Development of a dual targeting scaffold of SET7/MLL inhibitor for castration-resistant prostate cancer treatment.
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ABSTRACT:
SUBMITTER: Li G
PROVIDER: S-EPMC10404973 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
Development of a dual targeting scaffold of SET7/MLL inhibitor for castration-resistant prostate cancer treatment.
Li Guodong G Huang Qi Q Wai Wong Vincent Kam VK Wang Wanhe W Leung Chung-Hang CH
Genes & diseases 20230324 6
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Project description:Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Although prior work has focused on targeting AR directly, co-activators of AR signaling, which may represent new therapeutic targets, are relatively underexplored. Here we demonstrate that the mixed-lineage leukemia protein (MLL) complex, a well-known driver of MLL fusion-positive leukemia, acts as a co-activator of AR signaling. AR directly interacts with the MLL complex via the menin-MLL subunit. Menin expression is higher in CRPC than in both hormone-naive prostate cancer and benign prostate tissue, and high menin expression correlates with poor overall survival of individuals diagnosed with prostate cancer. Treatment with a small-molecule inhibitor of menin-MLL interaction blocks AR signaling and inhibits the growth of castration-resistant tumors in vivo in mice. Taken together, this work identifies the MLL complex as a crucial co-activator of AR and a potential therapeutic target in advanced prostate cancer.
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Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-02-27 | E-GEOD-60842 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below.
2015-02-27 | GSE60842 | GEO
Project description:Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Prior work has focused on targeting AR directly; however, the identification and targeting of co-activators of AR signaling remains an underexplored area. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR interacts with the MLL complex via its subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits tumor growth in vivo. Furthermore, we find that menin is up-regulated in CRPC and high expression correlates with poor overall survival. Our study identifies the MLL complex as a co-activator of AR that can be targeted in advanced prostate cancer. ASH2L / Menin / MLL1 were knocked down using shRNA /siRNA in two prostate cancer cell lines, VCaP and LNCaP.
2015-03-02 | E-GEOD-60836 | biostudies-arrayexpress
Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens MDV3100 (enzalutamide), durable responses are limited, presumably due to acquired resistance. Recently, JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer. Examination of ASH2L genome-wide binding in prostate cancer cells after AR stimulation.
2015-03-02 | E-GEOD-60841 | biostudies-arrayexpress
Project description:Resistance to androgen deprivation therapies and increased androgen receptor (AR) activity are major drivers of castration-resistant prostate cancer (CRPC). Prior work has focused on targeting AR directly; however, the identification and targeting of co-activators of AR signaling remains an underexplored area. Here we demonstrate that the MLL (mixed-lineage leukemia) complex, a well-known contributor in MLL-fusion-positive leukemia, acts as a co-activator of AR signaling. AR interacts with the MLL complex via its subunit, menin. Small molecule inhibition of the menin-MLL interaction blocks AR signaling and inhibits tumor growth in vivo. Furthermore, we find that menin is up-regulated in CRPC and high expression correlates with poor overall survival. Our study identifies the MLL complex as a co-activator of AR that can be targeted in advanced prostate cancer.
2015-03-02 | GSE60836 | GEO
Project description:Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. The development and progression to CRPC following androgen ablation therapy is predominantly driven by unregulated androgen receptor (AR) signaling. Despite the success of recently approved therapies targeting AR signaling, such as abiraterone and second-generation anti-androgens MDV3100 (enzalutamide), durable responses are limited, presumably due to acquired resistance. Recently, JQ1 and I-BET, two selective small molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit antiproliferative effects in a range of malignancies. Here we show that AR signaling-competent CRPC cell lines are preferentially sensitive to BET bromodomain inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1. Like the direct AR antagonist, MDV3100, JQ1 disrupted AR recruitment to target gene loci. In contrast to MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR mediated gene transcription including induction of TMPRSS2-ERG and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.
2015-03-02 | GSE60841 | GEO
Project description:Prognosis of castration-resistant prostate cancer (CRPC) carries is poor, and no effective therapeutic regimen is yet known. The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway played a predominant role and may be a promising molecular target for CRPC. However, the toxicity of the dual PI3K inhibitors in clinical trials limits their clinical efficacy for CRPC. To solve this problem, we employed a highly integrated precision nanomedicine strategy to molecularly and physically target CRPC through synergistic effects, enhanced targeted drug delivery efficiency, and reduced unwanted side-effects. Gedatolisib (Ge), a potent inhibitor of PI3K/mTOR, was formulated into our disulfied-crosslinked micelle plateform (NanoGe), which exhibits excellent water solubility, small size (23.25±2 nm), excellent stability with redox stimulus-responsive disintegration, and preferential uptake at tumor sites. NanoGe improved the anti-neoplastic effect of free Ge by 53 times in PC-3M cells and 13 times in C4-2B cells though its enhanced uptake via caveolae- and clathrin-mediated endocytic pathways and the subsequent inhibition of the PI3K/mTOR pathway, resulting in Bax/Bcl-2 dependent apoptosis. In an animal xenograft model, NanoGe showed superior efficacy than free Ge, and synergized with nanoformulated cabazitaxel (NanoCa) as a nanococktail format to achieve a cure rate of 83%. Taken together, our results demonstrate the potency of NanoGe in combination with NanoCa is potent against prostate cancer.
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Project description:Catalase (CAT) is an important antioxidant enzyme that breaks down H2O2 into water and oxygen. Inhibitor-modulating CAT activity in cancer cells is emerging as a potential anticancer strategy. However, the discovery of CAT inhibitors towards the heme active center located at the bottom of long and narrow channel has made little progress. Therefore, targeting new binding site is of great importance for the development of efficient CAT inhibitors. Here, the first NADPH-binding site inhibitor of CAT, BT-Br, was designed and synthesized successfully. The cocrystal structure of BT-Br-bound CAT complex was determined with a resolution of 2.2 Å (PDB ID:8HID), which showed clearly that BT-Br bound at the NADPH-binding site. Furthermore, BT-Br was demonstrated to induce ferroptosis in castration-resistant prostate cancer (CRPC) DU145 cells and eventually reduce CRPC tumors in vivo effectively. The work indicates that CAT has potential as a novel target for CRPC therapy based on ferroptosis inducing.
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Project description:Prostate cancer (PCa) is the most commonly diagnosed solid tumor and the second leading cause of cancer-related deaths in U.S. men in 2020. Androgen-deprivation therapy (ADT) is the standard of care for metastatic PCa. Unfortunately, PCa relapse often occurs one to two years after initiation of ADT, resulting in the development of castration-resistant PCa (CRPCa), a lethal disease. While several anticancer agents such as docetaxel, abiraterone acetate, and enzalutamide are currently utilized to extend a patient's life after development of CRPCa, patients will eventually succumb to the disease. Hence, while targeting androgen signaling and utilization of docetaxel remain the most crucial agents for many of these combinations, many studies are attempting to exploit other vulnerabilities of PCa cells, such as inhibition of key survival proteins, anti-angiogenesis agents, and immunotherapies. This review will focus on discussing recent advances on targeting therapy. Several novel small molecules will also be discussed.
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