Translating Human Cancer Sequences Into Personalized Porcine Cancer Models

Abstract

The global incidence of cancer is rapidly rising, and despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. Cancer is caused by the accumulation of a series of gene mutations called driver mutations that confer selective growth advantages to tumor cells. As cancer therapies move toward personalized medicine, predictive modeling of the role driver mutations play in tumorigenesis and therapeutic susceptibility will become essential. The development of next-generation sequencing technology has made the evaluation of mutated genes possible in clinical practice, allowing for identification of driver mutations underlying cancer development in individual patients. This, combined with recent advances in gene editing technologies such as CRISPR-Cas9 enables development of personalized tumor models for prediction of treatment responses for mutational profiles observed clinically. Pigs represent an ideal animal model for development of personalized tumor models due to their similar size, anatomy, physiology, metabolism, immunity, and genetics compared to humans. Such models would support new initiatives in precision medicine, provide approaches to create disease site tumor models with designated spatial and temporal clinical outcomes, and create standardized tumor models analogous to human tumors to enable therapeutic studies. In this review, we discuss the process of utilizing genomic sequencing approaches, gene editing technologies, and transgenic porcine cancer models to develop clinically relevant, personalized large animal cancer models for use in co-clinical trials, ultimately improving treatment stratification and translation of novel therapeutic approaches to clinical practice.

Keywords: clinical needs; exome sequencing; gene editing; personalized cancer models; translational research.

Figure 1

Co-clinical trial concept using genetically engineered personalized porcine cancer models. Co-clinical trials utilizing personalized porcine cancer models can improve the evaluation of cancer treatments by providing concurrent information from porcine trials on genetically relevant tumors, facilitating rapid evaluation of targeted therapeutics at reduced cost and accrual time compared to clinical trials. Patients in the clinic are screened for presence of the target driver mutational profiles and enrolled in the co-clinical trial. In parallel, porcine cells undergo CRISPR-Cas9 gene editing to develop a cohort of tumor bearing pigs harboring the target driver mutational profiles. A co-clinical trial is undertaken in which the therapeutic of interest is tested against human patients and personalized porcine cancer models harboring the same driver mutations. Therapeutic effectiveness can be rapidly evaluated in this co-clinical trial setting, reducing time and cost associated with clinical trial performance. In addition, adverse events and lack of response to therapy observed in the porcine cohort can result in early termination, reducing the costs and number of patients recruited to failed trails.