Repurposing old drugs for new cancer treatments

Treating our canine patients has become more expensive over the years, especially with newer drugs. Researchers evaluated older drugs and found that losartan and propranolol may have other uses.

Losartan is traditionally a drug for hypertension, but this angiotensin receptor blocker also has immunomodulatory actions involving monocytes and macrophages which inhibit the recruitment of monocytes into tumors. Normally, there are many macrophages and monocytes in the tumor microenvironment (TME), making them good therapeutic targets. By targeting these cells for elimination or reprogramming, we can alter the immunosuppressive effects of TME to better respond to the immune system.¹

The results of a recent study evaluating the combination of losartan and toceranib in dogs with lung metastases of osteosarcoma showed that a high dose of losartan with toceranib had a clinical benefit rate of 50% and that the survival was longer with the combination than in studies involving toceranib treatment alone,² making this combination a unique treatment option for dogs with advanced osteosarcoma. Since the findings of this study, researchers have evaluated a similar combination with losartan and sunitinib in a pediatric clinical trial for osteosarcoma.

Propranolol is a β-adrenergic blocker that helps regulate heart rhythm and has been used in the past as a blood pressure medication (although it has been superseded by newer blood pressure medications). 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 immunosuppressive cell known as myeloid-derived suppressor cells (MDSCs). When MDSCs are depleted, this removes this important brake on tumor immunity, allowing T cells to function more efficiently 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 on 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. The 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 clinically well tolerated.

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

Rachel Venable, DVM, MS, DACVIM (oncology), is a board-certified medical oncologist by the American College of Veterinary Internal Medicine. She received her veterinary degree from the University of Missouri at Columbia, with honors, 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 research clinical trials and cutting-edge therapies for her patients. Venable has authored numerous publications and has been a speaker locally and nationally. She is the founder of Pet Cancer Care Consulting, an innovative teleconsultation service that consults with the family veterinarian and pet owner to provide personalized answers and the information needed to make an informed decision on treatments.

References

1. Regan DP, Coy JW, Chahal KK, et al. Losartan, an angiotensin receptor blocker, suppresses the growth of lung 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. Losartan blocks monocyte recruitment caused by osteosarcoma and, in combination 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/func.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