Integrating in vivo and in silico models of prostate cancer-bone interactions to overcome anti-tumor therapy resistance

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PROJECT SUMMARY/ABSTRACT Bone metastasis is the most frequent and lethal complication in prostate cancer patients. The interaction between prostate cancer and stromal cells has recently emerged as a key player in supporting disease progression and therapeutic response (and relapse). A major challenge in addressing this cooperation, however, is due to the lack of suitable experimental systems that exploit a bone-centric approach for testing treatment options. Consequently, the establishment of novel models that account for bone-epithelial interplays, including multiscale computational models integrated with experimental evidence, is central to improve the outcome of men with prostate cancer lesions in bone. In this context, we recently developed a strategy based on multiphoton microscopy monitoring of prostate cancer in bone combined to an Agent-Based Model of Bone Metastasis named A(BM)2, which consists of cancer cells growing within an acellular bone compartment. The A(BM)2 was applied to the study of Radium 223 (223Ra), a bone-targeting radioisotope approved for the treatment of metastatic prostate cancer. 223Ra induces profound but zonally confined cancer cell lethality at the bone interface with no perturbation of the tumor core. Therefore, micro-tumors are eradicated or significantly reduced while macro-tumors persist and expand due to low tissue penetrance of alpha radiation (~100 µm). The relative inefficacy in controlling large tumors points to application of 223Ra in early bone-metastatic disease or in combinatorial regimens for major lesions. Our initial findings gained the confidence of clinicians at Genitourinary Medical Oncology Department, MD Anderson, which are planning a clinical trial to test efficacy of 223Ra in oligometastatic prostate cancer patients. We here hypothesize that 223Ra will synergize with an agent targeting the core of established lesions, thus impairing the main resistance niche. Accordingly, we will explore the combination of 223Ra with cabozantinib, a kinase inhibitor that targets tumor blood vessels, prolongs progression free survival, and exerts a profound impact on microenvironment remodeling. To this purpose, we will refine our A(BM)2 by adding tumor vessels and bone stromal cells (osteoblasts, osteoclasts), retrieving their pathophysiological features by advanced ex vivo multiphoton microscopy experiments. The therapy response to 223Ra and cabozantinib will be precisely integrated in the mathematical model based on own data and further preclinical evidence made available by Genitourinary Medical Oncology Department. To generate confidence in the A(BM)2, the response to cabozantinib will be initially simulated, followed by combinatorial experiments with 223Ra. This strategy will explore an extensive number of possible combinations, including different tumor sizes, drug doses, treatment schedules and onset of resistance mechanisms and the best predicted outcome will be further validated with ad hoc in vivo preclinical experiments. Overall, these indications could provide a strong rationale for this combined regimen and be further exploited in clinical trials, directly impacting patient care.