Figure 1

This presentation will summarize our recent work in canine hemangiosarcoma (HSA) and highlight research abstracts that will be presented at this meeting. We will show emerging evidence supporting a cellular origin of HSAs from bone marrow nurse cells, an ontogeny that is consistent with the tumors’ anatomic predilection for organs with hematopoietic capacity and/or with complex vascular networks.

Despite a possible shared ontogeny, HSAs eventually diverge into distinct molecular subtypes. We previously defined angiogenic, inflammatory, and adipogenic subtypes of HSA based on gene expression profiling, and our recent work has identified the existence of a fourth possible subtype with characteristics resembling both the angiogenic and inflammatory subtypes. The mutational landscape of HSA seems to be intrinsically linked to disease progression: while HSAs accumulate a diversity of private mutations, pathogenic mutations of TP53 that lead to loss of function of p53, and/or of PIK3CA, PIK3R, or PTEN that lead to gain of function of the phosphoinositide-3-kinase (PI3K) pathway are recurrently present in angiogenic and mixed angiogenic/inflammatory HSAs, while inflammatory HSAs are virtually devoid of recurrent mutations. In some angiogenic HSAs, fusion genes where at least one partner acts in parallel to—or downstream from—PI3Ks seem to combine with loss of function mutations of TP53 to promote the angiogenic phenotype.

The cellular composition and the molecular phenotypes of HSAs are remarkably consistent. Inflammatory HSAs have increased numbers of immune and inflammatory cells within the tumor stroma. Because HSA cells create a favorable niche for hematopoiesis, it remains unclear if the immune and inflammatory cells arise from progenitors recruited into the niche, or possibly from the multipotent tumor cells themselves, or if they infiltrate the tumors as part of a host response. Yet, the fact that inflammatory HSAs account for virtually all of the cases where dogs show long-term survival supports the hypothesis that the immune and inflammatory cells are part of a host response that promotes more favorable biological behavior.

The presence of recurrent, targetable mutations of PIK3CA in aggressive angiogenic HSAs, at least, would imply that a subset of these tumors might respond to therapies targeting PI3K or its downstream pathways. Work that will be presented by Dr. Kim supports this notion. However, the therapeutic opportunities for targeted compounds might be limited because signaling from driver mutations might not be essential for tumor survival once the cells have organized into a malignant tissue. A subset of HSAs might also have metabolic vulnerabilities. Elegant work that will be presented by Dr. Dickerson suggests that propranolol might disrupt lipid metabolism and activate the ER stress response, inducing a catastrophic catabolic state that can enhance chemosensitivity of HSA cells. Furthermore, work that will be presented by Ms. Schulte adds to the evidence for pro-immune effects of the drug eBAT by depletion of tumor-associated macrophages in sarcomas with enhanced tumor phagocytosis by infiltrating CD11b+ myeloid cells and increased infiltration of T cells.

We have dedicated considerable efforts to develop strategic, rationally designed approaches for cancer prevention. Work presented by Ms. DePauw will describe the Shine On Study and update the performance of the SOS test, which can be used to assign dogs into risk profiles for the eventual development of HSA in advance of disease when treatments might be most effective. We are pairing these tests with the drug eBAT as a rationally designed, safe and effective chemopreventative, expanding the applications of precision medicine to the field of canine cancer prevention.