Response of Osteosarcoma Cell Lines to a Novel CHD1L Inhibitor.

Osteosarcoma (OSA) is a primary tumor of bone that occurs in both humans (hOSA) and dogs (cOSA) and has been recognized as being very similar across these species. In fact, OSA is probably the best example where surgical, radiological and drug trials have been translated from testing in pet dogs with OSA to trials in human patients. In both humans and dogs treated for OSA, the primary treatment modalities are surgery and cytotoxic chemotherapy with doxorubicin and platinum-based drugs standard for both and methotrexate also commonly added in humans. The treatment of OSA in both dogs and humans has been virtually unchanged in the last 40 years leading to stagnation in outcome improvement with lung metastasis and drug resistance being the primary mechanism of disease progression and patient morbidity and mortality. Thus, drug treatments that can effectively treat OSA and inhibit disease progression at metastatic sites are badly needed. Chromodomain Helicase DNA-binding protein 1-Like (CHD1L), a.k.a. Amplified in Liver Cancer (ALC1), is an oncogene that was originally identified in hepatocellular carcinoma. It has recently gained more attention with regards to resistance to PARP inhibitors in BRCA-mutant cancers as well as a potential target for anticancer drug therapy. Studies have also suggested that CHD1L plays a role in resistance to platinum-based chemotherapy agents through the modulation of DNA repair processes. This has led to a great deal of interest into drugs that can inhibit CHD1L. The first and only known small molecule CHD1L inhibitors (CHD1Li) have recently been reported by Dr. LaBarbera's lab in the CU School of Pharmacy (Mol Cancer Ther 19:1598, 2020) who has an active medicinal chemistry program developing these molecules. Preliminary analysis of CHD1L gene expression in cOSA cell lines and tumors shows that expression levels are significantly higher in cOSA cell lines as opposed to other canine cell lines and that CHD1L expression is higher in cOSA tumors as opposed to normal bone. Treatment of cOSA and hOSA cell lines with a CHD1Li show a steep dose-response of inhibition of cell proliferation and induction of cell death with IC values ranging between 2 and 3 μM and LD values between 3 and 4 μM. These μM drug concentrations are safely achievable in mice dosed daily with this drug based on in vivo studies. The results suggest that CHD1L inhibition should be further pursued for therapeutic development in OSA and that cOSA and hOSA cell lines have a similar response to these agents.