Abstract
The epichaperome is a new cancer target composed of hyperconnected networks of chaperome members that facilitate cell survival. Cancers with an altered chaperone configuration may be susceptible to epichaperome inhibitors. We developed a flow cytometry-based assay for evaluation and monitoring of epichaperome abundance at the single cell level, with the goal of prospectively identifying patients likely to respond to epichaperome inhibitors, to measure target engagement, and dependency during treatment. As proof of principle, we describe a patient with an unclassified myeloproliferative neoplasm harboring a novel PML-SYK fusion, who progressed to acute myeloid leukemia despite chemotherapy and allogeneic stem cell transplant. The leukemia was identified as having high epichaperome abundance. We obtained compassionate access to an investigational epichaperome inhibitor, PU-H71. After 16 doses, the patient achieved durable complete remission. These encouraging results suggest that further investigation of epichaperome inhibitors in patients with abundant baseline epichaperome levels is warranted.
Highlights
Precision medicine (PM) approaches in cancer treatment are designed to offer patient-specific, mechanistically driven selection of therapeutic strategies
The patient was diagnosed with an unclassified myeloproliferative disorder (MPD) and underwent matched unrelated donor (MUD) allogeneic stem cell transplantation conditioned with Fludarabine/Melphalan
We have previously reported a positive correlation between the epichaperome and a hyperactivated signalosome in acute myeloid leukemia (AML) cells[6], which was confirmed in this patient while evaluating the novel PML-SYK fusion
Summary
Precision medicine (PM) approaches in cancer treatment are designed to offer patient-specific, mechanistically driven selection of therapeutic strategies. Independent of the tissue of origin and the genetic background of tumors, stressors associated with malignant transformation aberrantly rewire PPI networks to provide a survival advantage under conditions of stress. These proteome-wide changes are enabled by the restructuring of the chaperome, an assembly of molecular chaperones, co-chaperones and other co-factors, into new entities termed epichaperome networks[1,4]. By providing the backbone upon which protein networks become aberrantly reorganized, epichaperomes are essential to cancer cell viability They present vulnerability and in turn, a target for therapeutic intervention with drugs that impair epichaperome formation and/or its function
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