siRNA Lipid Nanoparticle Potently Silences Clusterin and Delays Progression When Combined with Androgen Receptor Cotargeting in Enzalutamide-Resistant Prostate Cancer

Yamamoto, Yoshiaki; Lin, Paulo J.C.; Beraldi, Eliana; Zhang, Fan; Kawai, Yosuke; Leong, Jeffrey; Katsumi, Hidemasa; Fazli, Ladan; Fraser, Robert; Cullis, Pieter R.; Gleave, Martin

doi:10.1158/1078-0432.ccr-15-0866

Cited by 64 publications

(52 citation statements)

References 40 publications

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“…It is argued that management of cancer is more feasible and holds better promise with the use of drug combinations that can hit multiple targets (8–11). Combination chemotherapy has several advantages such as lower dose requirement which subsequently lessens the side effects and circumvents drug resistance; and inhibits or delays metastasis (12–18). Zhang et al (13) showed that genistein enhances the response to cabazitaxel treatment in mCRPC cells.…”

Section: Introductionmentioning

confidence: 99%

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Mukhtar

Adhami

Siddiqui

et al. 2016

Molecular Cancer Therapeutics

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Although treatment of prostate cancer (PCa) has improved over the past several years, taxanes such as cabazitaxel remain the only form of effective chemotherapy that improves survival in patients with metastatic castration-resistant PCa. However, the effectiveness of this class of drugs has been associated with various side effects and drug resistance. We previously reported that fisetin, a hydroxyflavone, is a microtubule stabilizing agent and inhibits PCa cell proliferation, migration, and invasion and suggested its use as an adjuvant for treatment of prostate and other cancer types. In this study, we investigated the effect of fisetin in combination with cabazitaxel with the objective to achieve maximum therapeutic benefit, reduce dose and toxicity and minimize or delay the induction of drug resistance and metastasis. Our data show for the first time that a combination of fisetin (20 μM) enhances cabazitaxel (5nM) and synergistically reduces 22Rν1, PC-3M-luc-6, and C4-2 cell viability and metastatic properties with minimal adverse effects on normal prostate epithelial cells. In addition, the combination of fisetin with cabazitaxel was associated with inhibition of proliferation and enhancement of apoptosis. Furthermore, combination treatment resulted in inhibition of tumor growth, invasion and metastasis when assessed in two in-vivo xenograft mouse models. These results provide evidence that fisetin may have therapeutic benefit for patients with advanced PCa through enhancing the efficacy of cabazitaxel under both androgen-dependent and androgen-independent conditions. This study underscores the benefit of the combination of fisetin with cabazitaxel for the treatment of advanced and resistant PCa and possibly other cancer types.

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Section: Introductionmentioning

confidence: 99%

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Mukhtar

Adhami

Siddiqui

et al. 2016

Molecular Cancer Therapeutics

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“…The induction of such innate immune responses is known as a bottleneck in the clinical development of RNAi drugs. Meanwhile, to avoid such an intrinsic issue, the siRNA of Patisiran (ONPATTRO ® ), the first approved therapeutic form of RNAi that was originally formulated in lipid nanoparticles, is directly conjugated with an N ‐acetylgalactosamine in this formulation, which can facilitate the delivery of RNAi molecules to hepatocytes . DFP‐10825, an RNAi formulation for local administration, avoids such systemic adverse events, because very little of the TS shRNA in the DFP‐10825 formulation escapes into blood circulation from the peritoneal cavity after intraperitoneal injection (Figure A), and as a result, the formulation does not accumulate in immune organs such as the spleen (Figure B).…”

Section: Discussionmentioning

confidence: 99%

A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model

Ando

Fukushima

Eshima³

et al. 2019

Cancer Medicine

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Purpose In advanced gastric cancer, peritoneal dissemination is a life‐threatening mode of metastasis. Since the treatment options with conventional chemotherapy remain limited, any novel therapeutic strategy that could control such metastasis would improve the outcome of treatment. We recently developed a unique RNA interference therapeutic regimen (DFP‐10825) consisting of short hairpin RNA against thymidylate synthase (TS shRNA) and cationic liposomes. The treatment with DFP‐10825 has shown remarkable antitumor activity in peritoneally disseminated human ovarian cancer–bearing mice via intraperitoneal administration. In this study, we expanded DFP‐10825 to the treatment of peritoneally disseminated gastric cancer. Methods DFP‐10825 was administered intraperitoneally into mice with intraperitoneally implanted human gastric cancer cells (MKN45 or NCI‐N87). Antitumor activity and host survival benefits were monitored. Intraperitoneal distribution of fluorescence‐labeled DFP‐10825 was monitored in this MKN45 peritoneally disseminated mouse model. Results Intraperitoneal injection of DFP‐10825 suppressed tumor growth in two peritoneally disseminated cancer models (MKN45 and NCI‐N87) and increased the survival time of the MKN45 model without severe side effects. Throughout the treatment regimen, no significant body weight loss was associated with the administration of DFP‐10825. Interestingly, after intraperitoneal injection, fluorescence‐labeled DFP‐10825 retained for more than 72 hours in the peritoneal cavity and selectively accumulated in disseminated tumors. Conclusions Intraperitoneal injection of DFP‐10825 demonstrated effective antitumor activity without systemic severe adverse effects via the selective delivery of RNAi molecules into disseminated tumors in the peritoneal cavity. Our current study indicates that DFP‐10825 could become an alternative option to improve the outcomes of patients with peritoneally disseminated gastric cancer.

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“…But surprisingly, clusterin targeting oligonucleotides did not show favorable benefit in a recent clinical trial . However, co‐targeting clusterin and AR delayed the tumor growth of Enz‐resistant PCa in preclinical studies …”

Section: Molecular Chaperones Stabilize the Armentioning

confidence: 99%

Interference with the androgen receptor protein stability in therapy‐resistant prostate cancer

Lakshmana

Baniahmad

2018

Intl Journal of Cancer

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The androgen receptor (AR) plays a central role in the pathogenesis of prostate cancer (PCa). Most PCa cases develop eventually from an androgen-dependent stage to castration-resistant prostate cancer (CRPC) with AR-signaling still being active. Thus, inhibition of AR remains a well-established promising drug target in CRPC. However, despite the improvements of current treatment for CRPC by targeting the AR, the evolution of adaptive AR-signaling leads to therapy-resistant CRPC. Treatment failure is based mostly on the inability to keep AR under long-term restraint due to adaptive responses of AR-signaling. One underlying mechanism appears to be the increased AR protein stability. Therefore, the regulation of AR protein stability and its degradation is another interesting path that could enhance our knowledge of carcinogenesis and tumor evolution possibly leading to novel therapeutic targets. In this review, we discuss various molecular mechanisms and factors that stabilize AR protein levels directly or indirectly. We summarize novel approaches to interfere with AR stability including targeting the glucocorticoid receptor (GR), heat shock proteins, and co-chaperones as well as E3-ligases using small chimeric molecules. These novel approaches in combination with antiandrogen treatment inhibit PCa growth through the regulation of AR protein levels.

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siRNA Lipid Nanoparticle Potently Silences Clusterin and Delays Progression When Combined with Androgen Receptor Cotargeting in Enzalutamide-Resistant Prostate Cancer

Cited by 64 publications

References 40 publications

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

Fisetin Enhances Chemotherapeutic Effect of Cabazitaxel against Human Prostate Cancer Cells

A novel intraperitoneal therapy for gastric cancer with DFP‐10825, a unique RNAi therapeutic targeting thymidylate synthase, in a peritoneally disseminated xenograft model

Interference with the androgen receptor protein stability in therapy‐resistant prostate cancer

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