Naturally occurring cancers in pet dogs and humans share many features, including histological appearance, tumour genetics, molecular targets, biological behaviour and response to conventional therapies. Studying dogs with cancer is likely to provide a valuable perspective that is distinct from that generated by the study of human or rodent cancers alone. The value of this opportunity has been increasingly recognized in the field of cancer research for the identification of cancer-associated genes, the study of environmental risk factors, understanding tumour biology and progression, and, perhaps most importantly, the evaluation and development of novel cancer therapeutics.

Translation of new cancer treatments from pet dogs to humans.

[Platelet-derived growth factor].

Current molecular models for NADPH oxidase regulation by Rac GTPase

Purpose: The purpose of this study was to determine the objective response rate (ORR) following treatment of canine mast cell tumors (MCT) with toceranib phosphate (Palla- dia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity through inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ. Secondary objectives were to determine biological response rate, time to tumor progression, dura- tion of objective response, health-related quality of life, and safety of Palladia. Experimental Design: Dogs were randomized to receive oral Palladia 3.25 mg/kg or pla- cebo every other day for 6 weeks in the blinded phase. Thereafter, eligible dogs re- ceived open-label Palladia. Results: The blinded phase ORR in Palladia-treated dogs (n = 86) was 37.2% (7 com- plete response, 25 partial response) versus 7.9% (5 partial response) in placebo-treated dogs (n = 63; P = 0.0004). Of 58 dogs that received Palladia following placebo-escape, 41.4% (8 complete response, 16 partial response) experienced objective response. The ORR for all 145 dogs receiving Palladia was 42.8% (21 complete response, 41 partial response); among the 62 responders, the median duration of objective response and time to tumor progression was 12.0 weeks and 18.1 weeks, respectively. Palladia-treated responders scored higher on health-related quality of life versus Palladia-treated nonresponders (P = 0.030). There was no significant difference in the number of dogs with grade 3/4 (of 4) adverse events; adverse events were generally manageable with dose modification and/or supportive care. Conclusions: Palladia has biological activity against canine MCTs and can be adminis- tered on a continuous schedule without need for routine planned treatment breaks. This clinical trial further shows that spontaneous tumors in dogs are good models to evaluate therapeutic index of targeted therapeutics in a clinical setting. Mast cell tumors (MCT) are the second most common malig- nant tumors in dogs. Most originate in the skin or s.c. tissues but they can occur as primary tumors in the intestines, liver, or spleen (1). Canine MCTs possess a wide range of biological

https://clincancerres.aacrjournals.org/content/clincanres/15/11/3856.full.pdf

Multi-center, Placebo-controlled, Double-blind, Randomized Study of Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase Inhibitor, for the Treatment of Dogs with Recurrent (Either Local or Distant) Mast Cell Tumor Following Surgical Excision

Kit is a receptor tyrosine kinase (RTK) that binds stem cell factor This receptor ligand combination is important for normal hematopoiesis, as well as pigmentation, gut function, and reproduction Structurally, Kit has both an extracellular and intracellular region Theintra-cellular region is comprised of a juxtamembrane domain (JMD), a kinase domain, a kinase insert, and a carboxyl tail Inappropriate expression or activation of Kit is associated with a variety of diseases in humans Activating mutations in Kit have been identified primarily in the JMD and the second part of the kinase domain and have been associated with gastrointestinal stromal cell tumors and mastocytosis, respectively There are also reports of activating mutations in some forms of germ cell tumors and core binding factor leukemias Since the cloning of the Kit ligand in the early 1990s, there has been an explosion of information relating to the mechanism of action of normal forms of Kit as well as activated mutants This is important because understanding this RTK at the biochemical level could assist in the development of therapeutics to treat primary and secondary defects in the tissues that require Kit Furthermore, understanding the mechanisms mediating transformation of cells by activated Kit mutants will help in the design of interventions for human disease associated with these mutations The objective of this review is to summarize what is known about normal and oncogenic forms of Kit We will place particular emphasis on recent developments in understanding the mechanisms of action of normal and activated forms of this RTK and its association with human disease, particularly in hematopoietic cells

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1634/stemcells.2004-0117

Normal and oncogenic forms of the receptor tyrosine kinase kit.

Purpose : The purpose of the following study was to investigate the safety and efficacy of the novel multitargeted indolinone receptor tyrosine kinase (RTK) inhibitor, SU11654, using a canine model of spontaneous tumors. This p.o. bioavailable compound exhibits potent inhibitory activity against members of the split kinase family of RTKs, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Kit, and Flt-3, resulting in both direct antitumor and antiangiogenic activity. Experimental Design : This was a Phase I trial in which successive cohorts of dogs with spontaneous tumors that had failed standard treatment regimens received escalating doses of SU11654 as oral therapy. Pharmacokinetics, toxicity, and tumor response were assessed. Results: Fifty-seven dogs with a variety of cancers were enrolled; of these, 10 experienced progressive disease within the first 3 weeks. Measurable objective responses were observed in 16 dogs (including 6 complete responses), primarily in mast cell tumors ( n = 11), mixed mammary carcinomas ( n = 2), soft tissue sarcomas ( n = 2), and multiple myeloma ( n = 1), for an overall response rate of 28% (16 of 57). Stable disease of sufficient duration to be considered clinically meaningful (>10 weeks) was seen in an additional 15 dogs, for a resultant overall biological activity of 54% (31 of 57). Conclusions : This study provides the first evidence that p.o. administered kinase inhibitors can exhibit activity against a variety of spontaneous malignancies. Given the similarities of canine and human cancers with regard to tumor biology and the presence of analogous RTK dysregulation, it is likely that such agents will demonstrate comparable antineoplastic activity in people.

https://clincancerres.aacrjournals.org/content/clincanres/9/7/2755.full.pdf

Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies,

OBJECTIVE: To determine the prevalence of activating internal tandem duplications (ITDs) in exons 11 and 12 of c-kit in mast cell tumors (MCTs) of dogs and to correlate these mutations with prognosis. SAMPLE POPULATION: 157 formalin-fixed, paraffin-embedded MCTs from dogs in the pathology database of the Veterinary Medical Teaching Hospital at the University of California, Davis. PROCEDURE: Genomic DNA was isolated from tumor specimens and a polymerase chain reaction procedure was performed to determine whether there were ITDs in exons 11 and 12. RESULTS: We identified ITDs in 1 of 12 (8%) grade-I, 42 of 119 (35%) grade-lI, and 9 of 26 (35%) grade-ll tumors (overall prevalence, 52 of 157 [33%]). Logistic regression analysis revealed that the odds of grade-II and -III tumors possessing an ITD were approximately 5 times greater than that for grade-I tumors, although these odds did not differ significantly. Although MCTs possessing an ITD were twice as likely to recur after excision and twice as likely to result in metastasis as those without an ITD, these values also did not differ significantly. CONCLUSIONS AND CLINICAL RELEVANCE: These results provide evidence that ITDs in c-kit occur frequently in MCTs of dogs. The high prevalence of c-kit activating mutations in MCTs of dogs combined with the relative abundance of mast cell disease in dogs provide an ideal naturally developing tumor in which to test the safety and efficacy of novel small-molecule kinase inhibitors such as imatinib mesylate.

Prevalence and importance of internal tandem duplications in exons 11 and 12 of c-kit in mast cell tumors of dogs.

Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors.

Mutations consisting of internal tandem duplications (ITDs) in exons 11 and 12 of the proto-oncogene c-kit are found in 30-50% of malignant canine mast cell tumors (MCTs). Traditionally, identification of such mutations in tumor specimens has been undertaken using standard polymerase chain reaction (PCR) and agarose gel electrophoresis. This procedure is limited to the detection of insertions and deletions larger than 9 base pairs in size. The purpose of this study was to compare the efficiency and accuracy of standard agarose gel electrophoresis with fluorescent polyacrylamide gel electrophoresis (PAGE) for the detection of ITDs in canine MCTs. The results of this study demonstrate that PAGE of labeled PCR products accurately predicts the size of the ITD in each tumor. In addition, other small insertions and deletions were not identified, suggesting that if they occur in canine MCTs, they do so infrequently. Because fluorescent and polyacrylamide formats are automated and have better resolution than agarose gels, fluorescent PAGE provides a more accurate, economical, and higher throughput method for the detection of c-kit mutations in canine MCTs.

https://vdi.sagepub.com/content/16/2/95.full.pdf+html

Detection of c-kit Mutations in Canine Mast Cell Tumors using Fluorescent Polyacrylamide Gel Electrophoresis:

Mast cell tumor (MCT) is one of the most common tumors of dogs. Some affected dogs develop multiple cutaneous tumors in various locations over months to years. In these cases, it is not clear whether the tumors have arisen de novo, or if each tumor represents a recurrence of the previously excised original tumor (ie, distant metastasis). We used the presence of an internal tandem duplication (ITD) in c-kit to demonstrate that in 2 dogs with recurrent cutaneous MCT that had developed over 1-2 years, each recurrent MCT tumor possessed an identical ITD when compared to the original MCT, indicating that the multiple tumors were clonal in origin. This study demonstrates that similar to the situation in humans, specific somatic mutations identified in oncogenes found in canine neoplasms can be used to provide evidence of tumor clonality.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1939-1676.2004.tb02644.x

May B. Chien

Papers

Phase I Dose-Escalating Study of SU11654, a Small Molecule Receptor Tyrosine Kinase Inhibitor, in Dogs with Spontaneous Malignancies,

Prevalence and importance of internal tandem duplications in exons 11 and 12 of c-kit in mast cell tumors of dogs.

Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors.

Detection of c-kit Mutations in Canine Mast Cell Tumors using Fluorescent Polyacrylamide Gel Electrophoresis:

Use of kit internal tandem duplications to establish mast cell tumor clonality in 2 dogs.