CLT-003 exerts anti-tumor activity in pancreatic cancer by blocking the PI3K/AKT/HIF-1α pathway

Objective: CLT-003 is a novel phenylphthalimide derivative encapsulated in poly (lactate-glycolic acid) copolymer nanoparticles using nanotechnology techniques. CLT-003 possesses anti-angiogenetic and antitumor activities. Nevertheless, the role and molecular mechanism underlying CLT-003 in pancreatic cancer remain to be elucidated. Methods: Cell proliferation and apoptosis were detected using CCK-8, real-time cell analysis (RTCA), EdU, and flow cytometric assays. Cellular mobility and invasive capacity were detected using wound-healing, Transwell, and cell motility assays. Tumor growth and metastasis were determined using the mouse subcutaneous and pancreatic cancer orthotopic liver metastasis models. The antitumor effects of CLT-003 were evaluated using patient-derived organoid (PDO) and patient-derived xenograft (PDX) models. Results: CLT-003 significantly inhibited cellular proliferation, enhanced cellular apoptosis, and attenuated cellular invasion and migration of pancreatic cancer cells. Mechanistically, CLT-003 suppressed the translation of HIF-1α by inhibiting the PI3K/AKT/mTOR signaling pathway. In the mouse tumor models, CLT-003 significantly inhibited the growth and metastasis of pancreatic tumors. Moreover, the PDO and PDX models showed increased sensitivity to CLT-003 in pancreatic cancer with high HIF-1α expression compared to pancreatic cancer with low HIF-1α expression. Conclusions: This study delineated the role and molecular mechanism of CLT-003 action in impeding the progression of pancreatic cancer and indicated its robust potential for the treatment of pancreatic cancer.