A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers

Goel, Sanjay; Desai, Kavita; Macapinlac, M. P.; Wadler, Scott; Goldberg, Gary L.; Fields, Abbie L.; Einstein, Mark H.; Volterra, Fabio; Wong, Benny; Martin, Russell; Mani, Sridhar

doi:10.1007/s10637-005-2378-2

Cited by 10 publications

(12 citation statements)

References 28 publications

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“…Downregulation of the AR was achieved with 3 different siRNAs (siAR‐1, siAR‐2 and siAR‐3). For siRNA‐mediated knockdown of PKA RIα, we used a target sequence, which corresponds to a previously described antisense oligonucleotide that has already reached clinical evaluation 22, 28, 29. Concentrations of 20 nM of each siRNA were sufficient to significantly reduce protein expression of AR and PKA RIα, respectively, in all 3 cell lines, LNCaP (Fig.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Enhanced antiproliferative and proapoptotic effects on prostate cancer cells by simultaneously inhibiting androgen receptor and cAMP‐dependent protein kinase A

Desiniotis

Schäfer

Klocker

et al. 2009

Intl Journal of Cancer

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The androgen-signaling pathway with the androgen receptor (AR) as its key molecule is widely understood to influence prostate tumor growth significantly even after androgen ablation. Under androgen-deprived conditions, the AR may be activated inappropriately through interaction with other molecules, including cyclic AMP-dependent protein kinase A (PKA). In a previous study, we have shown that knocking down the AR significantly inhibits prostate tumor growth. In this study, we show that combined inhibition of the AR and the regulatory subunit I alpha of PKA (RIa) with small interference RNAs significantly increased the growth-inhibitory and proapoptotic effects of AR knockdown. This treatment strategy was effective in androgen-sensitive and in androgen ablation-resistant prostate cancer cells. In addition, we report that downregulating PKA RIa was sufficient to inhibit PKA signaling and interestingly also impaired AR expression and activation. Vice versa, AR knockdown induced a decline in PKA RIa, associated with reduced PKA activity. This mutual influence on expression level was specific, because siRNAs against the AR did not affect expression of PKA RIa in AR negative DU-145 cells and a siRNA control did not affect protein expression. Another important finding of our study was that depletion of PKA RIa also potentiated the antiproliferative effect of the antiandrogen bicalutamide in androgen-sensitive LNCaP. We therefore concluded that combined inhibition of PKA RIa and AR may be a promising new therapeutic option for prostate cancer patients and might be superior to solely preventing AR expression.

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Section: Resultsmentioning

confidence: 99%

“…Overexpression of PKA RIα was revealed in different tumor types and therefore strongly associated with manifestation and progression of cancer cells 20, 21. PKA RIα has been selected in numerous studies as a target for treatment intervention, and an antisense oligonucleotide targeting PKA RIα has already reached clinical evaluation 28, 29…”

Section: Discussionmentioning

confidence: 99%

Enhanced antiproliferative and proapoptotic effects on prostate cancer cells by simultaneously inhibiting androgen receptor and cAMP‐dependent protein kinase A

Desiniotis

Schäfer

Klocker

et al. 2009

Intl Journal of Cancer

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“…Antisense oligonucleotides with gapmer designs employing 2 -O-methyl nucleosides have been well characterized, and these designs have advanced to human clinical trials (149). The use of 2 -O-methyl nucleosides (Figure 3) in siRNA oligonucleotides also holds promise.…”

Section: Sugar Modificationsmentioning

confidence: 99%

RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform

Bennett

Swayze

2010

Annu. Rev. Pharmacol. Toxicol.

1,162

1,085

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Dramatic advances in understanding of the roles RNA plays in normal health and disease have greatly expanded over the past 10 years and have made it clear that scientists are only beginning to comprehend the biology of RNAs. It is likely that RNA will become an increasingly important target for therapeutic intervention; therefore, it is important to develop strategies for therapeutically modulating RNA function. Antisense oligonucleotides are perhaps the most direct therapeutic strategy to approach RNA. Antisense oligonucleotides are designed to bind to the target RNA by well-characterized Watson-Crick base pairing, and once bound to the target RNA, modulate its function through a variety of postbinding events. This review focuses on the molecular mechanisms by which antisense oligonucleotides can be designed to modulate RNA function in mammalian cells and how synthetic oligonucleotides behave in the body.

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“…They provide several favorable properties to antisense drug molecules such as high metabolic stability, better affinity to target RNA, and a better toxicity profile. The 2'-O-methyl gapmer antisense oligonucleotides have advanced to human clinical trials [52]. There are several 2'-O-MOE gapmer antisense drugs in the clinical trials targeting metabolic disease, cardio vascular disorders and cancer [53][54][55].…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

2-Modified Oligonucleotides for Antisense Therapeutics

Prakash¹,

Bhat²

2007

CTMC

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Chemically modified antisense oligonucleotides are currently progressing in multiple clinical trials. Among several chemical modifications made, modification of the 2'-position has proved most successful. Second generation antisense oligonucleotides incorporating these 2'-modifications exhibit high binding affinity to target RNA, enhanced metabolic stability, and improved pharmacokinetic and toxicity profiles. This is, in part, due to the enhanced biophysical properties of second generation antisense oligonucleotides. 2'-Modifications that influence the sugar to adopt a 3'-endo sugar pucker can improve properties such as affinity. 2'-Modifications that provide a gauche effect and/or a charge effect can play a significant role in the level of nuclease resistance. The heterocyclic base modifications such as 2-thiothymine provides additive effect on the affinity of 2'-F and 2'-O-MOE modifications. This review summarizes the structural and biophysical properties of selected 2'-modified nucleosides which are candidates for use in oligonucleotide therapeutics.

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A phase I safety and dose escalation trial of docetaxel combined with GEM®231, a second generation antisense oligonucleotide targeting protein kinase A R1α in patients with advanced solid cancers

Cited by 10 publications

References 28 publications

Enhanced antiproliferative and proapoptotic effects on prostate cancer cells by simultaneously inhibiting androgen receptor and cAMP‐dependent protein kinase A

Enhanced antiproliferative and proapoptotic effects on prostate cancer cells by simultaneously inhibiting androgen receptor and cAMP‐dependent protein kinase A

RNA Targeting Therapeutics: Molecular Mechanisms of Antisense Oligonucleotides as a Therapeutic Platform

2-Modified Oligonucleotides for Antisense Therapeutics

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