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  • American Association for Cancer Research (AACR)  (5)
  • 2010-2014  (5)
  • 1
    Online Resource
    Online Resource
    Abstract A38: Development and implementation of immunohistochemistry (IHC)-based pharmacodynamic (PD) biomarkers demonstrate NAE pathway inhibition in MLN4924 solid tumor clinical trials.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. A38-A38
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A38-A38
    Abstract: MLN4924 is an investigational small molecule NEDD8 activating enzyme (NAE) inhibitor with antitumor activity in preclinical models of several tumor types that is currently in Phase I clinical development in both hematological and solid tumors. NAE is an essential controller of the NEDD8 conjugation pathway that is required for cullin-RING ligase (CRL) activity. MLN4924 forms a covalent adduct with NAE, inhibiting enzyme activity and thus preventing ubiquitination and proteasomal degradation of CRL substrate proteins. CRL substrates have important roles in cell-cycle progression, DNA replication (CDT1), oxidative stress response (NRF-2), and survival signaling; interfering with their degradation ultimately leads to apoptosis. MLN4924 is the first NAE inhibitor to enter clinical development and evidence of target inhibition and/or downstream pathway modulation were key objectives of the Phase I studies. Here we describe the development, validation and clinical implementation of IHC PD assays for MLN4924 that quantify levels of CRL substrates CDT1 and NRF-2 and demonstrate MLN-4924 NEDD8 adduct formation in both skin and solid tumors. Pre-clinical solid tumor xenograft models were treated with increasing doses of MLN4924. Tumors were collected at multiple post-dose time points (30 minutes to 48 hours) to develop clinical assays and establish the biopsy schedule. Levels of stabilized substrates CDT1 and NRF-2, and presence of MLN4924-NEDD8 adduct were measured by quantitative and semi-quantitative IHC, respectively. Slides were scanned as whole slide images using an Aperio XTscan scope and analyzed for a percent positive pixel count using Metamorph imaging software. Western blotting of xenograft material showed decreased cullin neddylation while IHC showed an increase of CRL substrates CDT1 and NRF-2. Regulation of all PD markers was dose and time dependent. Substrate levels were most robust in the highest dose groups and peaked between 2–8 hours after dosing, returning to base line levels by 24 hours. The MLN4924-NEDD8 adduct was observed in xenograft tumors within 30 minutes of treatment indicating that MLN4924 rapidly distributed to the tumor tissue and persisted up to 24 hours. These data supported the selection of a 3–6 hr window for post-dose biopsy sampling in the clinical studies. IHC assays were successfully adapted to clinical trial fine needle tumor biopsies and skin punch biopsies. In phase I studies levels of CDT1, NRF-2 and MLN4924-NEDD8 adduct in skin and tumor were compared in biopsies obtained at screening and 3–6 hours after the second day of dosing. CDT1 and NRF-2 IHC staining was quantified exclusively in regions of tumor or skin epidermal area. Elevations in CDT1 and NRF-2 substrate levels were observed in skin and tumor biopsies. Greater than 50% of all skin (n=38) and tumor biopsies (n=16) demonstrated a robust PD response suggesting target engagement. IHC analysis of MLN4924-NEDD8 adduct showed that drug was present in 100% of the post dose tumor biopsies. These data demonstrate evidence of inhibition of NAE activity and downstream pathway modulation by MLN4924 in skin and multiple tumor types. 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 A38.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-A38
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 2
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    Online Resource
    Abstract C26: Ethnic, gender, and age disparities and outcome of phase I clinical trials of biologically targeted anticancer agents
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 23, No. 11_Supplement ( 2014-11-01), p. C26-C26
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 23, No. 11_Supplement ( 2014-11-01), p. C26-C26
    Abstract: Background: Age, gender and ethnic-based differences in drug metabolism have been previously reported from large population-based studies. The potential impact of these factors on safety and efficacy outcomes in early phase clinical trials has not been well studied. Methods: We analyzed data from five investigator-initiated phase I clinical trials of targeted biologic agents in solid malignancies conducted at a single academic cancer center. Ethnic distribution of enrolled patients was compared to the referral population demographics at the city, metro and state level. We also analyzed all toxicity experience, dose limiting toxicity (DLT) and clinical benefit to determine any significant differences based on ethnicity i.e. African American, (AA) vs. Caucasian, age or gender. A multivariate logistic regression model was performed to identify significant predictors of DLT. Results: Data from 117 eligible patients was employed for this analysis: AA/Caucasians (27/85); male/female (66/51); median duration on study was 88 days. AA patients were younger in age than Caucasian patients (56 vs. 62 years, p=0.004), otherwise were comparable in terms of weight, Body Mass Index, frequency or grade of toxicity, DLT experience and gender distribution. GI toxicity of nausea/vomiting was more frequent in female patients (43% vs. 24%, p=0.03) but no disparity by age, gender or ethnicity with other types of toxicities or DLT experience. Using median duration of time on study as surrogate for treatment efficacy, there was no difference by gender (M/F 89 vs. 88 days, p=0.822) or ethnicity (AA/Caucasian: 113 vs. 91 days, p=0.840) but significant correlation with age (-0.194, p=0.038) and body weight (0.234, p=0.012) was observed. AA patients had worse overall survival 7.4 (95%CI: 5.3-16.1) vs. 11.4 (95%CI: 9.2-26.3) months with a higher risk of death on univariate [1.812 (95%CI: 1.079-3.045), p=0.025] and multivariate [HR: 2.037 (95%CI: 1.182-3.512), p=0.010] analyses. There was a modest increase in the risk of death in older patients [HR: 1.028, (95%CI: 1.000-1.056), p=0.046] a non-significant trend in improved survival for female patients [HR: 0.687 (0.357-1.321), p=0.260] . Conclusions: Age-, gender- and ethnic-based disparities were observed with specific toxicity and survival of phase I clinical trials of anticancer agents. An enrichment strategy for age and ethnic subgroups in phase I trials is warranted to ensure reliable generalization of study findings. Citation Format: Taofeek K. Owonikoko, Colleen Lewis, Adeniyi K. Busari, Sungjin Kim, Zhengjia Chen, David H. Lawson, Bradley C. Carthon, Bassel F. El-Rayes, Fadlo R. Khuri, John Kauh, R. Donald Harvey, Suresh S. Ramalingam. Ethnic, gender, and age disparities and outcome of phase I clinical trials of biologically targeted anticancer agents. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C26. doi:10.1158/1538-7755.DISP13-C26
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1538-7755.DISP13-C26
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 3
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    Online Resource
    Abstract DDT02-01: Discovery of GDC-0032: A beta-sparing PI3K inhibitor active against PIK3CA mutant tumors.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. DDT02-01-DDT02-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. DDT02-01-DDT02-01
    Abstract: Modifications of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway are frequent in cancer due to multiple mechanisms, including activating mutations of the alpha isoform of PI3K. The dysregulation of this pathway has been implicated in many processes involved in oncogenesis. Thus, PI3K is a promising therapeutic target for cancer. Previously we have disclosed GDC-0941, a class 1 selective PI3K inhibitor and our class 1 PI3K/mTOR kinase inhibitor, GDC-0980. In this presentation we describe the design and discovery of a new class of PI3K inhibitors, which selectively inhibit the activated PI3Kα isoform relative to the PI3Kβ isoform. A lead was identified from a high throughput screen (HTS) that resulted in a novel chemical series of kinase inhibitors. Through a structure-based approach, this lead was optimized to provide very potent inhibitors of PI3K. In addition, this chemical series allowed for designing molecules that have different selectivity patterns with respect to the class 1 PI3K isoforms. In particular, a series of inhibitors were designed that could preferentially inhibit PI3Kα relative to PI3Kβ (“beta-sparing”). Further modification of the physicochemical properties led to the discovery of GDC-0032. GDC-0032 is a potent inhibitor of PI3Kα (PIK3CA) isoform with a Ki =0.2 nM, and with reduced inhibitory activity against PI3Kβ. This selectivity profile allowed for greater efficacy in vivo at the maximum tolerated dose relative to a pan inhibitor in representative PI3Kα (PIK3CA) mutant xenografts. It is notable that GDC-0032 preferentially inhibited PI3Kα (PIK3CA) mutant cells relative to cells with wild-type PI3K. Taken together, GDC-0032 is a potent and effective beta-sparing PI3K inhibitor, which currently is in clinical trials. Citation Format: Alan G. Olivero, Timothy P. Heffron, Matthew Baumgardner, Marcia Belvin, Leanne Berry Ross, Nicole Blaquiere, Erin Bradley, Georgette Castanedo, Mika Derynck, Steven Do, Jennafer Dotson, Danette Dudley, Kyle Edgar, Adrian Folkes, Ross Francis, Tony Gianetti, Richard Goldsmith, Paul Goldsmith, Jane Guan, Trevor Harrison, Robert Heald, Jerry Hsu, Phillip Jackson, Graham Jones, Amy Kim, Aleks Kolesnikov, Mark Lackner, Leslie Lee, John Lesnick, Cristina Lewis, Michael Mamounas, Neville McLean, Jeremy Murray, Chudi Ndubaku, Jim Nonomiya, Jodie Pang, Neil Pegg, Wei Wei Prior, Laurent Salphati, Deepack Sampath, Stephen Sideris, Michael Siu, Steven Staben, Daniel Sutherlin, Mark Ultsch, Jeff Wallin, Lan Wang, Christian Wiesmann, Xiaolin Zhang, Lori S. Friedman. Discovery of GDC-0032: A beta-sparing PI3K inhibitor active against PIK3CA mutant tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr DDT02-01. doi:10.1158/1538-7445.AM2013-DDT02-01
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-DDT02-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 4
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    Online Resource
    Discovery of Biomarkers Predictive of GSI Response in Triple-Negative Breast Cancer and Adenoid Cystic Carcinoma
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Discovery Vol. 4, No. 10 ( 2014-10-01), p. 1154-1167
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 4, No. 10 ( 2014-10-01), p. 1154-1167
    Abstract: Next-generation sequencing was used to identify Notch mutations in a large collection of diverse solid tumors. NOTCH1 and NOTCH2 rearrangements leading to constitutive receptor activation were confined to triple-negative breast cancers (TNBC; 6 of 66 tumors). TNBC cell lines with NOTCH1 rearrangements associated with high levels of activated NOTCH1 (N1-ICD) were sensitive to the gamma-secretase inhibitor (GSI) MRK-003, both alone and in combination with paclitaxel, in vitro and in vivo, whereas cell lines with NOTCH2 rearrangements were resistant to GSI. Immunohistochemical staining of N1-ICD in TNBC xenografts correlated with responsiveness, and expression levels of the direct Notch target gene HES4 correlated with outcome in patients with TNBC. Activating NOTCH1 point mutations were also identified in other solid tumors, including adenoid cystic carcinoma (ACC). Notably, ACC primary tumor xenografts with activating NOTCH1 mutations and high N1-ICD levels were sensitive to GSI, whereas N1-ICD–low tumors without NOTCH1 mutations were resistant. Significance: NOTCH1 mutations, immunohistochemical staining for activated NOTCH1, and HES4 expression are biomarkers that can be used to identify solid tumors that are likely to respond to GSI-based therapies. Cancer Discov; 4(10); 1154–67. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 1103
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-13-0830
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 5
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    Abstract 15: Association of topoisomerase II expression and cancer-specific death in patients with surgically-resected clear cell renal cell carcinoma.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 15-15
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 15-15
    Abstract: PURPOSE: Despite the development of prognostic algorithms based on clinico-pathologic features, the ability to identify aggressive forms of clear cell renal cell carcinoma (ccRCC) remains suboptimal. Topoisomerase IIA (TOP2a) is a biomarker of DNA replication and a target for antineoplastic agents. Herein, we evaluate the association of TOP2a expression in ccRCC tumors with pathologic features of aggressiveness and risk of cancer-specific death. METHODS: We identified 947 patients who underwent nephrectomy to treat clinically localized ccRCC between 1/16/1990 and 9/27/2006. TOP2a expression was assessed using IHC and scored as number of positive cells per mm2. We evaluated TOP2a expression using a continuous variable and tertile categories. For associations with pathologic features we employed Kruskal-Wallis tests and for associations with cancer-specific survival we generated Cox proportional hazard regression models. RESULTS: Higher TOP2a expression is associated with later stage, higher grade and higher Mayo SSIGN score (all p & lt; 0.001). The risk of death from RCC increases with increasing TOP2a expression (p trend & lt; 0.0001). Compared to patients in the lowest tertile, those patients with tumors in the highest tertile of TOP2a expression were at increased risk of RCC death (HR=2.31 95% CI 1.64-3.25; p & lt;0.0001). Interestingly, among those patients with low risk disease (SSIGN score 0-3; ∼95% 10 year survival), those with high TOP2a were at increased risk of RCC death (HR=3.09 95% CI 1.29-7.40; p =0.01). CONCLUSION: Higher TOP2a expression is associated with more aggressive pathologic features and increased risk of cancer-specific death among patients undergoing surgery for localized ccRCC. If confirmed, these data support further inquiry for TOP2a as a prognostic and predictive biomarker for ccRCC patients. Citation Format: Richard W. Joseph, Dan Serie, Tracy Hilton, Mansi Parasramka, Jeanette Eckel-Passow, John Cheville, Bradley C. Leibovich, Alexander S. Parker. Association of topoisomerase II expression and cancer-specific death in patients with surgically-resected clear cell renal cell carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 15. doi:10.1158/1538-7445.AM2013-15
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-15
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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