Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer

Tumor-associated macrophages are key immune cells associated with cancer progression. Here we sought to determine the role of macrophages in castration-resistant prostate cancer (CRPC) using a syngeneic model that reflected the mutational landscape of the disease. A transcriptomic analysis of CRPC tumors following macrophage depletion revealed lower molecular signatures for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. Since cholesterol is the precursor of the five major classes of steroid hormones, we reasoned that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Indeed, macrophage depletion reduced the levels of androgens within prostate tumors and restricted androgen receptor (AR) nuclear localization in vitro and in vivo. Macrophages were cholesterol rich and had the ability to transfer cholesterol to tumor cells in vitro, and AR nuclear translocation was inhibited by activation of Liver X Receptor (LXR)-β, the master regulator of cholesterol homeostasis. Finally, combining macrophage depletion with androgen deprivation therapy increased survival, supporting the therapeutic potential of targeting macrophages in CRPC.

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ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling

Oncogene ◽

10.1038/s41388-021-01914-2 ◽

2021 ◽

Author(s):

Chengfei Liu ◽

Cameron M. Armstrong ◽

Shu Ning ◽

Joy C. Yang ◽

Wei Lou ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Cancer Progression ◽

Nuclear Translocation ◽

Treatment Resistance ◽

Hsp70 Expression ◽

Castration Resistant Prostate Cancer ◽

Downstream Target

AbstractTargeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR-targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies blocking continued AR signaling. Here, we identify a novel AR/AR-V7 degrader (ARVib) and found that ARVib effectively degrades AR/AR-V7 protein and attenuates AR/AR-V7 downstream target gene expression in prostate cancer cells. Mechanistically, ARVib degrades AR/AR-V7 protein through the ubiquitin-proteasome pathway mediated by HSP70/STUB1 machinery modulation. ARVib suppresses HSP70 expression and promotes STUB1 nuclear translocation, where STUB1 binds to AR/AR-V7 and promotes its ubiquitination and degradation. ARVib significantly inhibits resistant prostate tumor growth and improves enzalutamide treatment in vitro and in vivo. These data suggest that ARVib has potential for development as an AR/AR-V7 degrader to treat resistant CRPC.

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A randomized phase II study of OGX-427 plus prednisone (P) versus P alone in patients (pts) with metastatic castration resistant prostate cancer (CRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.4514 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 4514-4514 ◽

Cited By ~ 2

Author(s):

Kim N. Chi ◽

Sebastien J. Hotte ◽

Susan Ellard ◽

Joel Roger Gingerich ◽

Anthony Michael Joshua ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Single Agent ◽

Castration Resistant Prostate Cancer ◽

Disease Response ◽

Measurable Disease ◽

The Difference ◽

Ecog Ps

4514 Background: Heat Shock Protein 27 (Hsp27) is a multi-functional chaperone protein that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense oligonucleotide that inhibits Hsp27 expression with in vitro and in vivo efficacy and was well tolerated with single agent activity in phase I studies. Methods: Chemotherapy-naïve pts with no/minimal symptoms were randomized to receive OGX-427 600 mg IV x 3 loading doses then 1000 mg IV weekly with P 5 mg PO BID or P only. Primary endpoint was the proportion of pts progression free (PPF) at 12 weeks (PCWG2 criteria). A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) with 32 pts/arm provides 70% power to detect the difference at 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: 38 pts have been enrolled; 1st stage of accrual completed with 2nd stage accruing. In the 1st 32 pts randomized (17 to OGX-427+P, 15 to P), baseline median age was 71 years (53-89), ECOG PS 0 or 1 in 66% and 34% of pts, median PSA 66 (6-606), metastases in bone/lymph nodes/liver or lung was 75/56/9%, 31% had prior P treatment, and 93% had ≥5 CTC/7.5 ml. Predominantly grade 1/2 infusion reactions (chills, diarrhea, flushing, nausea, vomiting) occurred in 47% of pts receiving OGX-427+P. One pt on OGX-427+P developed hemolytic uremic syndrome. A PSA decline of ≥50% occurred in 41% of pts on OGX-427+P, and 20% of pts treated with P. A measurable disease partial response was seen in 3/8 (38%) evaluable pts on OGX-427+P and 0/9 pts on P. CTC conversion from ≥5 to <5/7.5 ml occurred in 50% of pts on OGX-427+P and 31% treated with P. Thus far, in 26 evaluable pts the PPF at 12 weeks was 71% (95% CI: 42-92) in OGX-427+P treated pts and 33% (95% CI: 10-65) in pts on P. Conclusions: These data provide clinical evidence for the role of Hsp27 as a therapeutic target in prostate cancer and support continued evaluation of OGX-427 for pts with CRPC. Funded by a grant from the Terry Fox Research Institute.

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Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

Frontiers in Oncology ◽

10.3389/fonc.2021.615568 ◽

2021 ◽

Vol 11 ◽

Author(s):

Zhengfang Liu ◽

Cheng Liu ◽

Keqiang Yan ◽

Jikai Liu ◽

Zhiqing Fang ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Nuclear Translocation ◽

Mrna Levels ◽

Castration Resistant Prostate Cancer ◽

Castration Resistant ◽

Specific Protease ◽

Hormone Sensitive

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

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ODM-204: A novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer—Preclinical data.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.7_suppl.221 ◽

2015 ◽

Vol 33 (7_suppl) ◽

pp. 221-221

Author(s):

Riikka Oksala ◽

Anu Moilanen ◽

Reetta Riikonen ◽

Petteri Rummakko ◽

Riikka Huhtaniemi ◽

...

Keyword(s):

Prostate Cancer ◽

Androgen Receptor ◽

Nuclear Translocation ◽

Leuprolide Acetate ◽

Male Rats ◽

Castration Resistant Prostate Cancer ◽

Dual Inhibitor ◽

Castration Resistant

221 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue/tumor androgens. Targeting AR and androgen biosynthesis together may be more effective than either alone. ODM-204 is a novel, non-steroidal dual inhibitor of CYP17A1 and AR, which has shown promising results in preclinical studies. Methods: The binding affinity of ODM-204 to wild type AR was determined in rat prostate cytosolic lysates. The potency and functional activity of ODM-204 to human AR were demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. In addition, assays for AR nuclear translocation and the transactivation of human AR mutants T877A, W741L, and F876L were conducted. The effects of ODM-204 on the growth of androgen-dependent VCaP and LNCaP cells in vitro and subcutaneously grafted VCaP cells in vivo with the oral dose of 50 mg/kg/day were studied. The inhibition of CYP17A1 by ODM-204 was studied in vitro by using human and rat testicular microsomes and a human adrenal cortex cell line, and in vivo in male rats coadministered with luteinizing hormone releasing hormone agonist leuprolide acetate to mimic clinical situation. Results: ODM-204 is a potent inhibitor of both AR and CYP17A1. It binds to AR with a high affinity (Ki=47 nM) and selectivity and has a high potency towards CYP17A1 (IC50=22 nM). In addition, ODM-204 inhibited testosterone-mediated nuclear translocation of AR and the mutant ARs (IC50 values for AR(T877A), AR(W741L), and AR(F876L) were 95, 277, and 6 nM, respectively), and suppressed androgen-induced cell proliferation of LNCaP (IC50=170 nM) and VCaP (IC50=280 nM) cells. In a VCaP xenograft model, ODM-204 showed significant antitumor activity (tumor growth inhibition=66%). In rats, inhibitory effects of leuprolide acetate on testosterone production and androgen-sensitive organ weights were potentiated by ODM-204. Conclusions: ODM-204 is a promising new dual CYP17A1 and AR inhibitor for the treatment of CRPC. Clinical trials in patients with mCRPC will be started in early 2015.

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Preclinical Study Using ABT263 to Increase Enzalutamide Sensitivity to Suppress Prostate Cancer Progression Via Targeting BCL2/ROS/USP26 Axis Through Altering ARv7 Protein Degradation

Cancers ◽

10.3390/cancers12040831 ◽

2020 ◽

Vol 12 (4) ◽

pp. 831 ◽

Cited By ~ 4

Author(s):

Hua Xu ◽

Yin Sun ◽

Chi-Ping Huang ◽

Bosen You ◽

Dingwei Ye ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Standard Of Care ◽

Preclinical Study ◽

Ros Generation ◽

Castration Resistant Prostate Cancer ◽

Enzyme Activity Assay ◽

Ubiquitin Proteasome

Background: The recently developed antiandrogen, Enzalutamide (Enz), has reformed the standard of care for castration resistant prostate cancer (CRPC) patients. However, Enz-resistance inevitably emerges despite success of Enz in prolonging CRPC patients’ survival. Here we found that Enz-resistant prostate cancer (PCa) cells had higher BCL2 expression. We aimed to test whether targeting BCL2 would influence Enz sensitivity of prostate cancer (PCa) and identify the potential mechanism. Methods: The study was designed to target Enz-induced BCL2 with inhibitor ABT263 and test Enz sensitivity in Enz-resistant PCa cells by MTT assay. Cellular reactive oxygen species (ROS) levels were detected with dihydroethidium staining, and in vitro deubiquitinating enzyme activity assay was used to evaluate ubiquitin specific protease 26 (USP26) activity. Results: ABT263 could increase Enz sensitivity in both Enz-sensitive and Enz-resistant PCa cells via inducing ROS generation. Elevated cellular ROS levels might then inhibit USP26 activity to increase the ubiquitination of androgen receptor (AR) and AR splice variant 7 (ARv7) and their ubiquitin/proteasome-dependent degradation, which contributed to the increase of Enz sensitivity. In vivo mouse model also demonstrates that ABT263 will suppress the PCa progression. Conclusion: This study demonstrated that targeting Enz-induced BCL2 with inhibitor ABT263 could increase Enz sensitivity in both Enz-sensitive and Enz-resistant PCa cells through induction of cellular ROS levels and suppression of USP26 activity with a consequent increase of ubiquitin/proteasome-dependent degradation of AR and ARv7 protein expression.

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Dehydrozingerone, a Curcumin Analog, as a Potential Anti-Prostate Cancer Inhibitor In Vitro and In Vivo

Molecules ◽

10.3390/molecules25122737 ◽

2020 ◽

Vol 25 (12) ◽

pp. 2737

Author(s):

Sariya Mapoung ◽

Shugo Suzuki ◽

Satoshi Fuji ◽

Aya Naiki-Ito ◽

Hiroyuki Kato ◽

...

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Cancer Progression ◽

Biological Activities ◽

Xenograft Model ◽

Castration Resistant Prostate Cancer ◽

Curcumin Analog ◽

Cycle Arrest

Curcumin (Cur) exhibits biological activities that support its candidacy for cancer treatment. However, there are limitations to its pharmacological effects, such as poor solubility and bioavailability. Notably, the use of Cur analogs has potential for addressing these limitations. Dehydrozingerone (DZG) is a representative of the half-chemical structure of Cur, and many reports have indicated that it is anticancer in vitro. We, therefore, have hypothesized that DZG could inhibit prostate cancer progression both in vitro and in vivo. Results revealed that DZG decreased cell proliferation of rat castration-resistant prostate cancer, PLS10 cells, via induction of the cell cycle arrest in the G1 phase in vitro. In the PLS10 xenograft model, DZG significantly decreased the growth of subcutaneous tumors when compared to the control via the inhibition of cell proliferation and angiogenesis. To prove that DZG could improve the limitations of Cur, an in vivo pharmacokinetic was determined. DZG was detected in the serum at higher concentrations and remained up to 3 h after intraperitoneal injections, which was longer than Cur. DZG also showed superior in vivo tissue distribution than Cur. The results suggest that DZG could be a candidate of the Cur analog that can potentially exert anticancer capabilities in vivo and thereby improve its bioavailability.

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SAT-114 Loss of DHEA-Targeting SULT2b1b Sulfotransferase Exacerbates Aggressive Traits of Prostate Cancer

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1448 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Chung Seog Song ◽

Sulgi Park ◽

Shoulei Jiang ◽

Pawel Osmulski ◽

Brett T Marck ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Gene Knockout ◽

Cell Mass ◽

Castration Resistant Prostate Cancer ◽

Mesenchymal Transition ◽

Precursor Pool ◽

Mrna Induction

Abstract The prostate-expressed sulfotransferase SULT2B1b (SULT2B) regulates intracrine androgen homeostasis by mediating 3β-sulfation of DHEA, thus reducing the precursor pool in the androgen biosynthesis pathway. We explored how loss of SULT2B might influence prostate cancer progression. Results show that SULT2B ablation in castration-resistant prostate cancer (CRPC) cells, generated by stable RNA interference or gene knockout, led to robust activation of the ERK1/2 Map kinase survival signal and induction of epithelial to mesenchymal transition (EMT). EMT activation was concluded on the basis of increased levels of vimentin (a mesenchymal protein) and the EMT-activating transcription factors SNAI1 (Snail) and TWIST1, shown by Western blotting, mass spectrometry and single-cell mass cytometry. Loss of SULT2B was associated with enhanced motility and invasive activity of CRPC cells in vitro and their growth escalation in vivo as xenografts. Higher invasion and metastasis potential of SULT2B-ablated CRPC cells was further indicated by results that these cells are less adhesive (i.e. easily detachable) and less stiff (i.e. more pliable) based on atomic force microscopy analysis of individual cells. Notably, AKR1C3, an aldo-keto reductase, which is elevated frequently in advanced prostate cancer, showed marked upregulation in SULT2B-deficient cells. AKR1C3 regulates androgen receptor (AR) signaling by promoting androgen biosynthesis and functioning as an AR-selective coactivator. While levels of AR and DHT did not change, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several fold higher in SULT2B-silenced cells. The DHT-metabolizing AKR1C2 aldo-keto reductase was also upregulated, which likely accounts for a steady-state androgen level despite elevated AKR1C3 expression. Phosphorylation of ERK decreased in AKR1C3-silenced cells, signifying a causal link between AKR1C3 upregulation and ERK1/2 activation. SULT2B was undetectable immunohistochemically in tissue microarrays of clinical CRPC metastases, while SULT2B-negative samples showed AKR1C3-positive immunostaining. Primary prostate cancer exhibited variable, Gleason score independent SULT2B levels -- varying from strong positive to significantly reduced or undetectable. The reciprocal expression pattern for SULT2B and AKR1C3 in clinical CRPC suggests that AKR1C3 upregulation, ERK1/2 activation and increased aggressive traits of SULT2B-ablated cells, observed in vitro in cell models, may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for delaying disease progression in SULT2B-deficient prostate cancer.Funding Support: 1I01BX000280, VA (BC); W81XWH-14-1-0606, DOD (BC); IK6 BX004207, VA (BC); P50 CA97186, NIH & W81XWH-12-1-0208, DOD (EAM)

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A randomized phase II study of OGX-427 plus prednisone versus prednisone alone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.5_suppl.121 ◽

2012 ◽

Vol 30 (5_suppl) ◽

pp. 121-121 ◽

Cited By ~ 11

Author(s):

Kim N. Chi ◽

Sebastien J. Hotte ◽

Susan Ellard ◽

Joel Roger Gingerich ◽

Anthony Michael Joshua ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Progression ◽

Single Agent ◽

Prior Treatment ◽

Castration Resistant Prostate Cancer ◽

Disease Response ◽

The Difference ◽

Ecog Ps

121 Background: Heat Shock Protein 27 (Hsp27) is a stress-activated, multi-functional chaperone protein highly expressed in cancer that regulates cell signaling and survival pathways implicated in cancer progression. In prostate cancer models, Hsp27 complexes with androgen receptor (AR) and enhances transactivation of AR-regulated genes. OGX-427 is a 2nd generation antisense that inhibits Hsp27 expression with in vitro and in vivo efficacy. Phase I studies have demonstrated tolerability and single agent activity. Methods: Patients (pts) with CRPC, no/minimal symptoms and any prior treatment other than chemotherapy were randomized 1:1 to receive prednisone (P) 5 mg PO BID or P with OGX-427 600 mg IV x 3 loading doses followed by 1000 mg IV weekly. Primary endpoint was the proportion of pts progression free (PSAWG 2 criteria) at 12 weeks. A 2-stage MinMax design (H0 = 5%, HA >20%, α=0.1, β=0.1) will enrol 32 pts total per arm and provide 70% power to detect the difference at a 0.10 1-sided significance. Secondary endpoints include PSA decline, measurable disease response, and circulating tumour cell (CTC) enumeration. Results: In the first 22 pts randomized (11 to OGX-427+P, 11 to P), baseline median age was 71 years (53-86), ECOG PS 0 or 1 in 64% and 36% of pts, median PSA 89 (6-606), metastases in bone/lymph nodes/liver or lung in 77%/64%/10%, 23% had prior treatment with P, and 91% had ≥5 CTC/7.5 ml (median 18/7.5 ml). Thus far, 82% of pts randomized to OGX-427+P have had a PSA decline (55% with ≥30% decline) and 18% a PSA increase; 40% of pts treated with P have had a PSA decline (20% with ≥30% decline), 10% no change and 50% with PSA increase. CTC conversion from ≥5 to <5/7.5 ml has occurred in 60% of pts randomized to OGX-427+P and 20% of pts treated with P alone. Grade 1-2 infusion reactions (e.g., chills, diarrhea, flushing) have occurred in 45% of pts receiving OGX-427+P and 1 pt developed hemolytic uremic syndrome after week 7 probably related to OGX. Conclusions: Preliminary data provide clinical support for the role of Hsp27 in AR signalling and as a therapeutic target for prostate cancer. Enrolment on this study continues. Funded by a grant from the Terry Fox Research Institute.

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YAP1 overexpression contributes to the development of enzalutamide resistance by induction of cancer stemness and lipid metabolism in prostate cancer

Oncogene ◽

10.1038/s41388-021-01718-4 ◽

2021 ◽

Author(s):

Hsiu-Chi Lee ◽

Chien-Hui Ou ◽

Yun-Chen Huang ◽

Pei-Chi Hou ◽

Chad J. Creighton ◽

...

Keyword(s):

Prostate Cancer ◽

Lipid Metabolism ◽

Critical Issue ◽

Castration Resistant Prostate Cancer ◽

Cancer Stemness ◽

New Treatment ◽

Underlying Mechanisms ◽

Transcriptional Complex

AbstractMetastatic castration-resistant prostate cancer (mCRPC) is a malignant and lethal disease caused by relapse after androgen-deprivation (ADT) therapy. Since enzalutamide is innovated and approved by US FDA as a new treatment option for mCRPC patients, drug resistance for enzalutamide is a critical issue during clinical usage. Although several underlying mechanisms causing enzalutamide resistance were previously identified, most of them revealed that drug resistant cells are still highly addicted to androgen and AR functions. Due to the numerous physical functions of AR in men, innovated AR-independent therapy might alleviate enzalutamide resistance and prevent production of adverse side effects. Here, we have identified that yes-associated protein 1 (YAP1) is overexpressed in enzalutamide-resistant (EnzaR) cells. Furthermore, enzalutamide-induced YAP1 expression is mediated through the function of chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) at the transcriptional and the post-transcriptional levels. Functional analyses reveal that YAP1 positively regulates numerous genes related to cancer stemness and lipid metabolism and interacts with COUP-TFII to form a transcriptional complex. More importantly, YAP1 inhibitor attenuates the growth and cancer stemness of EnzaR cells in vitro and in vivo. Finally, YAP1, COUP-TFII, and miR-21 are detected in the extracellular vesicles (EVs) isolated from EnzaR cells and sera of patients. In addition, treatment with EnzaR-EVs induces the abilities of cancer stemness, lipid metabolism and enzalutamide resistance in its parental cells. Taken together, these results suggest that YAP1 might be a crucial factor involved in the development of enzalutamide resistance and can be an alternative therapeutic target in prostate cancer.

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