Blockade of ARV7:HIF1α heterodimers after topotecan reverses enzalutamide resistance in 22Rv1 cells.

Fruehauf, John P.; Farrokhian, Nathan; Sarkissian, Sarmen; Kim, Jai-Hyun

doi:10.1200/jco.2016.34.15_suppl.e16594

Cited by 2 publications

(2 citation statements)

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“…In addition, we lacked sufficient tumor tissue to compare in vivo gene and protein expression of relevant pharmacodynamic biomarkers after treatment due to our xenograft study endpoint selection (33,35). Given the robust suppression of NLG207 on AR-FL/AR-V7, whether NLG207 has an effect on the heterodimerization of AR-FL with AR-V7 remains to be determined; however, preliminary evidence has been suggested by TPT treatment in 22Rv1 cells (50).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models

Schmidt

Chau

Strope

et al. 2021

Molecular Cancer Therapeutics

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Effective treatments for patients with metastatic castrationresistant prostate cancer following disease progression on enzalutamide are currently an unmet clinical need. Simultaneous inhibition of the hypoxia-inducible factor (HIF)-1a and androgen receptor (AR) pathways has been previously shown to overcome enzalutamide resistance in vitro. Combination treatment with NLG207, a nanoparticle-drug conjugate of camptothecin and inhibitor of HIF-1a, and enzalutamide was evaluated in preclinical prostate cancer models of enzalutamide resistance. The effect of NLG207 and enzalutamide on average tumor volume and tumor re-growth after 3 weeks of treatment was evaluated in vivo using the subcutaneous 22Rv1 xenograft and castrated subcutaneous VCaP xenograft models. Correlative assessments of antitumor activity were evaluated in vitro using cell proliferation and qPCR assays. NLG207 8 mg/kg alone and in combination with enzalutamide reduced average tumor volume by 93% after 3 weeks of treatment (P < 0.05) in comparison with vehicle control in the subcutaneous 22Rv1 xenograft model. Notably, the addition of NLG207 also enhanced the efficacy of enzalutamide alone in the castrated subcutaneous VCaP xenograft model, decreasing the median rate of tumor growth by 51% (P ¼ 0.0001) in comparison with enzalutamide alone. In vitro assessments of cell proliferation and gene expression further demonstrated antitumor activity via AR-HIF-1a crosstalk inhibition. Combination treatment with NLG207 and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. Clinical investigation of this treatment combination is ongoing (NCT03531827).

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Section: Discussionmentioning

confidence: 99%

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models

Schmidt

Chau

Strope

et al. 2021

Molecular Cancer Therapeutics

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“…In PCa, the overall literature also points to HIF1a's role as an oncogene, and is seen overexpressed in CRPC (37,(227)(228)(229)(230). Furthermore, it is known that AR-FL and AR-V7 can heterodimerise with HIF1a to drive transcription (231) and therefore it is expected that AR and HIF1a transcript levels would correlate, which is in contrast to the findings of Cato et al…”

Section: Hif1amentioning

confidence: 62%

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

et al. 2023

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Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.

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Blockade of ARV7:HIF1α heterodimers after topotecan reverses enzalutamide resistance in 22Rv1 cells.

Cited by 2 publications

References 0 publications

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models

Antitumor Activity of NLG207 (Formerly CRLX101) in Combination with Enzalutamide in Preclinical Prostate Cancer Models

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

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