Truly Man's Best Friend: Canine Cancers Drive Drug Repurposing in Osteosarcoma

In this issue of Clinical Cancer Research, Regan and colleagues (1) harness canine research to repurpose the CCL2-targeting activity of losartan for the treatment of osteosarcoma in combination with the tyrosine kinase inhibitor (TKI) taceranib. This sets up a preclinical justification for using the combination of losartan with a receptor TKI in human trials. Previously, this same group has identified that losartan is a noncompetitive inhibitor of CCL2-induced ERK1/2 activity. CCL2-CCR2 signaling has been identified as a key regulator of inflammatory monocyte recruitment to metastatic sites (2). Toceranib, the only canine-specific anticancer drug approved by the FDA, is a multikinase inhibitor and a sister compound of sunitinib (3). In parallel, off-label use of multireceptor TKIs is in the National Comprehensive Cancer Network guidelines for the treatment of osteosarcoma. In this trial, dose escalation of losartan in combination with toceranib was well tolerated and demonstrated the equivalent of sarcoma clinical benefit rate of 50% in 28 dogs with lung metastatic osteosarcoma. Pharmacodynamic analyses demonstrated a correlation reflecting modulation of CCL2 signaling and monocyte migration. Of note, the dose of losartan needed was 10 times the usual dose for dogs, which may require drug reformulation by medicinal chemists if humans cannot tolerate higher doses. A phase I clinical trial will determine whether the higher dose of losartan needed in canine models will be tolerable in humans when added to a TKI.

One of the quandaries in the treatment of osteosarcoma is the failure of immunotherapy to have a relevant role (4). Osteosarcoma is known for its high degree of genomic instability and high tumor mutational burden, making the lack of response to immunotherapy disappointing. Highlighted in the biology of Regan and colleagues is the ability to alter the tumor microenvironment with losartan. Supporting their biology in this direction, gene enrichment sets highlight changes in the immune signature. In addition, this work highlights the difference in osteosarcoma biology between primary tumors and lung metastases. The inflammatory monocytes once recruited to metastatic lung lesions differentiate into metastasis-associated macrophages that cause tumor cell extravasation, growth, and angiogenesis. Separating the treatment strategies for primary and metastatic sites is an evolving concept in osteosarcoma that has the potential to improve the efficacy of immunotherapy.

Canine models are of particular use in studying metastatic progression with the ability to test investigational agents in various combinations and doses in the adjuvant setting. The relatively quick accrual of these studies can highlight those agents with the most potential efficacy in human subjects and streamline clinical trials. As pointed out by Khanna and colleagues (5), there is a need for rigor in the testing of osteosarcoma drug development. Of primary importance, there must be a mechanism of action that applies to osteosarcoma. Second, there should be pharmacodynamic markers of effective exposure. Third, there should be testing in multiple animal models, including canine models. To this, I would add a fourth that there should be evidence of synergy in multiagent combinations. In the case of losartan with toceranib, we have mechanism (CCL2 inhibition), pharmacodynamic markers (monocyte number), and multiple animal models, though synergy was not formally tested.

The support for novel approaches for the treatment of rare cancers is ever-growing. First, the CURE Drug Repurposing Collaboratory in partnership with the FDA is an initiative created with the intent of open collaboration between investigators for the goal of identifying, evaluating, and implementing clinical trials utilizing existing drugs for new treatment indications. This is particularly useful in rare disease types such as sarcoma with high unmet clinical need and provides needed funding for clinical trials. Next, there is a commitment by St Baldrick's (www.stbaldricks.org) and Alex's Lemonade Stand (www.alexslemonade.org), among others, to invest in pediatric cancer preclinical and translational investigations. Finally, under the stewardship of Lee Helman and Chand Khanna, the Osteosarcoma Institute (osinst.org) is now formally funding translational grants and trials that are based on the same principles outlined in Khanna and colleagues (5) on how best to translate findings in osteosarcoma. The investment by these groups in Osteosarcoma has changed the landscape in the fight against pediatric cancers.

Overall, this work demonstrates drug repurposing utilizing canine osteosarcoma with the potential to translate to humans and back again (Fig. 1). This makes the translation of the combination of losartan and a TKI worthy of consideration in the clinical setting. The field of rare tumors is naturally a good fit for drug repurposing investigations (6). Examples of this include the off-label use of thalidomide and sirolimus for epithelioid hemangioendothelioma, propranolol for angiosarcoma, and TKIs such as cabozantinib, regorafinib, and sorafenib for osteosarcoma. The challenge for off-label drug development is the lack of preclinical models that recapitulate the biology of the various rare tumors that are treated by sarcoma physicians. While there are cell lines, patient-derived xenograft models and transgenic models that are used, they often fail to translate in the clinical setting, as preclinical models often fail to recapitulate the various rare cancers. Given the incidence of osteosarcoma in children at 500 cases in the United States per year, with another 500 cases in adults, a phase III clinical trial can be performed on average once every 5 years. As such, this puts great pressure on the Children's Oncology Group to choose the right agents to test among the many great ideas. The challenge that exists is in choosing the next trial from the long list of opportunities that include new TKIs, novel immunotherapy agents, therapies that target tumor metabolism, HER2-directed agents and other evolving therapeutic strategies. As such, canine osteosarcoma represents a unique resource that parallels human disease and provides a more efficient mechanism for studying disease pathophysiology and testing treatment strategies. Therefore, it will be easier to choose the next therapeutic trial for osteosarcoma when the agents fulfill the Khanna criterion. While it is truly unfortunate that osteosarcoma is a common tumor among dogs, the opportunity to partner with our veterinary colleagues may allow us not only to help the children and adults with osteosarcoma, but also their best friends.

B.A. Van Tine reports grants from Pfizer, Merck, Tracon Pharm, and GSK; personal fees from Epizyme, ADRx, Ayala Pharmaceuticals, Cytokinetics Inc, Bayer, Adaptimmune Limited, Bionest Partners, Intellisphere LLC, Apexigen Inc, Daiichi Sankyo, Deciphera Pharmaceuticals, Inc, Novartis, Lilly, and Polaris; and other support from Accuronix Therapeutics outside the submitted work. No disclosures were reported by the other authors.