Companion Animals as Models for Inhibition of STAT3 and STAT5

Abstract

The use of transgenic mouse models has revolutionized the study of many human diseases. However, murine models are limited in their representation of spontaneously arising tumors and often lack key clinical signs and pathological changes. Thus, a closer representation of complex human diseases is of high therapeutic relevance. Given the high failure rate of drugs at the clinical trial phase (i.e., around 90%), there is a critical need for additional clinically relevant animal models. Companion animals like cats and dogs display chronic inflammatory or neoplastic diseases that closely resemble the human counterpart. Cat and dog patients can also be treated with clinically approved inhibitors or, if ethics and drug safety studies allow, pilot studies can be conducted using, e.g., inhibitors of the evolutionary conserved JAK-STAT pathway. The incidence by which different types of cancers occur in companion animals as well as mechanisms of disease are unique between humans and companion animals, where one can learn from each other. Taking advantage of this situation, existing inhibitors of known oncogenic STAT3/5 or JAK kinase signaling pathways can be studied in the context of rare human diseases, benefitting both, the development of drugs for human use and their application in veterinary medicine.

Keywords: STAT3; STAT5; cancer models; companion animals; comparative oncology.

Figure 1

Advantages and disadvantages of different models during drug discovery. (A) Companion animals can be used as an intermediate step between the mechanistic work in murine models and clinical studies in humans, particularly with regard to comparative aspects of tumor biology. (B) Advantages and disadvantages of the individual models for translation into human clinical studies.

Figure 2

Cross-species conservation of STAT protein domains. (A) STAT1, STAT3, STAT5a and STAT5b from dog, cat and mouse are analyzed for their overall homology compared to the respective human protein (grey boxes, left). In the schematic representation of STAT protein domains, the amino acid positions are indicated above. All proteins share the same domain positions, except for murine STAT1, which has a five amino acid insertion in the DNA binding domain (numbers below the scheme indicate the aa position in this case). Percentages in the domain boxes of dog, cat and mouse STAT proteins show the homology of each domain to the human counterpart. Analyses were carried out using ClustalX. (B) Comparison of key phosphorylation sites in the transactivation domain of STAT1, STAT3, STAT5a and STAT5b from dog, cat and mouse to the human sequence. Amino acid sequence is shown, with phosphorylation sites in green and position indicated; positive amino acid exchanges (conserving protein function) are indicated in yellow, other exchanges in red. (STAT1: human NP_009330.1, dog XP_848353.1, cat XP_006935505.1, mouse NP_001192242.1; STAT3: human NP_644805.1, dog XP_005624514.1, cat XP_003996930.1, mouse NP_998824.1; STAT5a: human NP_001275647.1, dog XP_548091.2, cat XP_023099834.1, mouse NP_001157534.1; STAT5b: human NP_036580.2, dog XP_548092.1, cat XP_023100377.1, mouse NP_035619.3).