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FIGURE 5 from Concurrent Targeting of HDAC and PI3K to Overcome Phenotypic Heterogeneity of Castration-resistant and Neuroendocrine Prostate Cancers

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posted on 2023-11-20, 14:20 authored by Ailin Zhang, Nathan A. Lau, Alicia Wong, Lisha G. Brown, Ilsa M. Coleman, Navonil De Sarkar, Dapei Li, Diana C. DeLucia, Mark P. Labrecque, Holly M. Nguyen, Jennifer L. Conner, Ruth F. Dumpit, Lawrence D. True, Daniel W. Lin, Eva Corey, Joshi J. Alumkal, Peter S. Nelson, Colm Morrissey, John K. Lee

Fimepinostat significantly inhibits tumor growth in NEPC PDX models relative to the HDAC inhibitor romidepsin alone. NEPC PDX models (LuCaP 145.1 and LuCaP 208.1) were treated with 1.5 mg/kg romidepsin [(A) LuCaP 145.1, n = 11; (B) LuCaP 208.1 n = 11] or 75 mg/kg fimepinostat [(C) LuCaP 145.1, n = 9; (D) LuCaP 208.1 n = 11] or vehicle control (LuCaP 145.1, n = 8; LuCaP 208.1, n = 11) for up to 3.5 weeks. Blue = vehicle vs. red = romidepsin or fimepinostat. P values = *, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001.

Funding

HHS | NIH | National Cancer Institute (NCI)

DOD | USA | MEDCOM | CDMRP | DOD Prostate Cancer Research Program (PCRP)

Prostate Cancer Foundation (PCF)

HHS | NIH | NIH Office of the Director (OD)

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ARTICLE ABSTRACT

Castration-resistant prostate cancer (CRPC) consists of multiple phenotypic subtypes including androgen receptor (AR)-active prostate cancer (ARPC) and neuroendocrine prostate cancer (NEPC). Tumor cells with these phenotypes can coexist between metastases within a patient and within an individual tumor. Treatments that are effective across CRPC subtypes are currently lacking. Histone deacetylation is crucial for the regulation of chromatin structure and maintenance of cancer cell state and activation of the PI3K/AKT/mTOR signaling cascade is a tumor growth–promoting pathway. We therefore investigated combined targeting of histone deacetylase (HDAC) and PI3K using a rationally designed dual inhibitor, fimepinostat, in CRPC subtypes in vitro and in vivo. Dual HDAC1/2 and PI3K/AKT pathway inhibition by fimepinostat led to robust tumor growth inhibition in both ARPC and NEPC models including cell line– and patient-derived xenografts. HDAC1/2 inhibition combined with PI3K/AKT inhibition was more effective than targeting each pathway alone, producing growth inhibitory effects through cell-cycle inhibition and apoptosis. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition independent of tumor phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factors including AR in ARPC and Achaete-scute homolog 1 (ASCL1) in NEPC. Together, these results indicate that fimepinostat represents a novel therapeutic that may be effective against both ARPC and NEPC through CRPC subtype-dependent and -independent mechanisms. CRPC is a heterogeneous disease constituting multiple phenotypic subtypes that often co-occur within tumors or across metastases in patients. Existing targeted therapies for CRPC do not take this into account. Here we show that fimepinostat, a dual HDAC1/2 and PI3K/AKT inhibitor investigated clinically in other cancer types but not prostate cancer, may overcome this heterogeneity by effectively inhibiting both ARPC and NEPC subtypes of CRPC.

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