The epichaperome is a new cancer target defined by changes in the interaction strength between chaperone and cochaperone proteins to form stable hyperconnected networks that support oncoprotein stability and are vital for tumor. Cancers with this altered chaperone configuration may become susceptible to drugs that target the epichaperome, such as the inhibitor PUH71. We developed a novel flow cytometrybased test, the PUFITC binding assay, to evaluate epichaperome levels at the single cell level and successfully identified a patient who has a potential to respond to PUH71 treatment.
A 61-year-old woman was diagnosed with myeloproliferative neoplasm in 2013. After treatment with hydroxyurea, in 2013 she underwent a MUD transplantation. In 2016, she relapsed with atypial GvHD symptoms and mixed chimerism, and progressed to refractory AML in 2017. Patient-derived cells were found to harbor a novel fusion gene, PML-SYK, generated by translocation (9;15) and were constitutively activated of Syk, Stat5, Erk and ribosomal S6 kinase. Elevated epichaperome levels were found in the cell populations bearing PML-SYK, suggesting sensitivity to PUH71. In vitro, treatment of patient’s cells with PUH71 resulted in cell death and decreased colony formation. Based on laboratory data, the poor prognosis, and lack of effective therapies, the patient was granted compassionate access to this medication by the FDA. After 16 doses of PUH71 over 3 months, the patient has attained complete remission, with normalization of peripheral blood counts.
This refractory AML patient is presently in remission and the assay is being used to screen other potential patients.