SHR-168442

Cellular senescence can exert dual effects in tumors, either suppressing or promoting tumor progression. The senescence-associated secretory phenotype (SASP), released by senescent cells, plays a crucial role in this dichotomy. Consequently, the clinical challenge lies in developing therapies that safely enhance senescence in cancer, favoring tumor-suppressive SASP factors over tumor-promoting ones. Here, we identify the retinoic-acid-receptor (RAR) agonist adapalene as an effective pro-senescence compound in prostate cancer (PCa). Reactivation of RARs triggers a robust senescence response and a tumor-suppressive SASP. In preclinical mouse models of PCa, the combination of adapalene and docetaxel promotes a tumor-suppressive SASP that enhances natural killer (NK) cell-mediated tumor clearance more effectively than either agent alone. This approach increases the efficacy of the allogenic infusion of human NK cells in mice injected with human PCa cells, suggesting an alternative therapeutic strategy to stimulate the anti-tumor immune response in "immunologically cold" tumors.

Evaluating Drug‐Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady‐state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4‐component transporter cocktail. This open‐label, non‐randomized, 2‐period fixed‐sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18‐55 years with body mass index 18.5‐29.9 kg/m2. During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0‐∞) and the maximum measured concentration of the analyte in plasma (Cmax), and the secondary endpoint was the area under the concentration‐time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0‐tz). Steady‐state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (−2% to −9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE‐1/MATE‐2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0‐∞/Cmax/AUC0‐tz) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug‐transporter interactions in vivo.