Abstract
Chordoma is a devastating rare cancer that affects one in a million people. With a mean-survival of just 6 years and no approved medicines, the primary treatments are surgery and radiation. In order to speed new medicines to chordoma patients, a drug repurposing strategy represents an attractive approach. Drugs that have already advanced through human clinical safety trials have the potential to be approved more quickly than de novo discovered medicines on new targets. We have taken two strategies to enable this: (1) generated and validated machine learning models of chordoma inhibition and screened compounds of interest in vitro. (2) Tested combinations of approved kinase inhibitors already being individually evaluated for chordoma. Several published studies of compounds screened against chordoma cell lines were used to generate Bayesian Machine learning models which were then used to score compounds selected from the NIH NCATS industry-provided assets. Out of these compounds, the mTOR inhibitor AZD2014, was the most potent against chordoma cell lines (IC50 0.35 µM U-CH1 and 0.61 µM U-CH2). Several studies have shown the importance of the mTOR signaling pathway in chordoma and suggest it as a promising avenue for targeted therapy. Additionally, two currently FDA approved drugs, afatinib and palbociclib (EGFR and CDK4/6 inhibitors, respectively) demonstrated synergy in vitro (CI50 = 0.43) while AZD2014 and afatanib also showed synergy (CI50 = 0.41) against a chordoma cell in vitro. These findings may be of interest clinically, and this in vitro- and in silico approach could also be applied to other rare cancers.
Highlights
Chordoma tumors, which occur in both pediatric and adult populations, are known to overexpress multiple kinases[4]
In one published chordoma study 1097 compounds were screened against 3 chordoma cell lines (U-CH1, U-CH2, MUG-Chor1) and 27 had chordoma selective c ytotoxicity[20] and many of these were Epidermal Growth Factor Receptor (EGFR) inhibitors
Two FDA-approved EGFR inhibitors used in the treatment of non-small-cell lung carcinoma (NSCLC), individually inhibited U-CH1, U-CH7, UM-Ch-SCor[1], and MUGChor[1] cellular proliferation in dose-dependent m anners[20,34]
Summary
Chordoma tumors, which occur in both pediatric and adult populations, are known to overexpress multiple kinases[4]. We hypothesized that combinations of clinical kinase inhibitors in chordoma models and patients may act additively or synergistically by dampening oncogenic signaling in multiple pathways. Both primary targets and secondary targets can play a role in this. We evaluate the in vitro efficacy of EGFR/CDK inhibitor combinations prior to future in vivo PDX and CDX mouse model studies We envision that these proposed studies will enable and support future drug combination chordoma clinical trials
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