用于原位前列腺癌、膀胱癌、肝癌、胰腺癌和脑癌转化治疗研究的先进临床前癌症模型和成像方案

Introduction: Translatable animal models mimicking and predicting clinical disease outcomes are in high demand to increase the success rate of novel anti-cancer therapies. Orthotopic or metastatic cancer models, where tumors are established in their tissue of origin, have gained significant interest in drug development as they more accurately replicate the tumor microenvironment, metastatic behavior, and treatment response seen in patients. In these studies, we generated advanced orthotopic models of cancer including prostate, bladder and pancreas, as well as disseminated models of cancer spread to liver and brain. Furthermore, we developed imaging protocols to accurately monitor treatment responses and drug targeting engagement in preclinical studies. Methods: Murine and human prostate cancer cell lines engineered to express human PSMA (RM-1.hPSMA and PC-3.hPSMA, respectively) were injected into the prostate gland of immunodeficient and immunocompetent mice. Human UM-UC-3 bladder cancer cells were intramurally injected into the bladder wall under laparotomy. Human BxPC-3 pancreatic cancer cells were surgically inoculated into the head of pancreas. Seeding in the liver was established by intrasplenic injection of murine 4T1 breast cancer cells. Metastatic seeding in the brain was established by injection of MDA-MB-231 TNBC cells into the intracarotid artery (ICt). Tumor growth was monitored using bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and ultrasound (US), while SPECT/CT imaging was applied for target engagement of [¹⁷⁷Lu]Lu-PSMA-617. IHC and light sheet microscopy (LSM) were used to validate in vivo findings. Results: Orthotopic tumors were successfully established in pancreas, bladder and prostate with a take-rate >90%, >60% and >75%, respectively. Intrasplenic inoculation led to numerous liver metastases with a take rate of 100%, while ICt inoculation resulted exclusively in the formation of brain metastases with a take rate >70%. MRI imaging revealed 1-7 metastases per animal with intra- and intersubject variation in BBB permeability. MRI and US provided accurate tumor volumetry, while BLI monitored viable tumor burden with correlation to different modalities across the studies, verified by IHC and LSM. Conclusion: We successfully developed complex surgical procedures for establishing orthotopic models and models of metastatic spread for cancers with an unmet clinical need. All models presented with key characteristics of human disease. Combined with multimodal, reliable and state-of-the-art imaging readouts, this is an attractive platform to increase the translational value of preclinical studies with novel anti-cancer therapies and combinations.