SUMMARY: Researchers will look for mutations in hemangiosarcoma cases as a step toward developing new therapies.
THE PROBLEM: Hemangiosarcoma (HSA) is a highly malignant disease and is common in breeds including Golden Retrievers, German Shepherd, Boxer, and others. When detected, HSA is often advanced and spreads to other locations. Effective treatment of HSA is currently lacking, and affected dogs have a grave outcome. Thus, research that leads to effective intervention of this terrible disease is urgently needed.
THE PROJECT: Tumor cells often contain mutations that are absent in normal cells. Some of these mutations produce tumor-specific neoantigens (TSNAs). This offers unique opportunities for cancer treatment and prevention. First, TSNAs are new to the immune system, increasing efficacy. Second, TSNAs are absent in normal cells, reducing toxicity. Public TSNAs (pTSNAs) are derived from hotspot mutations (mutations shared among patients). pTSNAs and the corresponding T cells are especially attractive targets in developing cancer vaccine and other immunotherapies. These will lead to cancer prevention and treatment in a large portion of the population.
The team will expand on previous work. They’ve discovered hotspot mutations in canine HSA and their preliminary studies indicate that these hotspot mutations will yield pTSNAs. They propose to discover these pTSNA and the corresponding T cells. Their goal is to find targets for future development of cancer vaccine and other immunotherapies to treat and prevent HSA in 17% of the dog population in the USA and world-wide.
PROJECT UPDATE: The team is making steady progress on the two aims of this project.
For aim 1 (computationally predict potential pTSNAs from hotspot mutations in specific genes), the team has:
-Successfully modified their canine MHC-I genotyping software to genotype canine MHC class II (DLA-II), an important step toward developing the predictive value of potential pTSNAs.
-Genotyped ~3,000 canine samples with RNA-seq data, and ~7,000 canine samples with whole exome or genome sequencing data. They discovered breed-dominant alleles in >20 canine breeds, including Golden Retriever which is predisposed to hemangiosarcoma.
-Predicated pTSNAs in the 20 canine breeds.
For aim 2, the team has:
-Collected blood and/or tumor samples from ~30 canine patients with HSA and other diseases. They identified TP53, KRAS, and NRAS hotspot mutations in 3 cases in their samples.
-They’re performing interferon-g assays with PBMCs from dogs harboring hotspot mutations to validate the immunogenicity of the predicted pTSNA.
In the next 6-12 months, the team will:
-To publish the canine MHC-II genotyping work of Aim 1.
-Continue our canine sample collection (Aim 2).
-Continue the interferon-g assays with PBMCs from dogs harboring a hotspot mutation and an MHCI/II allele that yield a predicted pTSNA to validate the immunogenicity of the pTSNAs predicted (Aim 2).
POTENTIAL IMPACT: If successful, this work could lead to unique therapies that could improve survival in dogs affected by hemangiosarcoma.
Research Update Dr. Zhao regarding Search for Immune Stimulating Mutations in Canine Hemangiosarcoma