Abstract B36: Summary of 50 cases of patient-derived colorectal cancer xenografts; Problems and tips to obtain appropriate results in translational researches
Authors: Maekawa Hisatsugu , Yamaura Tadanori , Kawada Kenji , Sakai Yoshiharu 
Published: March 2017

Colorectal cancer (CRC) is one of the most common cancers worldwide, with more than 690,000 deaths estimated in 2012. Despite our increasing knowledge of the genetics of CRC, few biomarkers are available for successful anticancer therapies. The key drugs and therapeutic strategy against CRC are limited. The overall 5-year survival rate of patients with metastatic CRC is only ~12%.

Because of the heterogeneity of CRCs and the complexity in clinical conditions, traditional cell line models have not predicted clinical outcomes of anticancer therapies. Recent studies show that it is difficult to associate the specific genetic mutations with drug sensitivities in vitro. On the other hand, patient-derived tumor xenografts (PDXs) are preferable preclinical models as they preserve the genomic condition and tumor heterogeneity in primary lesions. Although the PDX is costly and time-consuming, its usefulness outweighs these limitations, and it is expected to help not only basic cancer studies but also development of personalized therapies in the clinical setting.

We have been establishing PDXs of advanced CRCs. In short, we dissect fresh tumor fragments (3-5mm cube) from resected tumors by surgical procedure after obtaining patients' informed consents in our hospital. We bring them to our laboratory on ice. We then wash tumor samples with medium twice and with PBS twice. The tumor samples are implanted to each flank of nude mice and/or NOD/SCID mice. The implanted tumor growth is measured at least once a week. We consider the implantation is successful when estimate tumor volumes become more than 1000 mm3. We excise tumor masses, cut and divide them into small fragments, and perform serial transplantation.

We have engrafted 50 cases of CRC tumors so far to establish PDXs. In 23 cases, we confirmed that engrafted tumors were successfully growing. In 8 cases, the implanted tumor disappeared within several weeks after transplantation, and we determined that PDXs in these cases failed to grow as any tumor masses were developed for 6 months. The remaining 19 cases are under study. We found that each PDX, even from the same tumor, showed different growth rate, which made it difficult to set-up PDX panels for drug-sensitivity tests. We conclude that it is rather difficult to prepare an enough number of homogeneous PDX models from each cancer for evaluation of its chemosensitivity. We are currently trying to minimize the growth rate differences of PDXs among individual transplants from a same patient. Such a technique may accelerate translational study using PDXs.

Our future aim is to optimize the care for individual patients with advanced CRC by selecting effective regimens that are predicted by the chemosensitivity test using PDXs. We will also study several genetic mutations that affect patient survival rate and their relationship with chemo-sensitivities so that we can improve CRC patient survival in our hospital.

Citation Format: Hisatsugu Maekawa, Tadanori Yamaura, Kenji Kawada, Yoshiharu Sakai. Summary of 50 cases of patient-derived colorectal cancer xenografts; Problems and tips to obtain appropriate results in translational researches. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B36.