Clear Cell Renal Cell Carcinoma

In this study, we applied the iSCORED pipeline for ultrafast, genome-wide CNV information of renal tumors with results showing complete concordance with established CNV analysis methods. This method could facilitate pathological diagnosis and potentially inform targeted treatment in less than 2 hours. Future directions include expanding analyzed tumor types and integrating methylation classification into the pipeline.

Conclusions To our knowledge, we report the most sensitive analysis in terms of ctDNA detection in mRCC pt compared to published cohorts. Longitudinal ctDNA assessments could help picture disease evolution on therapy and help refine strategies.

Conclusions Overall, these preliminary data reveal a potential crosstalk between deregulated cancer cell proliferation and MARCO+Mφs in mediating disease progression and ICI resistance of ccRCC. Mechanistic experiments will be performed to confirm this assumption and to test whether targeting cancer cell-deregulated proliferation (e.g. by FDA-approved CDK4/6-TAs) could reshape ccRCC-mediated Mφ polarization and improve ICI efficacy.

The five identified DEGs serve as potential novel prognostic biomarkers for KIRC. However, the crucial factors that lead to the downregulation and functional inactivation of these five key genes need to be explored in future studies.

RRM2 was the most prognostic gene from the discovered novel risk score signature associated with subtypes. Future research is essential to validate these insights and their therapeutic implications for ccRCC management.

P1, N=30, Suspended, City of Hope Medical Center | Recruiting --> Suspended

In addition to the existing risk factors for RCC recurrence, such as sarcomatoid features and Fuhrman grade, we propose that the CALLY index is a predictor of postoperative recurrence and that patients with a low CALLY index are good candidates for postoperative treatment. Our study may help select patients with pT3 disease with a high risk of recurrence who require postoperative treatment.

Results Compared with the normal tissue,the ccRCC tissue showed up-regulated mRNA and protein levels of PSMB8 (both P<0.001),which were associated with the TNM stage of patients with ccRCC (P<0.001).Compared with the negative control group,overexpression of PSMB8 promoted the proliferation (P=0.021,P=0.039),migration and invasion (all P<0.001) of 786-O and ACHN cells,and the knockdown of PSMB8 inhibited the proliferation (P=0.022,P=0.005),migration and invasion (all P<0.001) of 786-O and ACHN cells.The pathway enrichment analysis of co-expressed genes of PSMB8 predicted the mitogen-activated protein kinase signaling pathway (P<0.001).After the knockdown of PSMB8,786-O and ACHN cells showed lowered phosphorylation levels of MEK1/2 (P=0.017,P=0.016) and ERK1/2 (P=0.010,P=0.040) and down-regulated transcription levels of ERK downstream factors c-Myc (P=0.043,P=0.038),c-Fos (P=0.025,P=0.008),and CyclinD1 (P=0.006,P=0.047).Compared with the ERK agonist C16-PAF group,the PSMB8 knockdown + C16-PAF group showed inhibited proliferation (P=0.003,P=0.002),migration and invasion (all P<0.001) of 786-O and ACHN cells. Conclusion PSMB8 may promote the proliferation,migration,and invasion of ccRCC cells by activating the MEK/ERK signaling pathway.

P1/2, N=51, Active, not recruiting, Roswell Park Cancer Institute | Trial completion date: Jan 2025 --> May 2025 | Trial primary completion date: Jan 2025 --> May 2025

P1, N=20, Recruiting, Icahn School of Medicine at Mount Sinai | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Sep 2026

Our findings clarified the adverse outcome induced by high expression of ITGA5 in ccRCC patients. In vitro experiments and bioinformatical analysis identified ITGA5 function as predominantly cell proliferation, migration, angiogenesis, and macrophage recruitment. Further, we predicted immune infiltration and medication sensitivity regulation by ITGA5 and proposed a joint use of ITGA5 inhibitors and anti-angiogenetic drugs as a potential potent therapeutic strategy.

P1, N=60, Completed, AstraZeneca | Active, not recruiting --> Completed | Trial completion date: Jan 2025 --> Oct 2024 | Trial primary completion date: Jan 2025 --> Oct 2024

The patient did not undergo adjuvant therapy, and a 6-month follow-up showed no signs of recurrence or metastasis. This case emphasizes the importance of considering extrarenal ccRCC in differential diagnoses of adrenal masses.

P2, N=69, Completed, Queen Mary University of London | Active, not recruiting --> Completed | N=181 --> 69 | Trial completion date: Mar 2023 --> Jul 2024 | Trial primary completion date: Mar 2023 --> Jul 2024

This study elucidates a novel mechanism through which the activation of PIEZO1 leads to calcium influx, subsequent calpain activation, and YAP nuclear translocation, thereby contributing to the progression of KIRC driven by matrix stiffness.

Thus, inducing the GABPA-ACSL4 pathway activates ferroptosis, inhibits proliferation or metastasis, and exerts anticancer activity in ccRCC. These findings have important implications for regulating ccRCC occurrence and development.

Our findings suggest that the state of CII, epitomized by its assembly and SDHB levels, deteriorates with the progressive severity of ccRCC. These observations hold the potential for stratification of patients with worse prognosis and may guide the exploration of targeted therapeutic interventions.

P3, N=1069, Active, not recruiting, Eisai Inc. | Trial completion date: Jul 2024 --> Mar 2026

P1, N=35, Recruiting, Orhan Kemal Oz | N=80 --> 35 | Trial completion date: Aug 2026 --> Aug 2027 | Trial primary completion date: Aug 2025 --> Aug 2026

Furthermore, ZZW115 could improve the response to the PD-1 immune checkpoint blockade. The results demonstrate that the ATF4/NUPR1 signaling axis promotes ccRCC survival and facilitates tumor-mediated immunosuppression, providing a set of potential targets and prognostic indicators for ccRCC patients.

P2, N=172, Active, not recruiting, NiKang Therapeutics, Inc. | Recruiting --> Active, not recruiting | Trial completion date: Sep 2026 --> Jun 2026 | Trial primary completion date: Jun 2026 --> Jun 2025

Additionally, we found that ATL-I could decrease the level of EPAS1, which was upregulated in sunitinib-resistant cells, thus reversing sunitinib resistance. Collectively, our findings demonstrate that ATL-I is a robust antiangiogenic and antitumor lead compound with potential clinical application for ccRCC therapy.

This study preliminarily evaluated FABP7 as a differential diagnostic biomarker in RCC subtyping, showing higher expression in ccRCC than non-ccRCC. FABP7 may serve as a potential diagnostic and prognostic biomarker for ccRCC.

SYNE1 contributes to the modulation of sorafenib resistance in ccRCC cells through interacting with BIN1. Decitabine treatment enhances expressions of these two proteins to improve TKI response, suggesting a potential strategy for counteracting resistance and bettering patient outcomes.

TFE3 rearrangement is an independent prognostic factor for recurrence and contributes to a worse PFS, suggesting the necessity of careful follow-up. Diagnosis should be confirmed using FISH due to low specificity of IHC. Further studies are needed to confirm TFE3 IHC staining as a prognostic factor.

Molecular docking studies identified rucaparib as a potential drug targeting ZBP1. Our research findings suggest that targeting ZBP1 could represent a novel therapeutic approach to inhibit the progression of ccRCC.

From the global proteomics data detected in ccRCC, we propose 99 DEPs including vimentin as progression factors.

These findings demonstrate that upregulated ARHGAP9 indicates poor prognosis and immune infiltration in ccRCC. The current findings suggest that ARHGAP9 can be an effective biomarker and potential therapeutic strategy for ccRCC.

P1/2, N=98, Active, not recruiting, Fox Chase Cancer Center | Trial completion date: Apr 2025 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Apr 2025

P=N/A, N=100, Recruiting, Centre Hospitalier Universitaire de Saint Etienne | Trial completion date: Aug 2024 --> Aug 2026 | Trial primary completion date: Aug 2024 --> Aug 2026

P3, N=1040, Not yet recruiting, Alliance for Clinical Trials in Oncology

P3, N=1175, Active, not recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Sep 2025 | Trial primary completion date: Sep 2024 --> Sep 2025

The CRCS2 subtype was in a hypoxic state and was characterized by suppression and exclusion of immune function, which was sensitive to gefitinib, erlotinib, and saracatinib. Our findings highlight the key role of CSCs in shaping the ccRCC tumor microenvironment, crucial for therapy research and clinical guidance. Recognizing tumor stemness helps to predict treatment efficacy, recurrence, and drug resistance, informing treatment strategies and enhancing ccRCC patient outcomes.

The findings reveal increased Lon expression and ROS levels in VHL-knockdown HK-2 cells, along with elevated phospho-c-Jun N-terminal kinase (JNK) levels, emphasizing the complex interplay between VHL, Lon protease, inflammation, and ROS in kidney cell models. These insights point to potential therapeutic pathways for ccRCC.

In conclusion, our comprehensive analysis identifies EVI2A as a promising biomarker and a novel therapeutic target for intervening in KIRC. These findings hold significant implications for further research and potential clinical applications.

VHL Miss mutations delineate an aggressive ccRCC subtype with distinct clinical outcomes, likely attributed to its specific oncogenic, morphologic and immunologic features.

Importantly, inhibiting PTPRZ1 enhanced the sensitivity of ccRCC to TKIs and PD-1 blockade, an effect that was attenuated when RNF26 was simultaneously knocked down. These findings highlight the critical role of the PTPRZ1-RNF26 axis in ccRCC and suggest that combining PTPRZ1 inhibitors with current TKIs and PD-1 blockade therapies could significantly improve treatment outcomes for ccRCC patients.

P=N/A, N=1200, Completed, RenJi Hospital

P1, N=17, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2026

P3, N=343, Active, not recruiting, AVEO Pharmaceuticals, Inc. | Trial completion date: Aug 2025 --> Jul 2026 | Trial primary completion date: Aug 2024 --> Apr 2024

SP3-461aa played a pivotal role in mediating the oncogenic effects of circSP3 by interacting with the MYH9 protein and activating the PI3K-Akt signaling pathway. These findings suggested that circSP3 plays an important role in ccRCC development and could be a potential biomarker for the treatment and prognosis of ccRCC.

This risk score and nomogram are valuable tools assessing KIRC patients' prognosis. Poorer prognosis in high-risk categories may have relationship with activation of coagulation pathway and a higher TMB.