estimate of interaction HR = 0.71, 95% CI 0.51-0.99, P = 0.045). Using the top 20 BAP1 mutation-associated differentially expressed genes (DEGs) generated from the TCGA cohort, we developed the BAP1-score, negatively correlated with angiogenesis and positively correlated with multiple immune-related signatures concerning immune cell infiltration, antigen presentation, B/T cell receptor, interleukin, programmed death-1, and interferon. A high BAP1-score indicated remarkable PFS benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors (avelumab plus axitinib vs. sunitinib: HR = 0.55, 95% CI 0.43-0.70, P < 0.001; nivolumab vs. everolimus: HR = 0.72, 95% CI 0.52-1.00, P = 0.045), while these benefits were negligible in the low BAP1-score subgroup (HR = 1.16 and 1.02, respectively). In advanced ccRCCs, the BAP1-score is a biologically and clinically significant predictor of immune microenvironment and the clinical benefits from ICI-based immunotherapies over angiogenic/mTOR inhibitors, demonstrating its potential utility in optimizing the personalized therapeutic strategies in patients with advanced ccRCC.

Abstract 275: Harnessing chemerin signaling as a novel therapeutic vulnerability in ccRCC

Abstract Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive subtype of kidney cancer, accounting for 70-80% of the cases. While surgical resection of early-stage tumors remains the standard care for patients, advanced ccRCC, metastatic or recurrent, portends a 5-year survival rate of only 12%, primarily due to insensitivity toward conventional chemotherapy. ccRCC is identifiable histologically by its dramatic lipid storage phenotype, similar to adipocytes; yet the role of lipid metabolism in ccRCC is poorly understood. One of the well-established risk factors for ccRCC is obesity and given that adipose tissue is known to produce a variety of pro-adipogenic signaling molecules (called adipokines), we hypothesized that adipokine signaling might be involved in the etiology of ccRCC. We recently identified a pro-tumorigenic adipokine protein, chemerin (RARRES2), that is positively correlated with tumor aggressiveness. Suppression of chemerin via either monoclonal antibody or siRNA led to reduction in lipid storage and significant tumor growth impairment in both in vitro and in vivo models by inducing ferroptosis. We next investigated the signaling mechanisms of chemerin and have found that chemerin drives downstream cellular activities and lipid deposition through either of the two receptors, GPR1 and CMKRL1. We further demonstrated that chemerin signals to both receptors to drive the expression adipose triglyceride lipase (ATGL) that frees up fatty acid from lipid depositions. In addition, Chemerin/CMKLR1 signaling axis further drives the activation of SREBP-mediated lipogenesis pathway. By using a small molecule antagonist specific for CMKRL1, α-NETA, we could suppress ccRCC tumor growth by inhibiting intracellular lipid droplet formation both in vitro and in vivo through the activation of ATGL-mediated lipolysis pathway and suppression of SREBP-mediated lipogenesis pathway. We have therefore shown the possibility of targeting Chemerin/CMKLR1 axis both genetically and pharmacologically to suppress the growth of ccRCC by increasing ferroptosis. Overall, our studies have identified chemerin/CMKLR1 axis as a promising therapeutic target that weakens ccRCC by modulating its lipid metabolic profiles and validated such vulnerability by using a more clinically relevant PDX orthotopic model. Further mechanistic investigations revealed overlapping yet distinct pathways downstream of chemerin that could potentially yield combinational strategies to treat ccRCC patients. Citation Format: Dazhi Wang, Scott Welford, James Brugarolas, Sze K. Tan. Harnessing chemerin signaling as a novel therapeutic vulnerability in ccRCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 275.

Abstract 631: Single-cell analysis of immune and stroma cell remodeling in renal cell carcinoma primary tumors and bone metastatic lesions

Abstract Background: Renal cell carcinoma (RCC) is the most common renal tumor in adults, and among these clear cell RCC (ccRCC) is most common subtype and accounts for most renal cancer-related deaths. One-third of patients with advanced ccRCC present with bone metastases at the time of diagnosis. Despite therapeutic advances, once cancer has metastasized to the bone, it represents a highly morbid and ultimately lethal disease. Comprehensive genomic studies in ccRCC have provided important insights into the somatic alterations and intra-tumor heterogeneity. However, the bone metastatic niche in humans, including the immune and stromal microenvironments, has not been well-defined. Methods: We collected fresh patient samples directly from the operating room and performed single-cell transcriptomic profiling of human ccRCC tumors (ccRCC primary), solid metastatic tissue (Bone Met), liquid bone marrow at the vertebral level of spinal cord compression (Involved), liquid bone marrow from a different vertebral body distant from the tumor site but within the surgical field (Distal), as well as bone marrow stroma cells from patients undergoing hip replacement surgery (Benign) as control. We provide a comparative single cell transcriptomic analysis between ccRCC primary tumors and bone metastatic lesions. Results: Comparison of malignant cells from primary and metastatic sites reveal a distinct transcriptional signature that is predictive of metastatic potential and patient survival. The bone marrow in metastatic patients has sustained immune-suppressive microenvironment, featuring increased, exhausted CD8+ cytotoxic T-cells, T-regulatory cells and tumor-associated macrophages (TAM) with distinct transcriptional states in metastatic lesions. Bone marrow stroma from tumor samples demonstrated a tumor-associated mesenchymal stromal cell population (TA-MSC) that appears to be supportive of epithelial-to mesenchymal transition (EMT), bone remodeling, and a cancer-associated fibroblast (CAFs) phenotype. This stromal subset is associated with poor progression-free and overall survival, markedly upregulates bone remodeling through the dysregulation of RANK/RANKL/OPG signaling activity in bone cells, ultimately leading to bone resorption. Conclusions: These results provide insights into mechanisms underlying of ccRCC tumors progression leading bone metastasis. We also highlight potential communication channels and therefore therapeutic targets within both the immune and the tumor cell populations. Citation Format: Shenglin Mei, Adele M. Alchahin, Ioanna Tsea, Youmna Kfoury, Taghreed Taghreed, Hirak Sarkar, Shulin Wu, Alexander O. Subtelny, Yida Zhang, Keyan Salari, Chin-Lee Wu, Mark A. Randolph, David T. Scadden, Douglas Dahl, John Shin, Peter Kharchenko, Philip Saylor, David Sykes, Ninib Baryawno. Single-cell analysis of immune and stroma cell remodeling in renal cell carcinoma primary tumors and bone metastatic lesions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 631.

MP04-10 MACHINE LEARNING PREDICTS METABOLIC BIOMARKERS OF RESPONSE TO ANTI-VEGF DRUG SUNITINIB IN CCRCC

You have accessJournal of UrologyCME1 Apr 2023MP04-10 MACHINE LEARNING PREDICTS METABOLIC BIOMARKERS OF RESPONSE TO ANTI-VEGF DRUG SUNITINIB IN CCRCC Katiana Vazquez-Rivera, X. Amy Xie, Stephen Reese, Ritesh Kotecha, Martin Voss, Robert Motzer, Wesley Tansey, Ari Hakimi, and Ed Reznik Katiana Vazquez-RiveraKatiana Vazquez-Rivera More articles by this author , X. Amy XieX. Amy Xie More articles by this author , Stephen ReeseStephen Reese More articles by this author , Ritesh KotechaRitesh Kotecha More articles by this author , Martin VossMartin Voss More articles by this author , Robert MotzerRobert Motzer More articles by this author , Wesley TanseyWesley Tansey More articles by this author , Ari HakimiAri Hakimi More articles by this author , and Ed ReznikEd Reznik More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003215.10AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is a metabolic disease with multiple mutated genes involved in the regulation of cellular metabolic processes, however it remains unknown how ccRCC metabolites are associated with response to anti-VEGF or immunotherapy agents. Metabolomic signatures may serve as a biomarker of response or serve as future points of intervention for targeted agents. Thus, we sought to characterize metabolite signatures associated with response to anti-VEGF therapy in patients with ccRCC. METHODS: A machine learning algorithm called T-MIRTH (Transcriptomics-Metabolite Imputation via Rank-Transformation and Harmonization) was developed to identify key metabolites. In short, this algorithm imputes metabolite abundances from RNA sequencing data by modeling metabolite-RNA covariation across datasets with paired metabolomics and transcriptomics data. 262 well-predicted metabolites were used to test the association between imputed levels of individual metabolites by T-MIRTH and progression free survival (PFS) in 7 published sunitinib clinical trials in advanced ccRCC. Using a multivariable Cox proportional hazard model, metabolomic signatures were correlated with progression-free survival and regression results were aggregated using a random effects meta-analysis model. RESULTS: Our T-MIRTH algorithm was validated using 3 ccRCC datasets with paired metabolomics and transcriptomics data and we demonstrated that T-MIRTH can accurately predict metabolite levels using RNA sequencing data. We then demonstrated using the ccRCC TCGA that T-MIRTH predicted metabolic differences between both tumor/normal samples and high/low-stage samples. Our algorithm was able to identify 262 validated metabolites. The results from our meta-analysis across 7 clinical trial demonstrated 7 metabolites significantly associated with improved PFS in the sunitinib arm (FDR < 0.05). In particular, high levels of 1-methylimidazole acetate had improved PFS within the sunitinib arm across all trials. CONCLUSIONS: Using a novel algorithm, we identified 7 metabolites that were associated with improved PFS in patients treated with sunitinib across 7 clinical trials. These metabolites may serve as biomarkers of response and may also be important targets for future therapeutics. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e37 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Katiana Vazquez-Rivera More articles by this author X. Amy Xie More articles by this author Stephen Reese More articles by this author Ritesh Kotecha More articles by this author Martin Voss More articles by this author Robert Motzer More articles by this author Wesley Tansey More articles by this author Ari Hakimi More articles by this author Ed Reznik More articles by this author Expand All Advertisement PDF downloadLoading ...

MP04-09 NOVEL INHIBITOR OF PRO-SURVIVAL PROTEIN PHOSPHATASE 5 (PP5) LEADS TO APOPTOSIS IN CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyCME1 Apr 2023MP04-09 NOVEL INHIBITOR OF PRO-SURVIVAL PROTEIN PHOSPHATASE 5 (PP5) LEADS TO APOPTOSIS IN CLEAR CELL RENAL CELL CARCINOMA Elham Ahanin, Rebecca A. Sager, Sarah J. Backe, Natela Dushukyan, Michael Daneshvar, Gennady Bratslavsky, John Chisholm, Mark R. Woodford, Dimitra Bourboulia, and Mehdi Mollapour Elham AhaninElham Ahanin More articles by this author , Rebecca A. SagerRebecca A. Sager More articles by this author , Sarah J. BackeSarah J. Backe More articles by this author , Natela DushukyanNatela Dushukyan More articles by this author , Michael DaneshvarMichael Daneshvar More articles by this author , Gennady BratslavskyGennady Bratslavsky More articles by this author , John ChisholmJohn Chisholm More articles by this author , Mark R. WoodfordMark R. Woodford More articles by this author , Dimitra BourbouliaDimitra Bourboulia More articles by this author , and Mehdi MollapourMehdi Mollapour More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003215.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Despite good survival rates for localized renal cell carcinoma a proportion of patients present with or will progress to metastatic disease, which portends worse prognosis and poor overall survival. Survival has been improved with the use of new targeted therapies and immunotherapy regimens; many patients, however, ultimately develop resistance. There is therefore a need for identification and development of new therapeutics. Clear cell renal cell carcinoma (ccRCC), the most common histologic subtype, generally harbors loss of the tumor suppressor von Hippel Lindau (VHL). The serine/threonine protein phosphatase-5 (PP5) plays a role in the regulation of numerous signaling pathways essential for cancer growth. Previously we have shown that PP5 is targeted for ubiquitination and degradation by a VHL-containing E3 ubiquitin ligase complex in a hypoxia-independent manner. Expression and activity of PP5 is consequently increased in ccRCC, and it plays a pro-survival role. Knock-down of PP5 expression or targeting its activity through inhibition of the kinase casein kinase-1δ (CK1δ) caused apoptosis in VHL-null ccRCC. The objective of this study was to develop a novel PP5 inhibitor for ccRCC. METHODS: An in silico docking screen using the crystal structure of the PP5 active site and a large compound library was used to screen for candidate inhibitors. A series of candidates were then evaluated using both in vitro and cell-based assays for their ability to inhibit PP5 activity and cause apoptosis in ccRCC cells. In vitro PP5 activity was assessed using specific phospho-peptide substrates and in cells by immunoblotting to assess phosphorylation levels of known substrates. Two primary candidates were conjugated to biotin for PP5 pulldown experiments to assess specificity. RESULTS: Our in silico screen identified approximately 200 candidate inhibitors. Further screening of about 20 of these compounds identified two compounds, P5 and P13, which inhibit PP5 activity both in vitro and in ccRCC cells and were further refined based on structure. Pulldown using biotin-conjugated drugs demonstrated good inhibitor specificity. Furthermore, treatment with these inhibitors leads to apoptosis specifically in VHL-null ccRCC cell lines. CONCLUSIONS: PP5 promotes cell survival in ccRCC and knockdown or inhibition of PP5 leads to cellular apoptosis. We have identified a small molecule which specifically binds to and inhibits PP5. This novel PP5 inhibitor causes apoptosis in VHL-null ccRCC cells and may serve as a new therapeutic strategy for treatment of advanced ccRCC. Source of Funding: This work was supported by the National Institute of General Medical Sciences of the National Institutes of Health under award numbers R35GM139584 (M.M.) and DoD KC190038 (M.M.) © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e36 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Elham Ahanin More articles by this author Rebecca A. Sager More articles by this author Sarah J. Backe More articles by this author Natela Dushukyan More articles by this author Michael Daneshvar More articles by this author Gennady Bratslavsky More articles by this author John Chisholm More articles by this author Mark R. Woodford More articles by this author Dimitra Bourboulia More articles by this author Mehdi Mollapour More articles by this author Expand All Advertisement PDF downloadLoading ...

Dynamic and immunocytochemistry analysis of circulation tumor cells (CTCs) in blood samples from patients with advanced ccRCC starting first-line treatment in a Brazilian Cancer Center.

704 Background: Treatment of advanced clear cell renal carcinoma (ccRCC) improved dramatically in the last 20 years, but biomarkers development lagged behind. Circulating tumor cell (CTC) is used as a prognostic and predictive tool in many solid tumors but is poorly studied in ccRCC. Objective: Our aim was to evaluate CTC counts in serial blood samples from patients with advanced ccRCC that started first-line treatment and analyze the protein expression of PBRM1, BAP1, PD-L1 and CD133 in these cells. Methods: Blood samples (10mL) were collected in EDTA tubes at three different timepoints, 30 days apart, after treatment start. We used a filtration technique (ISET system, Rarecells/France) to isolate and collect CTCs. Protein expression was evaluated by immunocytochemistry. Results: Twelve patients were included. All had detectable CTCs at baseline (1st blood draw), with a median of 1.5 CTCs/mL. Patients with CTCs above the median had ≥2 metastatic sites (p=0.015) and worse progression free survival (PFS) (19.7 vs 31.1 months, p=0.35), although the difference was not statistically different. Favorable CTCs kinetics at the time of first follow-up (2nd blood draw) indicated better PFS (24.76 months) versus unfavorable (6.65 months; p=0.014). PBRM-1, BAP-1 and PD-L1 expression in CTCs was associated with better overall survival (OS), although without statistical significance. CD133 expression in CTCs at baseline was associated with worse OS (p=0.08). Conclusions: CTCs isolation was feasible in advanced ccRCC patients starting first-line treatment and were frequently detected by ISET method. CTC counts at baseline and at 30 days after treatment initiation had prognostic implication, as well as its dynamic evaluation after 30 days of treatment with a favorable kinetics associated with better outcome.

Phase 3 LITESPARK-022: Pembrolizumab (pembro) plus hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan as adjuvant treatment for clear cell renal cell carcinoma (ccRCC).

TPS748 Background: Treatment with the PD-1 inhibitor pembro produced significant improvement in disease-free survival after surgery for patients (pts) with ccRCC in the phase 3 KEYNOTE-564 trial. Based on these results, pembro was approved by the US Food and Drug Administration and the European Medicines Agency for adjuvant treatment of pts with RCC at increased risk of recurrence following nephrectomy or following nephrectomy and resection of metastatic lesions. Despite advances in the treatment landscape for RCC, more effective adjuvant treatment strategies are needed for pts at risk of recurrence after surgery. HIF-2α is an established oncogenic driver in ccRCC, and promising antitumor activity in advanced ccRCC and von Hippel-Lindau disease–associated RCC has been demonstrated with the HIF-2α inhibitor belzutifan. The multicenter, double-blind, randomized, phase 3 LITESPARK-022 study (NCT05239728) will evaluate the efficacy and safety of pembro plus belzutifan compared with placebo plus pembro as adjuvant treatment following nephrectomy in pts with ccRCC. Methods: Key eligibility criteria include adults with histologically or cytologically confirmed intermediate-high risk, high risk, or M1 with no evidence of disease (NED) RCC with a clear cell component; pts with no prior systemic therapy, nephrectomy, and/or metastasectomy ≤12 weeks before randomization; and pts who are tumor free per computed tomography/magnetic resonance imaging. Approximately 1600 pts will be randomly assigned to receive belzutifan 120 mg orally once daily plus pembro 400 mg intravenously (IV) every 6 weeks (Q6W) for ≤9 administrations (~54 weeks) or oral placebo plus pembro 400 mg IV Q6W for ≤9 administrations (~54 weeks) or until verified disease recurrence by blinded independent central review, start of new anticancer treatment, unacceptable toxicity, or decision to withdraw. Stratification factors are tumor grade (1 or 2 vs 3 or 4) and risk type (intermediate-high risk versus high risk versus M1 NED). Pts will be radiologically evaluated Q12W from randomization through year 2, Q16W in years 3 to 5, and Q24W in years 6 and beyond. Adverse events will be monitored throughout the study and for 30 days following cessation of study treatment (90 days for serious adverse events). The primary end point is disease-free survival. Secondary end points include overall survival, safety, disease recurrence–specific survival, and patient-reported outcomes. Recruitment is underway in Asia, Australia, Europe, North America, and South America. © 2022 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2022 ASCO Annual Meeting. All rights reserved. Clinical trial information: NCT05239728 .

Molecular characteristics of advanced clear cell renal cell carcinoma (ccRCC) harboring TERTmutations.

706 Background: There is a large unmet need for identifying prognostic and predictive biomarkers in advanced RCC. TERT is a catalytic subunit of the telomerase enzyme and TERT promoter mutations lead to increased telomerase activity, which promotes tumorigenesis by preventing telomere shortening. Emerging data suggests a correlation between TERT promoter mutations (pTERTmut) and improved responses to immune checkpoint inhibitors in urothelial carcinoma (UC), while there is paucity of such data in RCC. This study aims to analyze the immune biomarker environment and co-mutational landscape in TERT mutated versus wild-type RCC. Methods: A retrospective analysis of patients with advanced ccRCC who completed sequencing with the Tempus xT assay (DNA-seq of 648 genes at 500x coverage, full transcriptome RNA-seq) was performed. De-identified data was analyzed for presence of pTERTmut, all other TERT mutations (otherTERT), and TERT wildtype (wtTERT). Companion alterations and immune biomarkers were compared between these three groups. Results: A total of 866 samples was analyzed, with 58% from primary renal lesions and 42% from a metastatic site. The frequency of all TERT mutations was 8.2% (71/866). pTERTmut was present in 5.6% (28/502) of primary and 5.5% (20/364) of metastatic sites, while otherTERT was present in 3.0% (15/502) of primary and 2.2% (8/364) of metastatic sites. Tumor mutational burden (TMB) was performed in 764 samples and only 0.4% had TMB greater than 10 m/MB, all of which were wtTERT. Median TMB was 2.08 m/MB across all samples, with 1.91 m/MB in pTERTmut, 1.72 m/MB in otherTERT, and 2.31 m/MB in wtTERT. Only 0.2% of 834 samples harbored MSI-high and 1.4% of 295 samples were mismatch repair deficient (dMMR), all of which were wtTERT. PD-L1 status was available in 439 samples, with 14% scored as positive (PD-L1+) with a combined positive score &gt;10. Of PD-L1+, 4.8% was in pTERTmut, 3.2% in otherTERT, and 92.1% in wtTERT. Neoantigen tumor burden of all non-silent mutations was evaluated in 698 samples, with a median value of 2.11 in pTERTmut, 1.58 in otherTERT, and 2.11 in wtTERT. PBRM1 co-mutations were noted in 22.9% of samples with pTERTmut, 21.7% in otherTERT, and 33.2% in wtTERT. Additional RCC co-mutations are listed in the table. RCC mRNA and UC cohort data analysis is in progress. Conclusions: This is the largest analysis of the molecular and immune landscape of TERT mutated ccRCC. Interestingly, this dataset showcases that traditional immune biomarkers (TMB, MSI, dMMR, and PD-L1) do not appear to be highly prevalent in RCC and their use in clinical practice may be limited. Further investigation into the TERT biomarker candidate is warranted. [Table: see text]

Final results of phase Ib/II study of durvalumab and guadecitabine in advanced clear cell renal cell carcinoma (ccRCC) and biomarker analysis.

696 Background: Hypomethylating agents (HMA) can augment the anti-tumor immune response. Guadecitabine (G) is a novel HMA shown to induce a dose-dependent decrease of global DNA and gene-specific methylation in pre-clinical models. Methods: This is phase Ib/II clinical trial of Guadecitabine (G) and Durvalumab (D) in advanced ccRCC. Phase Ib tested two doses of G, de-escalated from 60 mg/m2 to 45 mg/m2 in combination with standard dose of D. Followed by two cohorts in phase II. Cohort 1 (C1, CPI naïve) allowed up to one prior line of treatment and Cohort 2 (C2, CPI refractory) enrolled patients with up to two prior systemic therapies including at least one CPI. Primary endpoint in phase 1b was safety, primary endpoint in phase II was overall response rate (ORR) and secondary endpoint of progression free survival (PFS) and overall survival (OS) and biomarkers evaluation. Results: Fifty-seven patients were enrolled, 42 were in C1 and 15 in C2. One dose limiting toxicity (DLT) of grade 3 neutropenia was noted with G 60 mg/m2. The combination of G 45 mg/m2 on days 1-5 along with D at 1500 mg on day 8, was deemed safe and the recommended phase II dose. Asymptomatic neutropenia was the most common adverse event (AE). Other AEs included thyroid dysfunction, diarrhea, pneumonitis, myalgia, and hepatotoxicity. No treatment-related deaths were reported. The ORR for C1 and C2 were 26% and 7% respectively. The median PFS for C1 and C2 were 18.4 and 3.9 months respectively. Median OS was not reached. Flow cytometry on peripheral blood (PB) collected before treatment demonstrated myeloid-derived suppressor cells (MDSC) to be inversely associated with response, showing the highest levels in progressive disease (PD) and the lowest in partial response (PR). Responders to treatment had the highest expression of IFN γ, IL-17 and RORyt in CD8+ T cells and lower Foxp3 expression in CD4+ T cells compared to non-responders. We observed a significant increase in serum CXCL9/CXCL10 with the study combination (p 0.00003 and p 0.000005 respectively) and this increase correlated with better clinical outcome. Conclusions: The combination of D and G has an acceptable toxicity profile and promising efficacy mainly PFS in CPI naïve ccRCC patients, that is worth further investigation in larger randomized clinical trial. Clinical trial information: NCT03308396 .

A pilot trial evaluating the rapid sequencing of approved therapies in patients (pts) with advanced clear cell renal cell carcinoma (ccRCC).

TPS751 Background: Five doublet combinations incorporating immune checkpoint inhibitor (ICI) with or without tyrosine kinase inhibitor (TKI) are now approved for the first line treatment (tx) of advanced ccRCC. In COSMIC-313, the triplet combination with cabozantinib (CABO)-ipilimumab (IPI)-nivolumab (NIVO) demonstrated promising efficacy compared to IPI-NIVO in pts with intermediate/poor risk disease, but definitive overall survival (OS) benefit has yet to be shown, and is associated with higher incidence of adverse events. Currently, the optimal first /subsequent lines of therapies remain to be defined, and predictive biomarker to guide optimal tx approach is urgently needed. Pre-clinical studies allude to the ability of TKIs, such as CABO, to promote an immune-permissive environment and thus enhance ICI response. This open-label, single-arm, investigator-initiated pilot trial will evaluate the rapid sequencing from CABO to IPI-NIVO with the hypothesis of enhanced efficacy when compared to IPI-NIVO doublet, and potentially lower toxicity when compared to the concurrent triplet combination. Correlative studies, before and after administration of each systemic therapy, will be performed with the goal of identifying potential predictive biomarkers of response and resistance. Methods: Advanced, ccRCC pts will be treated with CABO 60mg PO once daily (QD) for 12 weeks (W) followed by IPI 1mg/kg + NIVO 3mg/kg IV every (Q)3W for 4 cycles. Subsequent therapy is dependent on response, and can be NIVO 480mg IV Q4W (CR/PR/SD), lenvatinib 18mg + everolimus 5mg PO QD (PD on both prior regimens), or re-initiation of CABO 60mg PO QD (CR/PR/SD at CABO but PD on IPI-NIVO). Key inclusion criteria are histologically confirmed, metastatic or unresectable RCC with predominantly clear cell component (sarcomatoid differentiation &lt;50%), tx naïve in the advanced disease setting, and measurable disease per RECIST 1.1 criteria. IMDC or MSKCC favorable, intermediate, and poor risk groups are included. Pts with active CNS disease or contraindications to CABO, IPI, and/or NIVO are excluded. Tumor biopsies and blood/urine samples will be collected for correlative studies. The primary endpoint is efficacy of the sequential approach, based on overall response rate (ORR) as assessed by investigator per RECIST 1.1. The ORR will be estimated by a two-sided 95% confidence interval. The trial plan to enroll 20 pts, which will allow us to estimate a range of plausible ORRs from 0.42 to 0.62 with a precision of ±0.23. Additional efficacy endpoints (ORR per modified RECIST for immune response, duration of response, progression free survival, OS), safety, pt reported outcomes, correlative biomarkers and their association with clinical outcome as determined by tumor immune/genomic profiling will also be evaluated. The trial is currently enrolling pts. Clinical trial information: NCT05188118 .

Immunohistochemical Detection of 5T4 in Renal Cell Carcinoma.

5T4 (trophoblast glycoprotein encoded by TPBG ) is a cancer/testis antigen highly expressed in renal cell carcinoma (RCC) and many other cancers but rarely in normal tissues. Interest in developing 5T4 as a prognostic biomarker and direct targeting of 5T4 by emerging receptor-engineered cellular immunotherapies has been hampered by the lack of validated 5T4-specific reagents for immunohistochemistry (IHC). We tested 4 commercially available monoclonal antibodies (mAbs) for the detection of 5T4 in formalin-fixed, paraffin-embedded RCC and normal tissues. Using parental and TPBG -edited A498 cells, 3 mAbs showed 5T4 specificity. Further analyses focused on 2 mAbs with the most robust staining (MBS1750093, Ab134162). IHC on tissue microarrays incorporating 263 renal tumors showed high staining concordance of these 2 mAbs ranging from 0.80 in chromophobe RCC to 0.89 in advanced clear cell RCC (ccRCC). MBS1750093, the most sensitive, exhibited 2+/3+ staining in papillary RCC (92.2%) > advanced ccRCC (60.0%) > chromophobe RCC (43.6%) > localized ccRCC (39.6%) > oncocytoma (22.7%). RNA in situ hybridization also revealed high levels of TPBG RNA were present most frequently in papillary and advanced ccRCC. In advanced ccRCC, there was a trend towards higher 5T4 expression and regional or distant metastases. Normal organ controls showed no or weak staining with the exception of focal moderate staining in kidney glomeruli and distal tubules by IHC. These data identify mAbs suitable for detecting 5T4 in formalin-fixed, paraffin-embedded tissues and demonstrate both interpatient and histologic subtype heterogeneity. Our validated 5T4 IHC protocol will facilitate biomarker studies and support the therapeutic targeting of 5T4.

The role of immunotherapy in non-clear cell renal cell carcinoma.

The category of non-clear cell renal cell carcinoma (nccRCC) includes several clinically, histologically, and molecularly diverse entities. Traditionally, they comprise type 1 and type 2 papillary, chromophobe, unclassified, and other histologies (medullary, collecting duct carcinoma, and translocation-associated). Molecular knowledge has allowed the identification of some other specific subtypes, such as fumarate hydratase-deficient renal cell carcinoma (RCC) or succinate dehydrogenase-associated RCC. In addition, it has recognized some alterations with a possible predictive role, e.g., MET proto-oncogene receptor tyrosine kinase (MET) alterations in papillary tumors. Standard therapies for the management of advanced clear cell RCC (ccRCC), i.e., vascular endothelial growth factor receptor (VEGFR) pathway inhibitors and mammalian target of rapamycin inhibitors, have shown poorer results in nccRCC patients. Therefore, there is a need to improve the efficacy of the treatment for advanced nccRCC. Immunotherapy, especially immune checkpoint inhibitors (ICIs) targeting programmed death 1/programmed death ligand 1 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4), has demonstrated a significant survival benefit in several malignant neoplasias, including ccRCC, with a proportion of patients achieving long survival. The combinations of ICI or ICI + VEGFR tyrosine kinase inhibitors (TKIs) are the standard of care in advanced ccRCC. Unfortunately, major pivotal trials did not include specific nccRCC populations. In recent years, several studies have retrospectively or prospectively evaluated ICIs alone or in combination with another ICI or with TKIs in nccRCC patients. In this article, we review data from available trials in order to elucidate clinical and molecular profiles that could benefit from immunotherapy approaches.

Druggable Biomarkers Altered in Clear Cell Renal Cell Carcinoma: Strategy for the Development of Mechanism-Based Combination Therapy.

Targeted therapeutics made significant advances in the treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Resistance and serious adverse events associated with standard therapy of patients with advanced ccRCC highlight the need to identify alternative 'druggable' targets to those currently under clinical development. Although the Von Hippel-Lindau (VHL) and Polybromo1 (PBRM1) tumor-suppressor genes are the two most frequently mutated genes and represent the hallmark of the ccRCC phenotype, stable expression of hypoxia-inducible factor-1α/2α (HIFs), microRNAs-210 and -155 (miRS), transforming growth factor-beta (TGF-ß), nuclear factor erythroid 2-related factor 2 (Nrf2), and thymidine phosphorylase (TP) are targets overexpressed in the majority of ccRCC tumors. Collectively, these altered biomarkers are highly interactive and are considered master regulators of processes implicated in increased tumor angiogenesis, metastasis, drug resistance, and immune evasion. In recognition of the therapeutic potential of the indicated biomarkers, considerable efforts are underway to develop therapeutically effective and selective inhibitors of individual targets. It was demonstrated that HIFS, miRS, Nrf2, and TGF-ß are targeted by a defined dose and schedule of a specific type of selenium-containing molecules, seleno-L-methionine (SLM) and methylselenocystein (MSC). Collectively, the demonstrated pleiotropic effects of selenium were associated with the normalization of tumor vasculature, and enhanced drug delivery and distribution to tumor tissue, resulting in enhanced efficacy of multiple chemotherapeutic drugs and biologically targeted molecules. Higher selenium doses than those used in clinical prevention trials inhibit multiple targets altered in ccRCC tumors, which could offer the potential for the development of a new and novel therapeutic modality for cancer patients with similar selenium target expression. Better understanding of the underlying mechanisms of selenium modulation of specific targets altered in ccRCC could potentially have a significant impact on the development of a more efficacious and selective mechanism-based combination for the treatment of patients with cancer.

Identification and Validation of the Prognostic Panel in Clear Cell Renal Cell Carcinoma Based on Resting Mast Cells for Prediction of Distant Metastasis and Immunotherapy Response.

Clear cell renal cell carcinoma (ccRCC) has a high metastatic rate, and its incidence and mortality are still rising. The aim of this study was to identify the key tumor-infiltrating immune cells (TIICs) affecting the distant metastasis and prognosis of patients with ccRCC and to construct a relevant prognostic panel to predict immunotherapy response. Based on ccRCC bulk RNA sequencing data, resting mast cells (RMCs) were screened and verified using the CIBERSORT algorithm, survival analysis, and expression analysis. Distant metastasis-associated genes were identified using single-cell RNA sequencing data. Subsequently, a three-gene (CFB, PPP1R18, and TOM1L1) panel with superior distant metastatic and prognostic performance was established and validated, which stratified patients into high- and low-risk groups. The high-risk group exhibited lower infiltration of RMCs, higher tumor mutation burden (TMB), and worse prognosis. Therapeutically, the high-risk group was more sensitive to anti-PD-1 and anti-CTLA-4 immunotherapy, whereas the low-risk group displayed a better response to anti-PD-L1 immunotherapy. Furthermore, two immune clusters revealing distinct immune, clinical, and prognosis heterogeneity were distinguished. Immunohistochemistry of ccRCC samples verified the expression patterns of the three key genes. Collectively, the prognostic panel based on RMCs is able to predict distant metastasis and immunotherapy response in patients with ccRCC, providing new insight for the treatment of advanced ccRCC.

Multi-omics profiles refine L-dopa decarboxylase (DDC) as a reliable biomarker for prognosis and immune microenvironment of clear cell renal cell carcinoma.

Increasing evidence indicates that L-dopa decarboxylase (DDC), which mediates aberrant amino acid metabolism, is significantly associated with tumor progression. However, the impacts of DDC are not elucidated clearly in clear cell renal cell carcinoma (ccRCC). This study aimed to evaluate DDC prognostic value and potential mechanisms for ccRCC patients. Transcriptomic and proteomic expressions of and clinical data including 532 patients with ccRCC (The Cancer Genome Atlas RNA-seq data), 226 ccRCC samples (Gene Expression Omnibus), 101 ccRCC patients from the E-MTAB-1980 cohort, and 232 patients with ccRCC with proteogenomic data (Fudan University Shanghai Cancer Center) were downloaded and analyzed to investigate the prognostic implications of DDC expression. Cox regression analyses were implemented to explore the effect of DDC expression on the prognosis of pan-cancer. The "limma" package identified the differentially expressed genes (DEGs) between high DDC subgroups and low DDC groups. Functional enrichments were performed based DEGs between DDC subgroups. The differences of immune cell infiltrations and immune checkpoint genes between DDC subgroups were analyzed to identify potential influence on immune microenvironment. We found significantly decreased DDC expression in ccRCC tissues compared with normal tissues from multiple independent cohorts based on multi-omics data. We also found that DDC expression was correlated with tumor grades and stages.The following findings revealed that lower DDC expression levels significantly correlated with shorter overall survival (P <0.001) of patients with ccRCC. Moreover, we found that DDC expression significantly correlated with an immunosuppressive tumor microenvironment, higher intra-tumoral heterogeneity, elevated expression of immune checkpoint CD274, and possibly mediated malignant behaviors of ccRCC cells via the PI3k/Akt signaling pathway. The present study is the first to our knowledge to indicate that decreased DDC expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that DDC could serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC.