Repurposing old drugs for new cancer treatments

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Treating our canine patients has become more expensive over the years, especially with new medications. Researchers have been evaluating older drugs and found that losartan and propranolol can have other uses.

Losartan is traditionally a blood pressure medication, but this angiotensin receptor blocker also has immunomodulatory actions involving monocytes and macrophages that inhibit monocyte recruitment in tumors. Normally, there are numerous macrophages and monocyte cells in the tumor microenvironment (TME), which makes them good therapeutic targets. By targeting these cells for removal or reprogramming, we can change the immunosuppressive effects of the TME to better respond to the immune system.¹

Findings from a recent study evaluating the combination of losartan and toceranib in dogs with pulmonary metastasis from osteosarcoma showed that high-dose losartan with toceranib had a clinical benefit rate of 50%, and survival was longer with the combination than in studies involving treatment with toceranib alone,² making this combination a unique treatment option for dogs with advanced osteosarcoma. Since this study’s findings, researchers have been evaluating a similar combination with losartan and sunitinib in a pediatric osteosarcoma clinical trial.

Propranolol is a β-adrenergic blocker that helps regulate heart rhythm and in the past has been used as a blood pressure medication (although it has been replaced by newer antihypertensives). This drug has been documented to downregulate myeloid-derived suppressor cells in tumor tissues as well.³ Propranolol acts as an immune modulator by depleting and reprogramming a type of immune suppressive cell known as myeloid-derived suppressor cells (MDSCs). When MDSCs are depleted, it removes this important brake on tumor immunity, allowing T cells to function more effectively to control tumor growth. The FDA approved propranolol as a systemic treatment for infantile hemangiomas in 2014. Propranolol has also been found to sensitize sarcoma cells to doxorubicin, making it more effective in vivo.⁴ Ongoing research for propranolol and doxorubicin in dogs with hemangiosarcoma is taking place at the University of Minnesota.⁵

A study from the Flint Animal Cancer Center at Colorado State University combined losartan and propranolol with a canine tumor-cell lysate vaccine to treat gliomas. Dogs did not have surgery or radiation therapy for their tumors. The study found an overall clinical benefit rate of 80% with this immunotherapy combination alone, and the combination was also found to be well tolerated clinically.

Losartan and propranolol are relatively inexpensive drugs that have been available for a long time and can be purchased from most human pharmacies. Pet owners can give these pills at home. Although the drugs also appear to be safe in dogs, their use requires regular monitoring for kidney and heart function. It is exciting to see that older, more affordable medications can be used to help treat canine cancer when combined with other therapies.

Rachel Venable, DVM, MS, DACVIM (Oncology), is board certified as a medical oncologist by the American College of Veterinary Internal Medicine. She obtained her veterinary degree from the University of Missouri in Columbia, graduating cum laude, and pursued further training as a small animal intern at the University of Georgia in Athens. She then completed a 3-year medical oncology residency at Colorado State University Flint Animal Cancer Center in Fort Collins, during which she also earned a master’s degree and studied new cancer therapies and clinical trials. She continues to seek out clinical trials and cutting-edge therapies for her patients. Venable has authored numerous publications and served as a speaker on the local and national levels. She is the founder of Pet Cancer Care Consulting, an innovative teleconsulting service that consults with the family vet and pet owner together to give personalized responses and needed information to make an informed decision on treatments.

References

1. Regan DP, Coy JW, Chahal KK, et al. The angiotensin receptor blocker losartan suppresses growth of pulmonary metastases via AT1R-independent inhibition of CCR2 signaling and monocyte recruitment. J Immunol. 2019;202(10):3087-3102. doi:10.4049/jimmunol.1800619
2. Regan DP, Chow L, Das S, et al. Losartanblocks osteosarcoma-elicited monocyte recruitment, and combined with the kinase inhibitor toceranib, exerts significant clinical benefit in canine metastatic osteosarcoma. Clin Cancer Res. 2022;28(4):662-676. doi:10.1158/1078-0432.CCR-21-2105
3. Hylander BL, Gordon CJ, Repasky EA. Manipulation of ambient housing temperature to study the impact of chronic stress on immunity and cancer in mice. J Immunol. 2019;202(3):631-636. doi:10.4049/jimmunol.1800621
4. Saha J, Kim JH, Amaya CN, et al. Propranolol sensitizes vascular sarcoma cells to doxorubicin by altering lysosomal drug sequestration and drug efflux. Front Oncol. 2021;10:614288. doi:10.3389/fonc.2020.614288
5. Clinical evaluation of propranolol in combination with doxorubicin for the treatment of hemangiosarcoma. American Kennel Club Canine Health Foundation.May 3, 2021. Accessed October 24, 2022. https://www.akcchf.org/research/participate-in-
   research/Clinical-evaluation-of-propranolol-and-doxorubicin-for-the-treatment-of-hemangiosarcoma.html