Emerging target discovery and drug repurposing opportunities in chordoma

Abstract

The development of effective and personalized treatment options for patients with rare cancers like chordoma is hampered by numerous challenges. Biomarker-guided repurposing of therapies approved in other indications remains the fastest path to redefining the treatment paradigm, but chordoma’s low mutation burden limits the impact of genomics in target discovery and precision oncology efforts. As our knowledge of oncogenic mechanisms across various malignancies has matured, it’s become increasingly clear that numerous properties of tumors transcend their genomes – leading to new and uncharted frontiers of therapeutic opportunity. In this review, we discuss how the implementation of cutting-edge tools and approaches is opening new windows into chordoma’s vulnerabilities. We also note how a convergence of emerging observations in chordoma and other cancers is leading to the identification and evaluation of new therapeutic hypotheses for this rare cancer.

Animal model considerations for chordoma research: reproducing the tumor microenvironment in vivo with humanized mice

“…For example, the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) pathway has been widely studied by Zou and colleagues ( 35 , 62 , 128 , 139 , 140 ) as TILs and macrophages express PD-1 receptor ( 138 ). Besides the PD1/PDL1 pathway, TGF-beta-related genes, HHLA2, and cytotoxic T-lymphocyte antigen-4 (CTLA-4) are among some of the immune-associated molecules analyzed so far ( 128 , 129 , 131 ). Other examples of interactions between chordoma and the immune system are the above mentioned plastic macrophages that, via the ccl5/ccr5 axis, are recruited and polarized by chordoma to enhance the proliferation, invasion and migration capabilities of chordoma ( 136 ); galectin-9 that interacts with TIM3-positive TILs and that promotes cell apoptosis ( 141 ) and the expression of CTLA-4, a promising immune checkpoint inhibitor target that it is expressed by the TILs that are infiltrating chordoma ( 129 ).…”

Targeting mTOR Pathway in PTEN Deleted Newly Isolated Chordoma Cell Line

“…Generally, five-year overall age-adjusted relative survival is estimated to be approximately 61% [ 2 ], while the recurrence rate is 43–85% [ 4 ]. Thus, it is of paramount importance to develop new therapeutic strategies, which greatly depend on both histological and molecular features [ 8 ]. For this reason, different pre-clinical models of chordoma have been generated in the last few years [ 4 ].…”