To study resistance mechanisms, we developed the organoid drug resistance assay (ODR-test) with patient-derived organoids from our ovarian cancer biobank and identified sustained phenotypic reprogramming and cellular plasticity of organoids under carboplatin pressure as a conserved mechanism irrespective of the basal resistance level. Additionally, we found that KRT17 expression status (K-score) is a significant negative prognostic histopathological biomarker in a large cohort (N = 384) of patients with advanced HGSOC. In organoids, increased KRT17 levels enhanced sensitivity to PI3K/Akt inhibitors alpelisib and afuresertib, highlighting the potential of KRT17 as a stratification biomarker for targeted therapies.

P2, N=45, Recruiting, National Human Genome Research Institute (NHGRI) | Trial completion date: Mar 2028 --> Jul 2028 | Trial primary completion date: Mar 2026 --> Jul 2026

P1/2, N=22, Completed, Laekna Limited | Active, not recruiting --> Completed

Riz1 knockout mice (KO) were randomly treated with either the AKT inhibitor afuresertib or the mTOR inhibitor rapamycin. Mice treated with the inhibitors exhibited significantly suppressed AKT/mTOR signaling pathway in liver, muscle, and adipose tissues, as well as downregulation of genes associated with energy and lipid metabolism (L-Fabp, Pparα/γ, Ubiad1, Cyp4a12). These findings demonstrate that inhibition of either the AKT or mTOR molecules mitigates obesity and metabolic dysregulation in Riz1-/- mice, highlighting the critical role of the RIZ1/AKT/mTOR axis in maintaining metabolic homeostasis.

Drug sensitivity analysis indicated increased responsiveness of high-risk patients to agents such as Afuresertib and Venetoclax. The findings contribute to a more comprehensive understanding of the disease and provide a foundation for future clinical applications. Nevertheless, further large-scale validation is required to confirm these findings and enhance their clinical utility.

We revealed a positive correlation between the Nscore and macrophage M1, suggesting potential drug response mechanisms. Based on the identified AML subtypes and their distinct mutational landscapes, we predicted potential treatment options, with Paclitaxel, Afuresertib, and Mitoxantrone emerging as potential therapeutic agents for the AML subtypes.

The addition of afuresertib to paclitaxel did not significantly improve PFS/OS in patients with PROC. However, exploratory biomarker findings suggest potential efficacy in phospho-AKT positive patients, warranting further investigation. The safety/tolerability profile of A + P was consistent with prior AKT-inhibitor studies.

ANLN plays a crucial role in ATC progression by activating the RhoA/PI3K/AKT pathway, suggesting its potential as a therapeutic target in ATC.

Especially showing comparable stability to the reference molecule over 200 ns in MD simulations, the best top 2 hit compounds having binding affinity -10.7 kcal/mol for PCOS_ 133 (CID-164189) and -11.6 kcal/mol for PCOS3_42 (CID-158973) emerged as potential AKT1 inhibitors for cancer therapy in comparison to -11.6 kcal/mol and -14.7 kcal/mol binding affinity of Miransertib reference drug and IQO cocrystallized ligand of AKT1 protein PDB code 3O96. LEU-210, LEU-264, ASP-292, and TRP-80 are the important amino acid residues required for AKT1 inhibition. These results provide important new perspectives for the rational design and optimization of oxadiazole-based AKT1/PKB inhibitors, therefore laying a strong basis for experimental validation including further in-vitro and in vivo studies and PKB inhibitor development.

P2, N=45, Recruiting, National Human Genome Research Institute (NHGRI) | Trial primary completion date: Mar 2025 --> Mar 2026

P2, N=60, Active, not recruiting, Merck Sharp & Dohme LLC | Trial completion date: Sep 2026 --> Feb 2030 | Trial primary completion date: Sep 2026 --> Feb 2030

ANLN plays a crucial role in ATC progression by activating the RhoA/PI3K/AKT pathway, suggesting its potential as a therapeutic target in ATC.