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.

Improvements in ORR and PFS for L+P versus sunitinib in aRCC were observed consistently across a range of biomarker subgroups defined using RCC driver mutations, PD-L1, gene expression signatures, and molecular subtypes.

Our study elucidated a previously unidentified mechanism of lenvatinib action and identified the RRP15-KBTBD8 axis as a novel therapeutic target in HCC, offering new avenues for treatment strategies in combating HCC.

Molecular docking studies with Aurora-A Kinase revealed binding behaviors similar to the co-crystallized ligand sunitinib. Finally, this scaffold exhibits cytotoxic activity via apoptosis, enzyme downregulation, and suppression of cell division.

Sunitinib for c-KIT mutations did not meet the primary end point, but in this small sample size, a potential signal cannot be ruled out. Rate of eligible c-KIT mutations was low, affecting accrual to this arm.

Notably, the IKBKE inhibitor CYT387 restores sunitinib sensitivity in RCC cells by downregulating RRM2 expression. Collectively, these results indicate that inhibition of IKBKE restrains RCC progression and enhances sunitinib sensitivity by downregulating RRM2 through the RRM2-AKT pathway, suggesting that IKBKE may be a potential therapeutic target for RCC.

All the target compounds were evaluated against CAIX enzyme compared to dorzolamide and acetazolamide, subsequently the most potent CAIX inhibitors (3a, 3b, 3o, 6d, 6g, and 6i) were selected to evaluate their inhibitory activity against VEGFR-2 using sorafenib as a reference drug. Physicochemical predictions were examined using in silico techniques. In conclusion, these scaffolds present promising leads and furnish promising chemical backbones for the design of potent dual CAIX and VEGFR-2 inhibitors.b.

P=N/A, N=146, Recruiting, Tianjin Medical University Cancer Institute and Hospital | N=80 --> 146

P3, N=252, Recruiting, Sun Yat-sen University

We also show that MEN1703 downregulates stromal cytokines that promote cytokine-mediated resistance of AML blast cells to FLT3 inhibition. These results demonstrate the importance of the combination approach to overcome microenvironment-mediated resistance to FLT3 inhibitors.

AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.

Fifteen new synthetic spiro[benzofuran-3,3'-pyrroles] were prepared, character-ized, and evaluated for cytotoxicity affinities against FMS-like tyrosine kinase 3. Compound 12e showed strong binding affinity and potent inhibitory activity (IC50 = 2.5 μM), making it a promising candidate for further development as a therapeutic option for AML treatment. These findings lay the groundwork for further optimization and development of spiro[benzo-furan-3,3'-pyrroles] derivatives as potential therapeutics for AML treatment. Further studies are needed to explore their efficacy and safety profiles in preclinical and clinical settings.

P3, N=184, Completed, Chipscreen Biosciences, Ltd. | Recruiting --> Completed | Trial completion date: Dec 2025 --> Apr 2024 | Trial primary completion date: Dec 2024 --> Apr 2024

P2, N=51, Active, not recruiting, Institut Curie | Recruiting --> Active, not recruiting | Trial completion date: Sep 2028 --> Nov 2026 | Trial primary completion date: Jan 2027 --> May 2025

P2, N=47, Recruiting, Sun Yat-sen University

P=N/A, N=50, Recruiting, Regina Elena Cancer Institute | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jul 2024 --> Dec 2024

P2, N=60, Recruiting, University College, London | Trial completion date: Jul 2026 --> Jul 2030 | Trial primary completion date: Jul 2026 --> Jul 2028

P2, N=6, Active, not recruiting, Providence Health & Services | Recruiting --> Active, not recruiting | N=30 --> 6 | Trial primary completion date: Jun 2025 --> Dec 2024

P1/2, N=0, Withdrawn, Tel Aviv Medical Center | N=47 --> 0 | Not yet recruiting --> Withdrawn

P=N/A, N=50, Recruiting, The First Hospital of Jilin University

Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.

This study suggests that fuquinitinib can improve the survival of patients with metastatic colorectal cancer. Patients with high levels of PNI have a better prognosis and longer survival time, ensuring the nutritional status of patients can be a help to improve the treatment of fuquinitinib.

The predictive performance of the combined model established by integrating ultrasomics features and clinical baseline characteristics was improved, with the AUC, sensitivity, specificity, and accuracy of the RF machine learning combined model for the training and test dataset reaching 0.937 (95%CI, 0.884-0.971), 0.822 (95%CI, 0.702-0.909); 0.857, 0.833; 0.857, 0.800; 0.857, 0.817, respectively. To predict the status of EGFR expression in HCC patients, the ultrasomics model and combined model created by five machine learning algorithms can be utilized as efficient and noninvasive techniques, and the ultrasomics model and combined model established by RF classifier have the best predictive performance.

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.

Our findings revealed that triple therapy is an effective, well-tolerated regimen for HCC patients with EM. AFP level and NLR are prognostic risk factors for triple therapy in this patient population.

P3, N=180, Recruiting, Chipscreen Biosciences, Ltd. | Trial completion date: Dec 2024 --> Dec 2025

P3, N=131, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

P3, N=674, Completed, Merck Sharp & Dohme LLC | Active, not recruiting --> Completed

Although these Kampo medicines are reported to inhibit drug-metabolizing enzymes and drug transporters, the risk of drug interactions for patients receiving lenvatinib therapy is low. Patients should feel confident that they can receive Kampo medicines as supportive care for lenvatinib therapy without a risk of drug interactions that could affect treatment efficacy.

These results demonstrate the clinical impact of FLT3 inhibitors on survival outcomes in patients with FLT3-ITD-positive AML, particularly when combined with HCT. FLT3 inhibitors can improve the prognosis of AML with FLT3 mutations, especially in patients who undergo HCT.

The research findings indicate that sunitinib may induce cytotoxic effects in hepatocytes through mechanisms involving oxidative stress, endoplasmic reticulum stress, and mitochondrial damage. However, in the kidney, the toxicity mechanism is different from that of liver, and the endoplasmic reticulum stress does not seem to be involved in this mechanism.

Among the promising inhibitors tested, vatalanib, a VEGF-R inhibitor, demonstrated significant in vivo efficacy at inhibiting tumor growth and reducing tumor-associated myeloid cells, thereby underscoring its potential as a therapeutic agent. Our findings highlight specific kinase inhibitors with differential modulatory effects on HNSCC-associated myeloid subsets and caution the application of some as anti-cancer drugs. This experimental system may provide a robust platform for identifying new agents targeting tumor-associated myeloid cells in HNSCC and beyond, and for elucidating mechanistic insights into tumor-myeloid cell interaction.

The results of an in vitro enzymatic study were augmented by molecular docking (in silico) analysis. Their ADME (absorption, distribution, metabolism and excretion) properties have been evaluated on the most active compounds against α-glucosidase and/or α-amylase to predict their drug likeness.

In conclusion, HBV infection increases resistance to both sorafenib and lenvatinib in hepatoma cells by influencing the cell cycle regulatory genes and critical signaling pathways. However, the resistance mechanisms likely differ between the two medications.

P2, N=21, Not yet recruiting, Shanghai Zhongshan Hospital

We established an 11-gene prognostic model that effectively stratifies liver cancer patients based on differentially expressed genes between tumor and adjacent non-tumor cells clustered by scRNA-seq data. The two risk groups had significantly different molecular characteristics. We identified 14 drugs that might be effective for high-risk HCC patients. Our study provides novel insights into tumor cell characteristics, aiding in research on tumor development and treatment.

P2, N=30, Recruiting, Peking University Cancer Hospital & Institute | Not yet recruiting --> Recruiting

P2, N=11, Active, not recruiting, Washington University School of Medicine | Trial completion date: Feb 2027 --> Dec 2025 | Trial primary completion date: Jul 2025 --> Jul 2024

Our study revealed that lenvatinib-induced NETs inhibited the cuproptosis of HCC cells, suggesting that targeting the IL33/PADI4/NET axis represents a promising therapeutic strategy for ameliorating lenvatinib resistance in HCC.

P2, N=36, Not yet recruiting, Sun Yat-sen University | Initiation date: Jul 2024 --> Dec 2024

P1/2, N=30, Active, not recruiting, National Taiwan University Hospital | Trial completion date: Jun 2023 --> Dec 2024

Our research suggests Hsa_circ_0072732 enhanced renal cell carcinoma sunitinib resistance by inhibiting ferroptosis through miR-548b-3p/SLC7A11.