Thursday, May 9, 2024
5/9/2024
Glioblastoma (GBM), the most common primary malignant brain cancer, remains among the most lethal of cancers. The mechanistic target of rapamycin (mTOR) is dysregulated prominently in GBM, however existing inhibitors are limited by either poor target inhibition or poor pharmacology. CoPI Kevan Shokat therefore linked the clinical TORKi sapanisertib (MLN0128) to the allosteric mTORC1 inhibitor rapamycin. This first bisteric mTORC1 inhibitor, RapaLink-1, showed mTORC1-specific binding and blood brain barrier permeability. Like rapamycin, this agent bound tightly to the cellular chaperone FK506 Binding Protein 12 (FKBP12), a protein we showed to be expressed at high levels in GBM. Thus, RapaLink-1 potently blocked the catalytic ATP- and substrate-binding site of mTOR within mTORC1, and accumulated in brain tumor cells. We showed that RapaLink-1 was more potent than rapamycin or the TORKi sapanisertib, which we traced to its superior pharmacokinetic profile compared to sapanisertib. We next generated a strategy to potentiate the inhibition Rapalink-1 in GBM, while sparing mTOR inhibition outside the CNS, dosing mice with both RapaLink-1 and a brain-impermeable FKBP12 ligand that we synthesized, called RapaBlock. This drug combination mitigated the systemic effects of mTORC1 inhibitors but retained the efficacy of RapaLink-1 in orthotopic GBM xenografts. We furthered this strategy by designing cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds including FK-dasatinib. Outside of the CNS, these inhibitors were sensitive to deactivation by RapaBlock, enabling brain-restricted inhibition of respective kinase targets. A clinical bisteric mTOR inhibitor, RMC-5552 is currently in clinical trials. A GBM trial opens in 2023. Like RapaLink-1, RMC-5552 is FKBP12-dependent. We hypothesize that 1). RapaBlock will potentiate efficacy while decreasing peripheral toxicity of RMC-5552 in GBM, and 2). We can further develop our strategy to develop FKBP-dependent inhibitors of other targets in GBM, including targets with liabilities outside of the CNS. A1. Test the hypothesis that RapaBlock will enhance efficacy and reduce toxicity associated with use of rapamycin and the clinical bisteric mTORC1 inhibitor RMC5552 in GBM. A2. Test the hypothesis that linking FK506, a high-affinity FKBP12 ligand, to JAK1/2 inhibitors will generate an FKBP12-dependent JAK inhibitor. STAT3 drives progression and therapy resistance in GBM. JAK inhibitors block activation of STAT3, however hematologic toxicity limits their utility. We will generate an FKBP12- dependent version of the clinical JAK1/2 inhibitor ruxolitinib. We will combine FK-ruxolitinib with RapaBlock as a strategy to maximize inhibition of STAT3 in orthotopic GBM xenografts, while sparing hematological toxicities. Successful completion develops a preclinical strategy to improve brain penetration while sparing peripheral toxicities for kinase inhibitors; and provides the preclinical rationale to: 1). Test RMC-5552 and Rapablock in combination in GBM, and 2). Move forward with developing both FK-ruxolitinib and RapaBlock as drugs. 1
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
