P2, N=100, Not yet recruiting, Hoffmann-La Roche

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.

This study demonstrates a role of platinum-based chemotherapy on HSC activation in liver cancer. Selective targeting of PI3K p110α may provide a novel strategy to inhibit chemotherapy-induced HSC activation and improve treatment response.

Olaparib and temozolomide (OT) combination therapy is in clinical trial evaluation for rhabdomyosarcoma (RMS). The combination of OT + alpelisib also kills RMS cells which are resistant to standard-of-care combination chemotherapy and was effective in preclinical xenograft mouse models at curbing tumor growth. Our work defines a common resistance pathway in RMS and has credentialled PIK3CA/AKT inhibition as a preclinical strategy to kill therapy resistant RMS.

P=N/A, N=2424, Completed, Novartis Pharmaceuticals | Recruiting --> Completed

This article reports a case of tumor-associated Liver Injury (TALI) who suffered HER2-negative metastatic breast cancer with liver metastasis, but her liver function was recovery after treatment with Alpelisib, an anti-tumor drug, as meanwhile as achieving anti-tumor. Through this case we aims to emphasize to differentiate the causes of TALI and make the treatment strategies accordingly.

These findings indicate that metformin synergistically enhances the antitumor activity of alpelisib in HER2-positive breast cancer by inhibiting oncogenic signaling and stemness pathways. Beyond its metabolic benefit in mitigating hyperglycemia, metformin may potentiate PI3K-targeted therapies, supporting further preclinical and clinical evaluation of this combination strategy.

Furthermore, co-treatment with Pyrimethamine and Alpelisib significantly inhibited hyperproliferation and hyperkeratinization in the esophageal epithelium of Sox2CreER;LSL-Nrf2E79Q/+mice. Together, our data demonstrates the PI3K pathway as a downstream effector of NRF2 activation in the esophagus, and co-targeting of NRF2 and the PI3K pathway may offer a promising therapeutic strategy for NRF2Mut ESCC.

P2, N=7, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Aug 2025 --> Feb 2027

To gain insights into PI3K/mTOR pathway dysregulation in this context, we perform a human genome-wide CRISPR/Cas9 screen for hits that synergistically blocked EBVaGC proliferation together with the PI3K antagonist alpelisib...Rather than perturbing mTORC1 lysosomal recruitment, ZMYND19 and MKLN1 block the interaction between mTORC1 and Rheb and also with mTORC1 substrates S6 and 4E-BP1. Thus, CTLH enables cells to rapidly tune mTORC1 activity at the lysosomal membrane via the ubiquitin/proteasome pathway.

P=N/A, N=600, Completed, Novartis Pharmaceuticals | Recruiting --> Completed | N=200 --> 600 | Trial completion date: Sep 2025 --> Feb 2025 | Trial primary completion date: Sep 2025 --> Feb 2025

To address this, we developed a TME-responsive polymeric micelle co-delivering alpelisib (a pan-PI3K inhibitor) and cobomarsen (a miR-155-5p inhibitor) for targeted therapy. This dual-targeting strategy effectively suppressed PIK3CA-mutated tumor growth and epithelial-mesenchymal transition. These findings reveal the role of MDSC-driven metastatic potential via the exosomal miR-155-5p/SIRT1 axis in HR + breast cancer and present a novel nanotherapeutic approach for precision intervention.