SAN FRANCISCO, CA USA (UroToday.com) - Dr. Cory Abate-Shen presented an overview of preclinical models for bladder cancer.
When creating preclinical models, we must consider what to model, how to model it, if models are representative of disease in humans, and if they inform preclinical applications. For preclinical modeling, we must consider if we are modeling the appropriate cell of origin, tissue environment, and the right pathway/driver genes. Dr. Abate-Shen then provided an overview of the advantages and limitations of human-based preclinical models.
Cell lines (in vitro) can help elucidate mechanisms, but fail to capture the tumor microenvironment and recapitulate the diversity of bladder cancer. Orthotopic models are easy to manipulate and can be grown in the bladder microenvironment. However immune-deficient mice may not capture the naïve tumor microenvironment. Humanized mouse models are currently being developed which can overcome the aforementioned limitations. Patient-derived xenografts can be developed for individual patients and can provide the opportunity to personalize cancer treatment. However, it is not clear whether treatment response in patient-derived xenograft models reflects response in patients.
Genetically engineered mouse models can be used to model all disease stages (including CIS and metastases) and allow evaluation of pathway genes associated with disease. Two different types of models can be used. Transgenic models use “gain of function” based on introduction of DNA containing a tissue-specific promoter driving a gene of interest. Conversely, knock-in/knock-out models utilize gene recombination to achieve gain or loss of function. To achieve gene recombination in animal bladder, the authors injected an adenovirus-Cre recombinase directly into the bladder lumen, which can achieve gene deletion at the tissue level. The authors then used a number of conditional models and showed that combined deletion of Pten and p53 led to invasive bladder cancer in mice. Delineation of downstream pathways revealed activation of the PI3 kinase/mTOR signaling pathway. Administration of intravesical and systemic rapamycin (an mTOR inhibitor) resulted in significant tumor shrinkage. These promising pre-clinical studies are now being used to drive clinical trials of intravesical rapamycin for the treatment of NMIBC.
Highlights of a presentation by Cory Abate-Shen, PhD at the 2014 Genitourinary Cancers Symposium - January 30 - February 1, 2014 - San Francisco Marriott Marquis - San Francisco, California USA
Columbia University Medical Center, New York, NY USA