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  • American Society of Clinical Oncology (ASCO)  (5)
  • 1
    Online Resource
    Online Resource
    A phase I study of ISIS 481464 (AZD9150), a first-in-human, first-in-class, antisense oligonucleotide inhibitor of STAT3, in patients with advanced cancers.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. 8523-8523
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. 8523-8523
    Abstract: 8523 Background: ISIS 481464 is a synthetic bicyclic nucleic acid-containing antisense oligonucleotide that is complementary to the mRNA for signal transducer and activator of transcription 3 (STAT3). Methods: Primary objective of the dose-escalation study (3+3 design) was to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, tumor response, pharmacokinetics (PK), and pharmacodynamics (PD) using IL-6 and tumor markers. Patient (pt) eligibility included : 〉 18 yrs old, solid tumors or lymphomas refractory to at least 1 prior systemic therapy. ISIS 481464 was administered IV as a loading dose on Days 1, 3, and 5 and then weekly. Results: 15 pts were dosed (4 at 2 mg/kg and 11 at 4 mg/kg). 6 pts had advanced lymphoma (3 DLBCL, 2 Hodgkin’s lymphoma, 1 mantle cell lymphoma) and 9 pts solid tumors. There was one dose limiting toxicity (DLT), a possibly related thrombotic microangiopathy at 4 mg/kg. Treatment emergent thrombocytopenia was observed with an average reduction of approximately 70% from baseline. Three pts, 1 at 2 mg/kg and 2 at 4 mg/kg, experienced nadirs in platelet count below 50x10 9 /L (range 16 to 33x10 9 /L). MTD was not reached; however, given the thrombocytopenia at 4mg/kg, the RP2D was 2mg/kg. Partial responses were observed in 2/3 DLBCL pts. The 1st DLBCL pt (2 mg/kg) with 10 prior treatments had a durable 55% reduction in tumor size and is ongoing treatment at 11 months. This pt had a 76% reduction in IL-6. The 2nd DLBCL pt (4 mg/kg) with 2 prior treatments had a 65% reduction for 4 months and was able to undergo autologous stem cell transplantation. There were no responses in the solid tumor pts. PKs revealed increased plasma trough levels (indicative of tissue concentrations) with increased dose. Conclusions: ISIS 481462 was well-tolerated and the RP2D was determined to be 2 mg/kg. Initial tumor activity was observed in DLBCL pts and a dose expansion in advanced lymphomas is ongoing. Clinical trial information: NCT01563302.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.8523
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Effect of generation 2.5 antisense inhibitor of androgen receptor on MDV3100-resistant prostate cancer cell growth in vitro and in vivo.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 6_suppl ( 2013-02-20), p. 94-94
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 6_suppl ( 2013-02-20), p. 94-94
    Abstract: 94 Background: MDV3100 is a potent androgen receptor (AR) antagonist with activity in castration resistant prostate cancer (CRPC); however, progression to MDV3100-resistant (MDV-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length or variants in disease progression. We studied the activity of Generation 2.5 antisense oligonucleotide (ASO) targeting the AR full length (AR fl ) and splice variants in MDV-R CRPC models. Methods: and Results: ThreeASOs targeting exon 1, intron 1, or exon 8 were designed to suppress AR fl and known AR splice variants. We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both AR fl and AR-V7 compared to CRPC LNCaP cell lines. MDV-3100 induced time- and dose-dependent increases in AR fl and AR-V7 protein levels; AR fl levels were ~20-fold higher than AR-V7. All 3 AR-ASO decreased AR fl and PSA expression. Exon 1 ASO decreased expression of both AR fl and AR-V7 in MDV-R-LNCaP cells; in contrast, exon 8 ASO decreased AR fl without reducing AR-V7 levels. Exon 1 ASO also most potently suppressed AR fl and splice variants in M12 cells stably overexpressing AR splice variants AR-V7 and AR-V567es. Despite these differential effects on AR fl and splice variant knockdown, the AR ASO similarly inhibited cell growth and induced apoptosis and G1 cell cycle arrest in LNCaP-derived CRPC and MDV-R cell lines. In 22RV-1 cells (which express endogenous AR fl and AR-V7), exon 1 ASO more potently suppressed AR fl and AR-V7 levels, AR transcriptional activity and AR-regulated gene expression compared to exon 8 ASO, but inhibition of cell growth did not differ significantly. Exon 1 ASO was evaluated in vivo in MDV-R49F CRPC LNCaP xenografts; mean tumor volume and serum PSA levels decreased significantly by 40% and 50%, respectively, compared to controls. Conclusions: While MDV-3100 induces both AR fl and AR-V7 levels, the biologic consequences appear cell line dependent and mainly driven by AR fl . AR-ASO knockdown of AR fl and its splice variants suppresses MDV-R LNCaP tumor growth, providing pre-clinical proof of principle to support clinical evaluation in post-AR pathway inhibitor CRPC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.6_suppl.94
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Effect of androgen signaling in stromal cells on growth of prostate cancer.
    American Society of Clinical Oncology (ASCO) ; 2016
    In:  Journal of Clinical Oncology Vol. 34, No. 2_suppl ( 2016-01-10), p. 297-297
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 2_suppl ( 2016-01-10), p. 297-297
    Abstract: 297 Background: Interactions between epithelial and stroma cells are important in the development of prostate cancer (PCa). Cancer-associated fibroblasts (CAFs) have been to support tumor progression, metastasis, and differentiation. Androgen receptor (AR) and related pathways are known to support the growth and survival of prostate epithelial cancer cells, the roles of AR-dependent processes in cancerous stroma are less clear. We sought to investigate if AR-dependent pathways present in CAF cells influence the growth and tumorogencity of epithelial cancer cells in relation to androgen-deprivation therapy in prostate cancer. Methods: Murine CAFs were isolated from a well-described PTEN-dependent cancer mouse model (Liao, et al Cancer Res, 2010. 70(18):7294). A co-culture system was developed based on multiple lines of murine CAFs grown along with human prostate cancer epithelial cells, and a murine-specific anti-sense oligonucleotide (ASO) against murine AR was used to specifically suppress AR expression in murine CAFs in this system. RT-PCR was used to investigate changes in gene expression. Results: Using this co-culture system, we found that murine CAFs promoted cell proliferation and colony formation in several human prostate cancer cell lines. Further, these processes were decreased by suppression of AR-expression in CAFs. Expression of genes related to tumorigenicity in epithelial cells were investigated. Markers associated with epithelial-mesenchymal transition (EMT, N-Cad) and “stemness” (OCT4, Sox2, Nanog) were increased in human prostate cancer cells grown with low-AR CAFs. Conclusions: Our data indicates that suppression of AR in CAFs results in down-regulation in the growth and tumorigenicity of prostate cancer cells through pathways related to EMT and “cell reprograming”. As such, development of therapies which inhibit the tumor-promoting pathways present in stromal cells may be one approach to improve the treatment of prostate cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2016.34.2_suppl.297
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Biologic consequences of androgen receptor (AR) activity in MDV3100-resistant LNCaP cells and dependence on AR full length.
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 4_suppl ( 2014-02-01), p. 74-74
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 4_suppl ( 2014-02-01), p. 74-74
    Abstract: 74 Background: While recent reports link androgen receptor (AR) variants (AR-Vs) to castration resistant prostate cancer (CRPC), the biological significance of AR-Vs in AR-regulated cell survival and proliferation, independent of AR full length (AR-FL), remains controversial. To define the functional role of AR-FL and AR-Vs in MDV3100-resistant (MDV-R), we designed antisense oligonucleotide (ASO) targeting exon 1 and exon 8 in AR to knockdown AR-FL alone or in combination with AR-Vs and examined these effects in MDV-R LNCaP-derived cells in vitro and in vivo. Methods: We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both AR-FL and AR-V7 compared to CRPC LNCaP xenografts. Cell growth rates, protein and gene expression were analyzed using crystal violet assay, western blotting and real-time PCR, respectively. Exon 1 and 8 AR-ASO were evaluated in MDV-R49F CRPC LNCaP xenografts. Results: AR-V7 was transiently transfected in MDV-R49F cells and differential knockdown of AR-V7 and/or AR-FL by exon 1 versus exon 8 AR-ASO was used to evaluate relative biologic contributions of AR-FL versus AR-V7 in MDV-R LNCaP AR-V7 overexpressing cells. Exon 1 and 8 AR-ASO treatment in these cells similarly decreased prostate-specific antigen (PSA) expression and induced apoptosis as measured by caspase-3 and PARP cleavage and cell growth inhibition. To further define the functional role of AR-Vs in MDV-R LNCaP cells, we used a CE3 siRNA that specifically silenced AR-V7, but not AR-FL in MDV-R LNCaP cells. AR-V7 knockdown did not decrease PSA levels, did not induce apoptosis, and did not inhibit cell growth. In MDV-R LNCaP cells, exon 1 and 8 ASO similarly suppressed cell growth and AR-regulated gene expression in vitro and in vivo. Conclusions: These results indicate that the AR remains an important driver of MDV3100 resistance and, the biologic consequences mainly driven by AR-FL in MDV-R LNCaP models.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2014.32.4_suppl.74
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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  • 5
    Online Resource
    Online Resource
    Overcoming Resistance to Interferon-Induced Apoptosis of Renal Carcinoma and Melanoma Cells by DNA Demethylation
    American Society of Clinical Oncology (ASCO) ; 2006
    In:  Journal of Clinical Oncology Vol. 24, No. 23 ( 2006-08-10), p. 3771-3779
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 24, No. 23 ( 2006-08-10), p. 3771-3779
    Abstract: Epigenetic editing of gene expression by aberrant methylation of DNA may help tumor cells escape attack from the innate and acquired immune systems. Resistance to antiproliferative effects and apoptosis induction by interferons (IFNs) was postulated to result from silencing of IFN response genes by promoter hypermethylation. Treatment of human ACHN renal cell carcinoma (RCC) and A375 melanoma cells with the DNA demethylating nucleoside analog 5-AZA-2′-deoxycytidine (5-AZA-dC) synergistically augmented antiproliferative effects of IFN- alpha (α) 2 and IFN-beta (β). Either 5-AZA-dC or an antisense to DNA methyltransferase 1 (DNMT1) overcame resistance to apoptosis induction by IFNs with up to 85% apoptotic cells resulting from the combinations. No similar potentiation occurred in normal kidney epithelial cells. IFN response genes were augmented more than 10 times in expression by 5-AZA-dC. Demethylation by 5-AZA-dC of the promoter of the prototypic, apoptosis-associated IFN response gene XAF1 was confirmed by methylation-specific polymerase chain reaction. siRNA to XAF1 inhibited IFN-induced apoptosis; conversely, overexpression of XAF1 overcame resistance to apoptosis induction by IFN-β. As occurred with apoptosis-resistant melanoma cells in vitro, tumor growth inhibition in the nude mouse of human A375 melanoma xenografts resulted from treatment with 5-AZA-dC in combination with IFN-β, an effect not resulting from either single agent. The importance of epigenetic remodeling of expression of immune-modifying genes in tumor cells was further suggested by identifying reactivation of the cancer-testis antigens MAGE and RAGE in ACHN cells after DNMT1 depletion. Thus, inhibitors of DNMT1 may have clinical relevance for immune modulation by augmentation of cytokine effects and/or expression of tumor-associated antigens.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2005.03.4074
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2006
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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