Synergistic drug combinations and machine learning for drug repurposing in chordoma

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 (ic 50 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 (CI 50 = 0.43) while AZD2014 and afatanib also showed synergy (ci 50 = 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. Chordoma is a rare cancer that occurs in the bones of the skull base and spine which is part of a larger class of tumors known as sarcomas. Chordoma tumors develop from cells of the notochord, an embryonic structure that facilitates development of the spine 1. The notochord disappears when the fetus is about 8 weeks old, but some notochord cells remain in the bones of the spine and skull base 2. This is a rare occurrence, but when they do, these cells can turn into chordoma. A chordoma tumor usually grows slowly without symptoms for years before diagnosis, which is often in the 5 th and 6 th decades of life (although it can occur at any age). Studies have demonstrated that skull base chordomas are observed more often in children, whilst spinal chordomas are more frequently observed later in life 2,3. It has also been described that when chordomas metastasize they frequently distribute to the lungs, liver, bones, or lymph nodes. This occurs in 30 to 40 percent of people where the tumor metastasizes to other parts of the body 2. At this point in time there are no known environmental, dietary or lifestyle risk factors for this rare type of cancer. Chordomas often occur at random with no direct inherited genetic trait, however familial cases can be caused by duplications of the brachyury gene 4. A SNP in the brachyury gene occurs in 95 percent of people with this tumor 5,6 , and furthermore, chordomas have ...

Personalized chordoma organoids for drug discovery studies

“…The PI3K/mTOR targeting drugs sapanisertib and vistusertib showed efficacy in our organoid screenings (Figure 3). Both drugs have been found to be effective in chordoma cell lines 23,49 . Our screening additionally identified other PI3K/mTOR targeting drugs such as apitolisib and omipalisib.…”

“…EGFR targeting drugs such as lapatinib have shown some efficacy in controlling disease and are approved for use in EGFR positive chordomas 10,51 . Additional EGFR targeting drugs that have been tested in clinical trials for chordoma include erlotinib, linsitinib, afatinib, and the monoclonal antibody cetuximab 48,49 . We observed moderate efficacy of the EGFR targeting drug gefitinib in 3/7 samples.…”

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Machine learning in drug design: Use of artificial intelligence to explore the chemical structure–biological activity relationship

“…Based on the validation results, authors concluded that model could predict new drugs for psoriasis, with the highest prediction scores for budesonide (a corticosteroid, currently used to treat asthma and inflammatory bowel disease) and hydroxychloroquine (an antimalarial drug that is also used to treat lupus and rheumatoid arthritis). Anderson et al 129 used Bayesian ML models for drug repurposing in chordoma. Of the available data, the mTOR inhibitor AZD2014 was indicated as the most potent against chordoma cell lines (IC 50 0.35 μM U‐CH1 and 0.61 μM U‐CH2).…”