. Genomic deletions of major tumor suppressor genes are frequent events in cancer yet presently remain therapeutically unactionable for the purpose of precision oncology. Our lab has pioneered an innovative therapeutic paradigm known as collateral lethality, whereby genes neighboring a TSG locus encoding a key housekeeping enzyme are coincidentally deleted. We discovered that the metabolic vulnerabilities arising from such collateral deletions may be therapeutically exploited through inhibition of the enzyme?s redundant isoform. Emblematic of this framework are cancers harboring homozygous deletion of the glycolytic enzyme Enolase 1 (ENO1). As glycolysis is an essential bioenergetic process, ENO1-homozygous deleted cancers are entirely reliant on the ENO2 to perform glycolysis and ensure the cellular viability. Inhibition of ENO2 selectively kills ENO1-homozygous deleted the cancers while leaving normal tissues unperturbed. To pharmacologically act on this vulnerability, our lab has developed an ENO2-preferred inhibitor, HEX. As testament to the strong therapeutic viability of collateral lethality, we have shown that HEX is capable of completely eradicating ENO1- homzoygous deleted intracranial orthotopic models of glioblastoma in mice at concentrations well-tolerated in non-human primates. Such robust anti-neoplastic effects are unprecedented in the context of glioblastoma and speak to the power of the collateral lethality approach. One critique of the focus of collateral lethality is its scope: in the case of ENO1-deletions, only a small percentage of patients would be able to benefit. To broaden the therapeutic reach of collateral lethality, this proposal will focus on targeting ENO1-heterozygous deleted cancers, which comprise ~20% of all human cancers. This will be accomplished by adding tumor subtype-specific pro- drug moieties onto HEX to improve its delivery. While ENO1-heterozygous deleted cancers are deficient in total Enolase, they are not nearly as depleted as ENO1-homozygous deleted cancers are. As HEX is a negatively charged molecule, tumor-subtype specific pro-drug attachment onto HEX will not only enhance its cell permeability but will also improve its tumor specificity. Together, these two traits will enable drug dosing at lower concentrations to afford a therapeutic window sufficiently large to treat ENO1-heterozygous deleted cancers without the perturbing normal tissues. Overall, this proposal leverages the concept of rational pro-drug design to improve the specific of our core ENO2 inhibitor so that we may widen the therapeutic reach of collateral lethality.
. Precision oncology has been demonstrably successful for the treatment of certain cancers. However, it has largely been limited to targeting mutant activated oncogenes while overlooking other pervasive mutations such as deletions of tumor suppressor genes. Our laboratory has pioneered an innovative therapeutic strategy, known as collateral lethality, which enables genomic deletions to serve as targets of precision medicine. Under this paradigm, we have developed an inhibitor of the glycolytic enzyme Enolase (ENO2 isoform) for the treatment of poorly prognosed tumors harboring homozygous deletions in ENO1. The goal of this proposal is to broaden the therapeutic reach of collateral lethality through strategic pro-drug modification of our laboratory?s core ENO2-preferred inhibitor so that ENO1-heterozygous deleted cancers, which comprise ~20% of all human cancers, may also be targeted.
