A novel small molecule inhibitor of p300/CBP for the treatment of castration-resistant prostate cancer: Preclinical evaluation.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 168-168 ◽  
Author(s):  
Nigel Brooks ◽  
Neil Pegg ◽  
Jenny Worthington ◽  
Barbara Young ◽  
Amy Prosser ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Small Molecule ◽  
Binding Protein ◽  
Xenograft Model ◽  
Creb Binding Protein ◽  
Castration Resistant Prostate Cancer ◽  
Histone Acetyl Transferase ◽  
Castrate Resistant

168 Background: Targeted degradation of androgen receptor (AR) and androgen receptor variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related histone acetyl transferase proteins that act as transcriptional activators of AR. We have developed potent, selective and orally active small molecule inhibitors of the bromodomain of p300/CBP and investigated their role in regulating the expression and function of AR and ARV. Methods: Binding affinity to p300, CBP and BRD4 was measured in a surface plasmon resonance (SPR) assay and potency and functional activity was demonstrated in a panel of prostate cells lines representing hormone responsive (LNCaP), hormone independent (DU145, PC3) and castrate resistant disease (22Rv1, C4-2, VCaP, LNCaP-AR). Effects of p300/CBP inhibitors (and the BET inhibitor, JQ1), on AR, AR-V7 splice variant and c-Myc protein, as well as c-Myc, KLK3 and TMPRSS2 gene expression, were assessed in 22Rv1 cells in vitro. In vivoeffects on biomarkers were measured in a 22Rv1 xenograft model. Results: CCS1357, an in vitro probe compound, binds to p300 and CBP with high affinity (Kd=4nM) and selectivity (Kd=245nM; BRD4) and is a potent inhibitor of cell proliferation in castrate resistant cell lines (IC50=100nM in LnCaP-AR; 350nM in 22Rv1) with minimal effects in hormone independent lines. CCS1357 significantly down-regulated AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with JQ1 at equivalent proliferation IC50s. CCS1357 effects were reversed by the proteasome inhibitor, MG132. CCS1357 also caused a profound inhibition of c-Myc, KLK3 and TMPRSS2 genes measured by qPCR in 22Rv1 cells in vitro. A preclinical candidate (CCS1477) given as a single oral dose (30mg/kg) inhibited plasma PSA and tumour AR and AR-V7 in a 22Rv1 xenograft model. Conclusions: Small molecule inhibition of the bromodomain of p300/CBP, leads to down-regulation of AR, ARV and c-Myc as well as inhibition of key downstream PD biomarkers including PSA and TMPRSS2 and represents a promising new approach for the treatment of CRPC.

BPS-001, a complex biologic agent extracted from the medicinal leech (Huridinaria manillensis) for treatment of metastatic castration-resistant prostate cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 209-209
Author(s):  
M. Suzanne Stratton ◽  
Amr Ammar ◽  
Yuzhuo Wang ◽  
Mohamed Hessein ◽  
Emma Guns ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Tumor Growth ◽  
Adhesion Molecules ◽  
In Vitro Studies ◽  
Biologic Agent ◽  
Castration Resistant Prostate Cancer ◽  
Ki 67 ◽  
Mouse Prostate

209 Background: We established that subcutaneous BPS-001 reduced tumor size and inhibited tumor growth in PC3, LNCaP and 22RV-1 mouse xenografts; and, tumor lHC demonstrated an increase in caspase-3 and decreases in expression of P21, Ki-67 and PCNA. We also showed that BPS-001 reduced PSA expression in both In vitro and in In vivo xenografts (LNCaP and 22RV1). We now demonstrate that BPS-001 inhibits angiogenesis in the xenografts; and, In vitro studies demonstrate that BPS-001 affects expression of adhesion molecules and the androgen receptor. In addition, BPS-001 inhibited tumor growth in a TRAMP allograft model. Methods: CD31 expression was measured using IHC of the previous mouse xenografts. In vitro androgen receptor and adhesion molecule expression were assessed by Western blot. Transplantable TRAMP-C2 mouse prostate cancer in B57CL allografts were grown to 5 mm prior to initiation of treatment. Immune markers in TRAMP allograft tumors were measured by IHC. Results: Mechanistic studies show BPS-001 acts by blocking angiogenesis demonstrated by a > 50% decrease in expression of CD31 in the LNCaP and 22RV-1 xenografts. Furthermore, preliminary toxicology studies show similar efficacy to docetaxel with no weight loss in the longer-term PC3 xenograft study as was observed with docetaxel. Preliminary toxicology studies of BPS-001 also support a favorable toxicity profile, and the therapeutic dose (1-5 mg/Kg, QW or BIW) is well within the margin of safety. Dose limiting toxicity (bleeding) was observed at doses of 20mg/Kg daily. In vitro studies showed BPS-001 decreased expression of both N- and P- cadherins and the androgen receptor. BPS-001 inhibited tumor growth in the TRAMP allograft models. IHC analyses of the TRAMP allograft tumors suggest immunomodulation. Conclusions: BPS-001 exhibits anticancer activity with no observed toxicity in the therapeutic range. Effects of BPS-001 include inhibition of angiogenesis, downregulation of adhesion molecules associated with advanced prostate cancer and inhibition of androgen receptor signaling. Elucidation of the mechanism of action is ongoing.

scholarly journals PROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer

2016 ◽  
Vol 113 (26) ◽  
pp. 7124-7129 ◽  
Author(s):  
Kanak Raina ◽  
Jing Lu ◽  
Yimin Qian ◽  
Martha Altieri ◽  
Deborah Gordon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Molecule ◽  
Xenograft Model ◽  
The United States ◽  
Castration Resistant Prostate Cancer ◽  
Secondary Resistance ◽  
Cellular Models ◽  
Castration Resistant ◽  
Mouse Xenograft Model ◽  
Bet Inhibitors

Prostate cancer has the second highest incidence among cancers in men worldwide and is the second leading cause of cancer deaths of men in the United States. Although androgen deprivation can initially lead to remission, the disease often progresses to castration-resistant prostate cancer (CRPC), which is still reliant on androgen receptor (AR) signaling and is associated with a poor prognosis. Some success against CRPC has been achieved by drugs that target AR signaling, but secondary resistance invariably emerges, and new therapies are urgently needed. Recently, inhibitors of bromodomain and extra-terminal (BET) family proteins have shown growth-inhibitory activity in preclinical models of CRPC. Here, we demonstrate that ARV-771, a small-molecule pan-BET degrader based on proteolysis-targeting chimera (PROTAC) technology, demonstrates dramatically improved efficacy in cellular models of CRPC as compared with BET inhibition. Unlike BET inhibitors, ARV-771 results in suppression of both AR signaling and AR levels and leads to tumor regression in a CRPC mouse xenograft model. This study is, to our knowledge, the first to demonstrate efficacy with a small-molecule BET degrader in a solid-tumor malignancy and potentially represents an important therapeutic advance in the treatment of CRPC.

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

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.

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

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.

An oral androgen receptor PROTAC degrader for prostate cancer.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 381-381 ◽  
Author(s):  
Taavi Neklesa ◽  
Lawrence B Snyder ◽  
Ryan R Willard ◽  
Nicholas Vitale ◽  
Kanak Raina ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Drug Exposure ◽  
Point Mutations ◽  
Genetic Alterations ◽  
Significant Inhibition ◽  
Castration Resistant Prostate Cancer ◽  
Orally Bioavailable

381 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC that leads to ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, DMPK, toxicology and preclinical efficacy studies. Results: This AR PROTAC completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. The AR PROTAC degrades all clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, the AR PROTAC demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer.

New patient-derived models of castrate-sensitive and castrate-resistant prostate cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 151-151
Author(s):  
Mitchell Lawrence ◽  
David Clouston ◽  
Mark Frydenberg ◽  
Declan G. Murphy ◽  
Carmel Jo Pezaro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Ex Vivo ◽  
Castration Resistant Prostate Cancer ◽  
Preclinical Testing ◽  
Novel Treatments ◽  
Nsg Mice ◽  
Treatment Naïve ◽  
Castrate Resistant ◽  
Rapid Autopsy

151 Background: There are fewer preclinical models of prostate cancer compared to other common tumours. New models that represent the diverse features of castrate-sensitive and castration-resistant prostate cancer (CRPC) are required for thorough preclinical testing of novel treatments. Therefore, the goal of the Melbourne Urological Research Alliance (MURAL) is to develop patient-derived xenografts (PDXs) spanning the clinical trajectory of prostate cancer. Methods: We grafted >200 surgery, biopsy or rapid autopsy samples into testosterone-supplemented or castrated male NSG mice. Actively growing tumours were serially transplanted or grown as explants or organoids. PDXs were analysed using RNAseq, targeted genomic sequencing and histopathology review. Results: We previously reported 4 serially transplantable PDXs (Lawrence, et al., 2018, European Urology). Now we have established ~30 additional models spanning treatment naïve primary disease to CRPC. PDXs of CRPC were often from soft tissue metastases of patients who had failed docetaxel, cabazitaxel, enzalutamide, abiraterone and other contemporary treatments. Accordingly, they had diverse mechanisms of resistance, including AR mutations, genomic structural rearrangements, gene amplifications and expression of AR variants. In addition, several PDXs had AR-null phenotypes, including small cell prostate cancer. All PDXs closely reflected the genomic, transcriptomic and histopathological characteristics of the original patient tumours. As renewable sources of tissue, the PDXs could also be grown as ex vivo slice cultures and in vitro organoids, providing complementary models with different timescales and endpoints. Conclusions: We have developed a new collection of castrate-sensitive and castrate-resistant PDXs of prostate cancer, providing diverse tumours for preclinical testing of candidate treatments.

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