ATR as Cancer Target – It’s coming
Comparative oncology gives us a lot of insights on how to treat companion animals, and sometimes quite some joy.
ATR Kinase inhibitors are not exactly new, the first being developed around 1999, but every new target validated for vet science is a success.
And that’s this week’s success from Marta Henklewska et al.!
Short recap:
ATM, ATR and DNA-PKcs are first responders for DNA repair after DNA damage.
While ATM and DNA-PKcs mainly repair double-stranded breaks, ATR repairs single-stranded breaks.
So far so good.
ATM is quite often mutated, making it one of the most frequently mutated tumor suppressors in cancer.
- Bad news: the tumor can mutate faster
- Good news: the tumor is more reliant on ATR for maintaining genomic stability
Poor genomic stability -> Apoptosis or Necrosis. Yuppi!
This is the concept behind targeting ATR, and what makes this target so promising.
With her work, we are a step nearer to validating the target for canine Lymphoma and Leukemia.
Enjoy this week’s newsletter!
In Vitro
Using ATR Kinase Inhibitors to Treat Canine Lymphoma and Leukemia
Marta Henklewska and her team from Wrocław University of Environmental and Life Sciences , Poland, investigated ATR kinase inhibitors as a treatment for canine lymphoma and leukemia. They focused on the drug berzosertib, which targets cancer cells’ ability to repair DNA damage. The study showed berzosertib effectively kills cancer cells without harming healthy cells and works synergistically with the chemotherapy drug chlorambucil. This research suggests ATR inhibition could be a promising new approach for treating these cancers in dogs, though further studies are needed to confirm its potential and identify predictive biomarkers.
Henklewska, M., Pawlak, A. and Obmińska-Mrukowicz, B. (2024), Targeting ATR Kinase as a Strategy for Canine Lymphoma and Leukaemia Treatment. Vet Comp Oncol, 22: 602-612. https://doi.org/10.1111/vco.13014
Diagnostics & Biomarkers
STAT3 Overactivation in Canine Liver Cancer and Its Impact on Prognosis
Shin and colleagues from Seoul National University , South Korea, investigated the role of a protein called phosphorylated STAT3 (pSTAT3) in canine hepatocellular carcinoma (HCC), a type of liver cancer. Their study analyzed tissue samples from healthy dogs, dogs with non-cancerous liver conditions, and dogs with HCC to determine the levels of pSTAT3 and its link to disease progression. The findings revealed that high levels of pSTAT3 were significantly associated with larger tumor sizes, metastasis, and worse survival outcomes. This suggests that pSTAT3 plays a critical role in the aggressiveness of canine HCC. The study highlights its potential as both a marker to predict prognosis and a target for future therapies aimed at improving treatment outcomes for dogs with this condition.
Shin, H.K., Chung, H.J. and Kim, W.H. (2024), Overactivation of Signal Transducer and Activator of Transcription 3 in Canine Hepatocellular Carcinoma and Its Prognostic Significance. Vet Comp Oncol, 22: 490-499. https://doi.org/10.1111/vco.12998
Comparing Canine and Human Prostate Cancer to Find Resistance Mechanisms
Marcela Riveros Angel gel and colleagues from Oregon Health & Science University , USA, conducted a study to compare gene expression in canine and human prostate cancers, particularly focusing on advanced forms resistant to hormonal treatment, such as castration-resistant prostate cancer (CRPC) in humans and androgen-independent cancers in castrated dogs. Their analysis revealed significant molecular similarities, including shared dysregulated genes like ISG15 and AZGP1, which are linked to immune pathways. These findings suggest that canine prostate cancer could serve as a valuable model to better understand CRPC in humans and potentially guide the development of new therapies targeting shared molecular pathways
Angel, M.R., Séguin, B., Löhr, C.V., Beer, T.M., Feliciano, J., Ramsey, S.A. and Thomas, G.V. (2024), Comparative Transcriptomes of Canine and Human Prostate Cancers Identify Mediators of Castration Resistance. Vet Comp Oncol, 22: 629-640. https://doi.org/10.1111/vco.13017
Clinical
Testing a New IV Treatment for Canine Lymphoma Using L-Asparaginase
Botta and colleagues from the AniCura Animal Oncology and Imaging Center in Switzerland, conducted a pilot study to assess the safety and efficacy of monomeric L-asparaginase administered intravenously in dogs with multicentric lymphoma. This innovative treatment approach aimed to improve outcomes by targeting a critical metabolic vulnerability in lymphoma cells. The study demonstrated that monomeric L-asparaginase could be administered safely, with manageable side effects, and it showed promise in inducing remission in treated dogs. These findings suggest that this approach could complement or enhance existing chemotherapy protocols for canine lymphoma, warranting further research in larger clinical trials to confirm its benefits.
Botta, V., Camerino, M., Bicanová, L. et al. Pilot study investigating the intravenous administration of monomeric L-asparaginase to dogs with multicentric lymphoma. Vet. Oncol. 1, 10 (2024). https://doi.org/10.1186/s44356-024-00010-3
