A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer

Kurmis, Alexis A.; Yang, Fei; Welch, Timothy R.; Nickols, Nicholas G.; Dervan, Peter B.

doi:10.1158/0008-5472.can-16-2503

Cited by 57 publications

(53 citation statements)

References 19 publications

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“…A promising approach in this respect represents minor groove DNA-binding small molecules targeting nuclear receptor DNA-binding sites. As recently demonstrated in enzalutamide-resistant cells, a pyrrole-imidazole polyamide, targeting the AR/GR consensus site can inhibit both AR and GR signaling as well as transcription (50). As GR determines resistance to antiandrogens, dual AR/GR blockage may be a particularly promising treatment strategy for advanced prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Puhr

Hoefer

Eigentler

et al. 2018

Clinical Cancer Research

137

144

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The major obstacle in the management of advanced prostate cancer is the occurrence of resistance to endocrine therapy. Although the androgen receptor (AR) has been linked to therapy failure, the underlying escape mechanisms have not been fully clarified. Being closely related to the AR, the glucocorticoid receptor (GR) has been suggested to play a role in enzalutamide and docetaxel resistance. Given that glucocorticoids are frequently applied to prostate cancer patients, it is essential to unravel the exact role of the GR in prostate cancer progression. Assessment of GR expression and functional significance in tissues from 177 prostate cancer patients, including 14 lymph node metastases, as well as in several human prostate cancer models, including androgen-dependent, androgen-independent, and long-term antiandrogen-treated cell lines. Although GR expression is reduced in primary prostate cancer tissue, it is restored in metastatic lesions. Relapse patients with high GR experience shortened progression-free survival. GR is significantly increased upon long-term abiraterone or enzalutamide treatment in the majority of preclinical models, thus identifying GR upregulation as an underlying mechanism for cells to bypass AR blockade. Importantly, GR inhibition by RNAi or chemical blockade results in impaired proliferation and 3D-spheroid formation in all tested cell lines. GR upregulation seems to be a common mechanism during antiandrogen treatment and supports the notion that targeting the GR pathway combined with antiandrogen medication may further improve prostate cancer therapy. .

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Section: Discussionmentioning

confidence: 99%

The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Puhr

Hoefer

Eigentler

et al. 2018

Clinical Cancer Research

137

144

View full text Add to dashboard Cite

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“…BIRC6, a member of inhibitor of apoptosis pathways, could be also a target in enzalutamide resistance [ 45 ]. A pyrrole-imidazole polyamide is also active in these conditions [ 46 ].…”

Section: Potential Post-enzalutamide Therapiesmentioning

confidence: 99%

Molecular Mechanisms of Enzalutamide Resistance in Prostate Cancer

Čulig

2017

Curr Mol Bio Rep

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Purpose of ReviewCompensatory mechanisms leading to increased androgen receptor expression and activity after androgen ablation or anti-androgen treatment have been identified in prostate cancer. After hydroxyflutamide and bicalutamide were used in therapy of prostate cancer over many years, novel anti-androgen enzalutamide showed improved clinical activity. However, enzalutamide resistance develops over a certain time period, and molecular mechanisms responsible for this process are heterogeneous.Research FindingsAs with other anti-androgens, these mechanisms include alterations of AR but also may be associated with overexpression of oncogenes which should be targeted by novel therapies. Androgen receptor splice variants have been frequently described in patients who developed enzalutamide resistance. Mutant AR F876L has been detected in patients who are resistant to enzalutamide. Glucocorticoid receptor overexpression has been observed in patient tissues and in pre-clinical models of enzalutamide resistance.SummaryThere is a heterogeneous picture of enzalutamide resistance in prostate cancer and, therefore, the development of appropriate post-enzalutamide treatment remains a challenge.

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“…The major transcription product of SMN2 leads to a shorter and nonfunctional SMN protein primarily because exon 7 of SMN2 pre-mRNA (abbreviated throughout as exon 7) is skipped in the process of splicing (9), as a result of a C-to-T transition at position +6 on exon 7 (4). Despite the challenges associated with the development of small molecule therapeutics targeting nucleic acids (5)(6)(7)(8)(9)(10)(11)(12), several exon 7 splicing regulators have been identified including the splicing activator, SRSF1 (13), the splicing repressor, hnRNP A1 (14), an SR-like protein, Tra2β1 (15), and various members in hnRNP family (16). The secondary structure or higher-order folding of SMN2 pre-mRNA is also crucial for accurate mRNA splicing: a stem-loop structure at the 5′-splice site (5′-ss) of exon 7, namely terminal stem-loop 2 (TSL2), has been shown to be a negative regulatory element for exon 7 splicing (17).…”

mentioning

confidence: 99%

Mechanistic studies of a small-molecule modulator of SMN2 splicing

Wang

Schultz

Johnson

2018

Proc. Natl. Acad. Sci. U.S.A.

115

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RG-7916 is a first-in-class drug candidate for the treatment of spinal muscular atrophy (SMA) that functions by modulating pre-mRNA splicing of the gene, resulting in a 2.5-fold increase in survival of motor neuron (SMN) protein level, a key protein lacking in SMA patients. RG-7916 is currently in three interventional phase 2 clinical trials for various types of SMA. In this report, we show that SMN-C2 and -C3, close analogs of RG-7916, act as selective RNA-binding ligands that modulate pre-mRNA splicing. Chemical proteomic and genomic techniques reveal that SMN-C2 directly binds to the AGGAAG motif on exon 7 of the SMN2 pre-mRNA, and promotes a conformational change in two to three unpaired nucleotides at the junction of intron 6 and exon 7 in both in vitro and in-cell models. This change creates a new functional binding surface that increases binding of the splicing modulators, far upstream element binding protein 1 (FUBP1) and its homolog, KH-type splicing regulatory protein (KHSRP), to the SMN-C2/C3-SMN2 pre-mRNA complex and enhances SMN2 splicing. These findings underscore the potential of small-molecule drugs to selectively bind RNA and modulate pre-mRNA splicing as an approach to the treatment of human disease.

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A Pyrrole-Imidazole Polyamide Is Active against Enzalutamide-Resistant Prostate Cancer

Cited by 57 publications

References 19 publications

The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

The Glucocorticoid Receptor Is a Key Player for Prostate Cancer Cell Survival and a Target for Improved Antiandrogen Therapy

Molecular Mechanisms of Enzalutamide Resistance in Prostate Cancer

Mechanistic studies of a small-molecule modulator of SMN2 splicing

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