Clear Cell Renal Cell Carcinoma

Its association with immune subtypes suggests a potential role in the tumor immune microenvironment. These findings support BIRC5 as a therapeutic target for cancer treatment.

The machine learning-based pathomics model effectively predicts the OS of ccRCC patients and differentiates between subtypes. The critical roles of the immune-related gene CTLA4 and the PI3K-Akt, HIF-1, and MAPK signaling pathways offer new insights for further research on the molecular mechanisms, diagnosis, and treatment strategies for ccRCC.

P2, N=118, Active, not recruiting, Peloton Therapeutics, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA) | Trial completion date: Aug 2025 --> Feb 2027 | Trial primary completion date: Aug 2025 --> Feb 2027

Loss of PBRM1, SMARCA2/BRM, and SMARCA4/BRG1 expression is significantly associated with ccRCC progression, with PBRM1 loss prevalent in advanced stages and SMARCA2/BRM and SMARCA4/BRG1 in earlier stages. ARID1A and SMARCA2/BRM losses correlate with reduced CD8 + counts and stage-specific CD4 + infiltration, highlighting their potential as biomarkers for disease progression and immunotherapeutic response.

P2, N=28, Recruiting, RenJi Hospital | Trial completion date: Jul 2026 --> Oct 2026

Overexpression of MICAL-L2 stimulated cell migration, proliferation, and rendered KIRC cells insensitive to sunitinib and everolimus, two traditional therapies for KIRC. Furthermore, MICAL-L2 overexpression accelerated cancer progression and resistance to therapy in KIRC cells by interacting with its downstream regulator α-actinin-4 (ACTN4) in a Rab13-dependent manner, which reduced the degradation of ACTN4, leading to increased Vimentin expression. All these findings indicate that MICAL-L2 plays a crucial role in the progression of KIRC and suggest that MICAL-L2 may serve as a potential therapeutic target for KIRC treatment.

While promising, these results require validation in larger, controlled studies due to sample size and variability limitations. This approach could enhance the radiogenomic assessment of ccRCC, supporting noninvasive insights into tumor metabolism and progression.

Our results demonstrate that OBP-801 promotes MHC class I presentation through LMP2 upregulation in tumor cells and thereby potentiates PD-1-targeting therapy. These data suggest that the combination of OBP-801 and anti-PD-1 treatment is a promising therapeutic strategy for ccRCC.

MRPL23 protein expression is a potential independent prognostic biomarker in ccRCC, emphasizing its utility in predicting patient outcomes and potentially guiding therapeutic decisions. These findings highlight the importance of further research into the role of MRPL23 in ccRCC pathogenesis and its potential as a therapeutic target.

This pilot study in ccRCC patients has demonstrated the safety, acceptable radiation dosimetry, favorable biodistribution, and exceptional tumor uptake of [18F]AlF-NYM005. The preliminary diagnostic study indicated the potential utility of [18F]AlF-NYM005 PET/CT, showing promising results in the diagnosis of primary or metastatic ccRCC.

As a result, the efficacy of anti-PD-1 immunotherapy is enhanced, leading to improved overall survival rates in syngeneic mouse tumor models. Overall, this finding suggest the clinical application of PB1-p62 and provide a novel approach for enhancing the effectiveness of immunotherapy in RCC patients with wild-type PBRM1.

Furthermore, we have also described the potential mechanism of action of LAMP1 in renal cancer. LAMP1 is a promising target for the treatment of ccRCC.

P2, N=31, Not yet recruiting, RenJi Hospital

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

In conclusion, our data demonstrate significant levels of CLDN3 expression in many different tumor entities and identify reduced CLDN3 expression as a potential prognostic marker in RCC.

In vivo, ALKBH5 was shown to enhance tumor growth and lung metastasis. Mechanistically, our studies suggest that ALKBH5 accelerates the malignant progression of ccRCC by binding to heterogeneous nuclear ribonucleoprotein D-like (HNRNPDL), facilitating the nuclear translocation of MEK, ERK, and p38, and activating downstream targets such as c-Myc and PCNA.

Our results suggest that immunosympathectomy is a novel approach to weaken tumor microenvironment immunosuppression and synergistically enhance CAR T-cell efficacy against solid tumors.

This study demonstrates that FBXO8 serves as a biomarker for KIRC and plays a role in regulating cell proliferation, migration, and apoptosis.

Spatial transcriptomics of samples of 3 patient cohorts with cRCC tumors indicates that COL4A1 and ITGAV are more autocorrelated in immunotherapy-exposed stroma compared to immunotherapy-naïve tumors, with high expression among fibroblasts, tumor cells, and endothelium. Further research is needed to understand changes in the ccRCC tumor immune microenvironment and explore potential therapeutic role of integrin after immunotherapy treatment.

In addition, dual-luciferase assays showed that the transcriptional activity of BEX4 was positively regulated by activation transcription factor 3 (ATF3). Our study suggests that BEX4 plays a role in inhibiting tumor progression in ccRCC and maybe a new diagnostic and therapeutic target for ccRCC patients.

P2, N=88, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Jan 2025 --> Jan 2027 | Trial primary completion date: Jan 2025 --> Jan 2027

The study corroborates that PAT and CAR's maximum radiodensity are independent markers for predicting Fuhrman grade, tumor size and SSIGN. These non-invasive methods are likely to improve traditional prognostic prediction and possibly effect new therapeutic strategies for patients with non-metastatic ccRCC.

P=N/A, N=3, Terminated, Gustave Roussy, Cancer Campus, Grand Paris | N=60 --> 3 | Trial completion date: Nov 2024 --> May 2024 | Recruiting --> Terminated | Trial primary completion date: Nov 2024 --> May 2024; Recruitment challenges: competition with another microbiome trial, patient refusal to join a dietary intervention study, poor tolerance of oral DPD (Grade 2 mucositis), and issues with organizing biological sample collection.

P1/2, N=12, Recruiting, Genenta Science

P1, N=31, Active, not recruiting, City of Hope Medical Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

This study shows that HLA-DRA and the M1/M2 ratio are indicators of favorable prognosis in patients with ccRCC. HLA-DRA promotes M1-like polarization by regulating NF-κB, which can be used as a therapeutic target to enhance anti-tumor immunity.

Presenilin enhancer gamma-secretase subunit (PSENEN), the straight target of metformin, is highly expressed in several cancers...PSENEN may be involved in regulating the immune microenvironment of KIRC, and oxidative phosphorylation may also be a pathway for its involvement in cancer development. PSENEN is a novel prognostic marker for KIRC.

P1, N=17, Active, not recruiting, National Heart, Lung, and Blood Institute (NHLBI) | Trial completion date: Dec 2032 --> Mar 2026

Furthermore, knocking down B7-H3 expression in renal cancer cells by siRNA and CRISPR/Cas resulted in lower 2D and 3D cell proliferation and viability as well as increased sensitivity to TKI axitinib. Together, our findings suggest a pro-oncogenic and immune evasive role for B7-H3 in ccRCC and highlight B7-H3 as an actionable novel immune checkpoint protein in combination with TKI in advanced renal cancer.

In vitro and in vivo assays both confirmed that the FOXD2-AS1/MYC/EGLN3 axis could accelerate the progression of ccRCC. FOXD2-AS1 activated EGLN3 to accelerate ccRCC cell functions via binding to the transcription factor MYC.

TiMER2 results indicated POP7 had a positive correlation with T cell regulatory (Tregs) and myeloid-derived suppressor cells (MDSC) in ccRCC and was an immunosuppressor for ccRCC. POP7 was a reliable immunosuppressor, predictor and biomarker for ccRCC.

Moreover, immune infiltration and expressions of Th1/IFNγ gene signature were also significantly different between the two clusters. Our study revealed m6A regulators were important participants in the development of ccRCC, with a close relationship with the TME.

This report highlights the importance of CENPK in ccRCC and sheds new light on the underlying mechanism of this cancer type. Therefore, CENPK has the potential to serve as a viable candidate target for treating ccRCC.

This study presents a novel three-gene prognostic model based on UBE2RGs that demonstrates significant predictive value for OS, immunotherapy, and chemotherapy in ccRCC patients. The findings underscore the potential of UBE2 family members as biomarkers and therapeutic targets in ccRCC, warranting further investigation in prospective clinical trials.

Our results show that PLCG2 functions as a potential biomarker and an independent prognostic indicator for ccRCC. PLCG2 may modulate angiogenesis by influencing the expression of VEGFA. Therefore, targeting PLCG2 could potentially lead to drug discovery and improved cancer treatment strategies.

No abstract available

P2, N=15, Not yet recruiting, M.D. Anderson Cancer Center

P1, N=12, Not yet recruiting, Kousai Bio Co., Ltd.

Importantly, single-cell RNA-sequencing (sc-RNA-seq) data demonstrated that surgical removal of the tumor increased antigen-presenting dendritic cell population with a concurrent reduction in KDM6B-expressing immune-suppressive myeloid cells in the peripheral blood. Together, this study highlighted the feasibility of combining ICT with cytoreductive surgery in a metastatic setting and demonstrated the potential enhancement of immune responses following ICT plus cytoreductive surgery in patients with metastatic disease.

We find that the expression of ERV3-16A3_LTR may itself be a negative prognostic biomarker in ccRCC. Our findings highlight the convergence of malignant epigenetic programs across ccRCC tumors and suggest that BAP1 loss, potentially through ERV3-16A3_LTR dysregulation, is associated with an IFN response-high epigenetic program.

Therefore, the non-accessibility of the histone methyltransferase activity domain of SET7 with IMPHY002979 can downregulate H3K4me1 and, thereby, the expression of genes potentially responsible for immunosuppressive TME. Thus, patient stratification based on molecular markers for immunotherapy and combining epigenetic modulators with therapeutic drugs will improve the efficacy of immunotherapy in ccRCC.

Furthermore, STAT2 was identified as a core component of a potential upstream transcriptional factor complex for SLC27A3. Our findings shed new light on the underlying mechanism of SLC27A3 in ccRCC TKI resistance, which may provide a novel therapeutic target for the management of ccRCC.