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  • American Association for Cancer Research (AACR)  (6)
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  • American Association for Cancer Research (AACR)  (6)
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  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3249-3249
    Abstract: The molecular chaperone heat shock protein 90 (HSP90) is involved in folding and stabilization of a wide range of client proteins, including key proteins involved in cancer. Through structure-based design, we synthesized a novel imidazopyridine class of potent HSP90 inhibitors. The synthesis and SAR surrounding this class of compounds will be discussed. The extensive SAR study and lead optimization resulted in the identification of the development candidate CUDC-305, later renamed Debio 0932. Debio 0932 displays high oral bioavailability (96% in mouse), high drug concentrations and a prolonged half-life (20 hr) in tumor tissues. In vitro, Debio 0932 displays potent HSP90 inhibitory activity (IC50, 100 nM) as well as anti-proliferation and apoptosis-inducing activities against a broad range of cancer cell lines (IC50, 40 – 900 nM). In vivo, Debio 0932 is highly effective against various cancer models including NSCLC, AML, breast and colorectal cancers, as well as brain cancers, benefited by its ability to cross the blood-brain barrier to reach therapeutic levels in brain tissue. Debio 0932 also exhibits high selectivity and a favorable safety profile. It was therefore selected as a drug candidate and is currently in Phase 1 clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3249. doi:10.1158/1538-7445.AM2011-3249
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 8_Supplement ( 2012-04-15), p. 3744-3744
    Abstract: Recent evidence indicates that both PI3K-Akt-mTOR signaling pathway and HDAC are validated targets in hematological cancers. In order to overcome primary resistance and prevent secondary resistance resulting from compensatory/feedback mechanisms in cancer cells, CUDC-907 was designed to inhibit all isoforms of Class I PI3K and Class I and II HDAC, based on previous observations that synergistic effects can be achieved by inhibition of both HDAC and PI3K in cancer cells. In cell proliferation assays, this compound displays potent anti-proliferation activity in hematological cancer cell lines including non-Hodgkin's lymphoma (NHL), and multiple myeloma (MM). Mechanistically, CUDC-907 is able to simultaneously suppress PI3K-Akt-mTOR as well as other essential signaling pathways due to epigenetic modifications via HDAC inhibition. CUDC-907 is orally bio-available in dogs, has a long half-life in murine tumors, induces apoptosis and inhibits cancer cell proliferation in xenograft tumors. In efficacy studies in NHL and MM models, CUDC-907 is more efficacious than either a single-agent PI3K or HDAC inhibitor reference compound or a combination of the two agents given at maximally tolerated doses (MTD). Furthermore, CUDC-907 is more efficacious than the PI3Kα-selective inhibitor CAL-101 when dosed at MTD doses. These observations are related to our findings that, all isoforms of PI3K are expressed in most hematological cancer models. Therefore, the efficacy of isoform selective PI3K inhibitors may be limited only to those cancers driven by a specific PI3K subtype. In addition, a synergistic antitumor effect can be achieved in efficacy studies when CUDC-907 is combined with standard of care agents in both NHL and MM models. In conclusion, through broad network disruption, CUDC-907 may offer a greater therapeutic benefit than isoform-specific PI3K inhibitors as a novel anti-cancer treatment of hematological malignancies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3744. doi:1538-7445.AM2012-3744
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 3
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2010
    In:  Clinical Cancer Research Vol. 16, No. 1 ( 2010-01-01), p. 34-44
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 1 ( 2010-01-01), p. 34-44
    Abstract: Purpose: To identify the pattern of interleukin-1 receptor–associated kinase (IRAK-1) protein expression in non–small cell lung carcinoma (NSCLC) and corresponding preneoplastic lesions. Experimental Design: Archived tissue from NSCLC (adenocarcinoma and squamous cell carcinoma; n = 306) and adjacent bronchial epithelial specimens (n = 315) were analyzed for the immunohistochemical expression of IRAK-1, and the findings were correlated with patients' clinicopathologic features. Furthermore, we investigated the correlation between IRAK-1 expression and expression of NF-κB and IL-1α in tumor specimens. Results: NSCLC tumors showed significantly higher cytoplasmic and lower nuclear IRAK-1 expression than normal epithelium. Squamous dysplasias had significantly higher cytoplasmic IRAK-1 expression than normal epithelium. In tumors, a significant positive correlation was detected between IRAK-1 expression (nuclear and cytoplasmic; P = 0.011) and IL-1α cytoplasmic expression (P & lt; 0.0001). The correlation between the expression of the markers and patients' clinicopathologic features varied according to tumor histologic type and sex. High IRAK-1 cytoplasmic expression correlated with worse recurrence-free survival in women with NSCLC [hazard ratio (HR), 2.204; P = 0.033], but not in men. In adenocarcinoma, combined low level of expression of nuclear IRAK-1 and NF-κB correlated significantly with worse overall (HR, 2.485; P = 0.007) and recurrence-free (HR, 3.058; P = 0.006) survivals in stage I/II patients. Conclusions: IRAK-1 is frequently expressed in NSCLC tissue specimens, and this expression is an early phenomenon in the sequential development of lung cancer. IRAK-1 is a novel inflammation-related marker and a potential target for lung cancer chemopreventive strategies. Clin Cancer Res; 16(1); 34–44
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 4
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 21, No. 10_Supplement ( 2012-10-01), p. A88-A88
    Abstract: Background: Perceived discrimination among the US population has been associated with lower utilization of cancer screening tests. Data from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL) Socio-cultural Ancillary Study were analyzed to determine if perceived discrimination was associated with adherence to breast, cervical and colorectal cancer screening tests. Methods: Respondents included 5,313 participants from Bronx NY, Chicago IL, Miami FL, and San Diego CA recruited using a 2-stage area household probability design. Of these, 3,083 women aged 18-74 and 840 men aged 50-74 were included in the analysis. Cancer screening behaviors, income, health insurance status, and having a usual source of healthcare were assessed via self-report. Perceived discrimination was measured using the Perceived Ethnic Discrimination Questionnaire (PEDQ). Acculturation was measured using the Short Acculturation Scale for Hispanics. Adherence to cervical and breast cancer screening tests was defined as receipt of a Pap smear within the last 2 years (in women 18-74) and receipt of a mammogram within the last 2 years (in women 40-74), respectively. In all participants 50-74, adherence to fecal occult blood testing (FOBT) was defined as having FOBT within the 1 year; adherence to colonscopy/sigmoidoscopy was defined as having had either test in the last 5 years. Chi-square tests were used to test for differences between groups. Multivariate polytomous logistic regression models were fit to assess the association between perceived discrimination and cancer screening adherence. Models were adjusted for income, health insurance status, having a usual source of care, location, and acculturation. Results: Among women, 72.1% were adherent to cervical cancer screening and 54.2% were adherent to breast cancer screening. In participants aged 50-74, 23.5% of women and 27.2% of men were adherent to FOBT; 36.9% of women and 30.0% of men were adherent to colonscopy/sigmoidoscopy. After adjustment for covariates, men in the highest quartiles of perceived discrimination were more likely be non-adherent to FOBT compared to men in the lowest quartile of perceived discrimination (Q3 vs. Q1, OR: 2.3 [1.1-4.7]; Q4 vs. Q1, OR: 4.4 [2.0-9.7] ). We observed no association between perceived discrimination, and breast or cervical cancer screening, or colonoscopy/sigmoidoscopy. Not having health insurance was a significant independent predictor of non-adherence to breast, cervical, and colorectal cancer screening (breast cancer, OR: 2.5 [1.7-3.5]; cervical cancer, OR: 1.7 [1.2-2.4] ; FOBT in women, OR: 2.6 [1.3-4.9]; colonoscopy/sigmoidoscopy in women, OR: 5.5[2.7-11.3] ; in men, OR: 3.4 [1.5-7.4]). Greater degree of acculturation to the dominant US culture was associated with non-adherence to cervical and colorectal cancer screening in women (cervcal cancer, OR: 1.4 [1.1-1.8] ; FOBT, OR: 2.0 [1.3-3.2]; colonscopy/sigmoidoscopy, OR: 1.7 [1.1-2.8] ). Conclusions: For breast, cervical and colorectal cancer screening behaviors, not having health insurance and being more acculturated to US culture were significant predictors of lower rates of cancer screening; perceived discrimination was not significantly related. The finding that higher levels of discrimination are associated to non-adherence to FOBT among men warrants further research. Citation Format: Cristina Valdovinos, Carmen Isasi, Molly Jung, Heather Greenlee, Robert Kaplan, Frank J. Penedo, Rebeca A. Espinoza, Patricia Gonzalez, Vanessa L. Malcarne, Krista Perreira, Hugo Salgado, Melissa A. Simon, Lisa M. Wruck. Perceived discrimination and cancer screening behaviors in U.S. Hispanics: Preliminary results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Sociocultural Ancillary Study. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr A88.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
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  • 5
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. C70-C70
    Abstract: In order to achieve cancer signaling network disruption and overcome primary and/or secondary resistance to standard of care agents in hematologic cancers, we have developed a novel class of dual HDAC and PI3K inhibitors by integrating a HDAC inhibitory functionality into a pharmacophore of PI3K inhibitors. Utilizing structure-based design and extensive SAR approach, CUDC-907 has been selected as a clinical candidate that inhibits not only PI3K directly but also other essential signaling pathways indirectly through epigenetic regulation following HDAC inhibition. Enzymatic assays indicate that CUDC-907 potently inhibits Class I PI3K subtypes as well as Class I and II HDAC subtypes. In anti-proliferation assays, CUDC-907 displays potent inhibition of proliferation of a variety of hematologic cancer cells (mean IC50 = 27nM in 23 cell lines). In mechanism studies, CUDC-907 potently and durably inhibits HDAC and PI3K, as indicated by increase of acetylated histone H3, inhibition of phospho-AKT and phospho-STAT3, decrease of anti-apoptotic molecules (BCL-2, survivin, etc.), and induction of P21, acetylated P53 and cleaved caspase3. CUDC-907 is orally bioavailable in animals, and displays a favorable PK profile in tumor-bearing animals. PD studies in xenograft models exhibit that CUDC-907 dose-dependently inhibits both targets, decreases tumor cell proliferation, and induces apoptosis in hematologic tumor xenografts, correlating well with its drug exposure in tumors. In efficacy studies, CUDC-907 inhibits growth of subcutaneously implanted tumor xenografts of hematologic cancers in a dose-dependent manner. Furthermore, in a Daudi NHL model, CUDC-907 is more efficacious than either a single PI3K or HDAC inhibitor reference compound or a combination of the two single agents at maximally tolerated doses. CUDC-907 also displays a favorable safety profiles. Taken together, CUDC-907 may offer greater therapeutic benefits through broad network disruption in hematologic cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C70.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    SSG: 12
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 9 ( 2010-05-01), p. 3647-3656
    Abstract: Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647–56. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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