Oncopig bladder cancer cells recapitulate human bladder cancer treatment responses in vitro.

Introduction: Bladder cancer is a common neoplasia of the urinary tract that holds the highest cost of lifelong treatment per patient, highlighting the need for a continuous search for new therapies for the disease. Current bladder cancer models are either imperfect in their ability to translate results to clinical practice (mouse models), or rare and not inducible (canine models). Swine models are an attractive alternative to model the disease due to their similarities with humans on several levels. The Oncopig Cancer Model has been shown to develop tumors that closely resemble human tumors. However, urothelial carcinoma has not yet been studied in this platform. Methods: We aimed to develop novel Oncopig bladder cancer cell line (BCCL) and investigate whether these urothelial swine cells mimic human bladder cancer cell line (5637 and T24) treatment-responses to cisplatin, doxorubicin, and gemcitabine in vitro. Results: Results demonstrated consistent treatment responses between Oncopig and human cells in most concentrations tested (p>0.05). Overall, Oncopig cells were more predictive of T24 than 5637 cell therapeutic responses. Microarray analysis also demonstrated similar alterations in expression of apoptotic (GADD45B and TP53INP1) and cytoskeleton-related genes (ZMYM6 and RND1) following gemcitabine exposure between 5637 (human) and Oncopig BCCL cells, indicating apoptosis may be triggered through similar signaling pathways. Molecular docking results indicated that swine and humans had similar Dg values between the chemotherapeutics and their target proteins. Discussion: Taken together, these results suggest the Oncopig could be an attractive animal to model urothelial carcinoma due to similarities in in vitro therapeutic responses compared to human cells.

Perspective: Humanized Pig Models of Bladder Cancer.

Bladder cancer (BC) is the 10th most common neoplasia worldwide and holds expensive treatment costs due to its high recurrence rates, resistance to therapy and the need for lifelong surveillance. Thus, it is necessary to improve the current therapy options and identify more effective treatments for BC. Biological models capable of recapitulating the characteristics of human BC pathology are essential in evaluating the effectiveness of new therapies. Currently, the most commonly used BC models are experimentally induced murine models and spontaneous canine models, which are either insufficient due to their small size and inability to translate results to clinical basis (murine models) or rarely spontaneously observed BC (canine models). Pigs represent a potentially useful animal for the development of personalized tumors due to their size, anatomy, physiology, metabolism, immunity, and genetics similar to humans and the ability to experimentally induce tumors. Pigs have emerged as suitable biomedical models for several human diseases. In this sense, the present perspective focuses on the genetic basis for BC; presents current BC animal models available along with their limitations; and proposes the pig as an adequate animal to develop humanized large animal models of BC. Genetic alterations commonly found in human BC can be explored to create genetically defined porcine models, including the BC driver mutations observed in the FGFR3, PIK3CA, PTEN, RB1, HRAS, and TP53 genes. The development of such robust models for BC has great value in the study of pathology and the screening of new therapeutic and diagnostic approaches to the disease.

Porcine cancer models: potential tools to enhance cancer drug trials.

INTRODUCTION: The amount of time and money invested into cancer drug research, development, and clinical trials has continually increased over the past few decades. Despite record high cancer drug approval rates, cancer remains a leading cause of death. This suggests the need for more effective tools to help bring novel therapies to clinical practice in a timely manner. AREAS COVERED: In this review, current issues associated with clinical trials are discussed, specifically focusing on poor accrual rates and time for trial completion. In addition, details regarding preclinical studies required before advancing to clinical trials are discussed, including advantages and limitations of current preclinical animal cancer models and their relevance to human cancer trials. Finally, new translational porcine cancer models (Oncopig Cancer Model (OCM)) are presented as potential co-clinical trial models. EXPERT OPINION: In order to address issues impacting the poor success rate of oncology clinical trials, we propose the incorporation of the transformative OCM 'co-clinical trial' pathway into the cancer drug approval process. Due to the Oncopig's high homology to humans and similar tumor phenotypes, their utilization can provide improved preclinical prediction of both drug safety and efficacy prior to investing significant time and money in human clinical trials.