Dr. McKiernan started his talk by noting that 2018 is the 100th anniversary for animal models of cancer. He went on to describe the ideal animal models of cancer, which can recapitulate human counterpart with similar histology, growth and progression, and allow for prevention and therapeutic study that can translate into human trials. Currently, the majority of carcinogen-induced mouse models of bladder cancer utilize N- butyl-N-(4-hydroxybutyl) nitrosamine (BBN), which is delivered in the drinking water. BBN is highly relevant to human bladder cancer since it is very similar to the major carcinogen associated with tobacco smoke. BBN-treated mice develop a range of bladder cancer phenotypes, including hyperplasia, dysplasia, CIS, and muscle-invasive bladder cancer, as well as metastases in certain strain backgrounds. p53 mutations and the molecular profiles of tumors from BBN-treated mice share similarity with those of human invasive bladder cancer. The other carcinogen-induced model is N-methyl-N-nitrosourea (MNU), which is instilled intravesically, creates tumor that is unstable and is slightly challenging to recreate repetitively. Among transplantable models, there are syngeneic which can be used to study the effect of immunologic agents, and xenograft models which are immunodeficient models.
Dr. McKiernan then highlighted some of the examples of genetically engineered mice model (GEMM) such as 1) gene knockout Cre-loxP system, 2) H-ras knockout model which generates low grade non-muscle invasive bladder cancer, and 3) H-ras and p53 double knockout models which generates high-grade CIS and muscle-invasive bladder cancer. At Columbia, Dr. Abate-Shen’s lab has developed a reproducible knockout model with deletion of p53 and PTEN using adenoviral vector and Cre recombinase enzyme. This model creates a high penetrance tumor within 24 weeks.
Dr. McKiernan then talked about some of the newer models that are being developed which can target the cells of origin, to induce models that replicate both basal and luminal phenotypes. He provided an overview of the pre-clinical models and trials undergoing at Columbia University using these mouse models, where they tested tumors mediated by upregulation of mammalian target of rapamycin (mTOR) pathway. They used rapamycin both systemically and intravesically to block bladder tumorigenesis in preclinical studies, and it worked well in mice, but when translated into human phase I study in BCG refractory tumor, had an inadequate response. They then used platinum-based intravesical chemotherapy along with combination drugs such as Docetaxel and Gemcitabine with impressive results and will report their results from the human phase I study at the AUA meeting next year in Chicago. He also highlighted recent publication from their group in Cell by Lee et al., which shows patient-derived bladder tumor organoids represent a reliable model system for studying tumor evolution and treatment response in the context of precision cancer medicine.
Dr. McKiernan then concluded his brilliant summary by stressing that not all animal models are created equal, and that heterogeneity is hard to re-create in GEMM models, whereas the carcinogen-induced model tends to replicate human cancers more closely. Preclinical trials can occasionally translate into effective treatments in humans, and there is a need for more translational research in this area. He also pointed out that cellular specificity is now possible in GEMM models, and genomic profiling and PDX models will allow for the creation of custom models in the future.
Presented By: James M. McKiernan, MD, Columbia University, New York, NY
Lee SH, Hu W, Matulay JT et al. Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer.Cell. 2018 Apr 5;173(2):515-528.e17.
Kobayashi T, Owczarek TB, McKiernan JM, Abate-Shen C. Modelling bladder cancer in mice: opportunities and challenges.Nat Rev Cancer. 2015 Jan;15(1)
Written by: Abhishek Srivastava, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center, Philadelphia, PA, @shekabhishek, at the 19th Annual Meeting of the Society of Urologic Oncology (SUO), November 28-30, 2018 – Phoenix, Arizona