Abstract 4833: Pharmacodynamic and tumor biomarker analysis of a PLK1 inhibitor, PCM-075, in a phase 1b/2 trial for acute myeloid leukemia
Authors: Maya Ridinger, Karena Kosco, Latifa Hassaine, Jeffrey N. Miner, Mark Erlander
Journal: Cancer Research (2018)

Abstract Acute myeloid leukemia (AML) is an aggressive hematologic disease that is characterized by the accumulation of immature myeloid precursor cells. Treatment options for patients are selected based on factors such as age, comorbidities, and cytogenetics. For patients deemed ineligible for standard intensive induction chemotherapy, treatments include either low-dose cytarabine (LDAC) or hypomethylating agents (e.g., azacitidine and decitabine) but when used as single agents, relapses are inevitable. Polo-like Kinase 1 (PLK1), a serine/threonine kinase that is a master regulator of cell-cycle progression, is overexpressed in a number of cancer types including AML. Depletion of PLK1 preferentially induces cell death in tumor versus normal cells. Inhibition of PLK1 in preclinical AML models results in significant efficacy. PCM-075, a highly selective PLK1 inhibitor, is currently in a phase 1b/2 trial (NCT03303339) in combination with standard-of care (LDAC or decitabine) for AML. Collection and processing of blood and bone marrow samples from patients is being performed pre- and post-treatment to assess 1) the inhibition of PLK1 kinase activity and downstream effects by measurement of pharmacodynamic (PD) and mechanism of action (MOA) biomarkers (blood), and 2) the genomic profile of blast cell population(s) from individual patients (blood and bone marrow). For each patient, blood is collected into CellSave, EDTA, and PAXgene blood RNA tubes at various time points as per the clinical protocol schedule of events. PBMCs isolated from CellSave blood tubes are used to assess the phosphorylation status of PD biomarkers using Western blot and phospho-flow cytometry. DNA extracted from blasts (EDTA tube) is used to detect somatic alterations and RNA extracted from the total cell population (PAXgene) is used to detect fusions and determine gene expression profiles by next-generation sequencing. To identify potential PD biomarkers that would enable assessment of PLK1 inhibition in AML patients treated with PCM-075, nine candidate substrates phosphorylated by PLK1 were screened in the AML cell line MV4-11 by Western blot using selected phospho-antibodies. Of these, phosphorylation of Translational Control Tumor Protein (TCTP) at Ser46 was both time- and dose-dependently inhibited by PCM-075. pTCTP detection by Western blot and phospho-flow cytometry was first optimized in PBMCs isolated from healthy donors and later in blast cells from AML patients resulting in a functional biomarker. Additional downstream MOA biomarkers of PCM-075 activity (DNA content, phospho-histone H3, cleaved caspase 3) and tumor DNA biomarkers that enable categorization of AML molecular subtypes have been validated. We present preliminary patient data from the ongoing phase 1b/2 trial and describe biomarker assays that will be used to evaluate target engagement of PCM-075 in AML patients. Citation Format: Maya Ridinger, Karena Kosco, Latifa Hassaine, Jeffrey N. Miner, Mark Erlander. Pharmacodynamic and tumor biomarker analysis of a PLK1 inhibitor, PCM-075, in a phase 1b/2 trial for acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4833.