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DNA methylation as a therapeutic target in RB1 deficient and neuroendocrine prostate cancer and rational co-targeting with B7-H3 [RRBS]

ABSTRACT: Aberrant DNA methylation has been implicated as a key driver of prostate cancer lineage plasticity and histologic transformation to neuroendocrine prostate cancer (NEPC). DNA methyltransferases (DNMT) are highly expressed, and global DNA methylation levels are elevated in NEPC. We identified that deletion of DNMT genes decreases expression of neuroendocrine lineage markers and markedly reduced NEPC tumor development and metastasis in vivo. Decitabine, a global DNMT inhibitor, significantly attenuated tumor growth in NEPC patient-derived xenograft (PDX) models, as well as RB1-deficient castration-resistant prostate adenocarcinoma (CRPC) models compared with RB1-proficient CRPC. We further discovered that DNMT inhibition increased expression of B7-H3, an emerging druggable target, via demethylation of B7-H3 CpG islands. We tested DS-7300a, a novel antibody-drug conjugate (ADC) targeting B7-H3, alone and in combination with decitabine. There was potent single agent antitumor activity of DS-7300a in both CRPC and NEPC models bearing high expression of B7-H3. In B7-H3 low models, combination therapy of decitabine plus DS-7300a resulted in a synergistic response. Overall, we report that DNMT inhibition is a novel therapeutic target for NEPC and RB1-deficient CRPC and may sensitize B7-H3-low prostate cancer to the ADC DS-7300a through increasing target expression. NEPC and RB1-deficient CRPC represent prostate cancer subgroups with poor prognosis. The development of novel biomarker-driven therapeutic strategies for this population may ultimately help improve patient outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE216050 | GEO | 2024/03/27

REPOSITORIES: GEO

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Project description:Following treatment with androgen receptor (AR) pathway inhibitors, ~20% of prostate cancer patients progress by shedding their dependence on AR. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). Currently, no targeted therapies are available for CRPC-NEPCs. A major hurdle in the development of new therapies and treatment of CRPC-NEPC is the lack of accurate models to test candidate treatments. Such models would ideally capture components of the tumor microenvironment (TME) factors, which likely regulate the phenotypic, genetic, and epigenetic underpinnings of this aggressive subset. The TME is a complex system comprised not only of malignant prostate cells but also stromal and inflammatory cells and a scaffold of extracellular matrix (ECM). ECM proteins are implicated in the survival and progression of cancer and development of chemoresistance, while are equally integral to the development of prostate cancer organoids. Here, using a combination of patient tumor proteomics and RNA sequencing, we define putative ECM cues that may guide the growth of prostate tumors in patients. Using this molecular information, we developed synthetic hydrogels that recapitulate the tumor ECM. Organoids cultured in the synthetic hydrogel niches demonstrate that ECM subtypes regulate the morphology, transcriptome, and epigenetics hallmarks of CRPC-Adeno and CRPC-NEPC. CRPC-NEPC organoid showed a differential response to small molecule inhibitors of epigenetic repressor EZH2 and Dopamine Receptor D2 (DRD2), the latter being a novel target in CRPC-NEPC when grown in tumor-specific ECM. Finally, in those synthetic ECM niches where drug resistance was observed in CRPC-NEPCs, cellular reprogramming by a synergistic combination of EZH2 inhibitors with DRD2 antagonists inhibited tumor growth. The synthetic platform can provide a more realistic prostate-specific microenvironment and subsequently enable the development of effective targeted therapeutics for prostate cancers.

Project description:Histone deacetylation is crucial for the regulation of chromatin structure, gene transcription and the epigenetic state of the cell. With the emergence of the neuroendocrine (NE) phenotype in castration-resistant prostate cancer (CRPC), we hypothesized that the inhibition of HDAC1/2 would disrupt the epigenetic events involved in the conversion of prostate adenocarcinoma to a NE prostate cancer (NEPC) phenotype. Additionally, monotherapies tend to have limited efficacy in cancer treatment and combination treatments show more promise. Since the PI3K/AKT/mTOR pathway is a well-established tumor growth-promoting pathway and a promising target in CRPC and NEPC, we investigated the tumor suppressing activities of fimepinostat, a dual HDAC and PI3K inhibitor, on both prostate adenocarcinoma and NEPC. We evaluated multiple cell lines and patient-derived xenograft (PDX) models of prostate adenocarcinoma and NEPC to determine the roles of HDAC1/2 and AKT inhibition, both individually and in combination, in suppressing CRPC and NEPC tumor growth in vitro and in vivo. HDAC1/2 inhibition in combination with PI3K/AKT inhibition was more efficacious than targeting each pathway alone, induced growth inhibitory effects (in some cases synergistic) through cell cycle inhibition and apoptosis across an array of prostate adenocarcinoma and NEPC patient-derived xenografts (PDX) and cell lines in vitro and in vivo. Molecular profiling revealed on-target effects of combined HDAC1/2 and PI3K/AKT inhibition as well as a common downregulation of Myc, E2F, DNA repair, and G2M checkpoint targets, independent of prostate cancer phenotype. Fimepinostat therapy was also associated with the suppression of lineage transcription factor expression including androgen receptor (AR) in prostate adenocarcinoma and Achaete-scute homolog 1 (ASCL1) in NEPC. Our findings demonstrate that dual HDAC1/2 and PI3K/AKT pathway inhibition leads to robust tumor growth inhibition in both adenocarcinoma and NEPC, suggesting that fimepinostat may represent a novel therapeutic for both prostate adenocarcinoma and NEPC phenotypes of CRPC.

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DNA methylation as a therapeutic target in RB1 deficient and neuroendocrine prostate cancer and rational co-targeting with B7-H3 [RRBS]

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