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  • American Association for Cancer Research (AACR)  (5)
  • 1
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 5387-5387
    Abstract: Concomitant inhibition of multiple cancer-driving kinases is an established strategy to improve the durability of clinical responses to targeted therapies. The difficulty of discovering kinase inhibitors with an appropriate multi-target profile has, however, necessitated the application of combination therapies, which can pose significant clinical development challenges. Epigenetic reader domains of the bromodomain family have recently emerged as novel targets for cancer therapy. Here we have used BROMOscan™ bromodomain ligand binding assays to identify several clinical kinase inhibitors that also inhibit bromodomains with therapeutically relevant potencies and are best classified as dual kinase/bromodomain inhibitors. Nanomolar activity on BRD4 by clinical PLK1 and JAK2/FLT3 kinase inhibitors is particularly noteworthy as these combinations of activities on independent oncogenic pathways exemplify a novel strategy for rational single agent polypharmacological targeting. Importantly, cell-based data show that these dual inhibitors suppress c-Myc expression (a hallmark of BRD4 inhibition) and induce complex polypharmacological phenotypes reflecting dual kinase/bromodomain inhibition across a panel of primary human cell assay systems that model complex tissue and disease state environments (BioMap™). Furthermore, rich structure-activity relationships for related inhibitors and co-crystal structures identify design features that enable a general platform for the rational design of dual kinase/bromodomain inhibitors. Citation Format: Elizabeth R. Quinn, Pietro Ciceri, Susanne Müller-Knapp, Alison O'Mahony, Oleg Fedorov, Panagis Filippakopoulos, Jeremy P. Hunt, Elisabeth A. Lasater, Gabriel Pallares, Sarah Picaud, Christopher Wells, Lisa M. Wodicka, Neil P. Shah, Stefan Knapp, Daniel K. Treiber. Dual kinase/bromodomain inhibitors for rationally designed polypharmacology. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5387. doi:10.1158/1538-7445.AM2014-5387
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS1-17-PS1-17
    Abstract: Background: Over the last decade, patients with early-stage breast cancer have been undergoing total mastectomy (TM) with increasing frequency. Our center reported that local recurrence rates with breast conserving therapy (BCT) declined throughout the 27-year period: from 7.1% for patients treated during 1970–1984 to 1.3% for patients treated during 1994–1996. More recently, several groups have published slightly improved survival rates in patients undergoing BCT compared with TM. The aim of this study was to evaluate trends in TM rates and compare overall survival (OS), distant metastasis-free survival (DMFS), local-regional recurrence (LRR) and disease-specific survival (DSS) between BCT and TM in patients with early-stage breast cancer undergoing upfront surgery. Methods: We identified women with clinical stage T1–2, N0–1, M0 breast cancer who underwent surgery as first treatment modality from 1/1/2000 to 12/31/2014 at our center. TM rates and survival outcomes were evaluated. Because the decision for surgery for those patients was not random, differences in patient, tumor and treatment characteristics with respect to surgery types were adjusted using inverse probability weighting (IPW) based on propensity scores. Variables in the model included age at diagnosis, clinical tumor T category, clinical nodal category, estrogen receptor (ER), human epidermal growth factor receptor 2 (HER2) status and year of surgery, and a multinomial logit model was used for surgery treatment assignment and a Gamma model was used for the time to censor. IPW models were used to adjust for impact of surgery types on survival outcomes. Similar analysis was used in 6 subsets: Stage I & hormone receptor (HR)+/HER2-, Stage I & HER2+, Stage I & triple negative breast cancer (TNBC), Stage II & HR+/HER2-, Stage II & HER2+, Stage II & TNBC. Patients undergoing TM with RT were excluded from subset analysis due to small sample size. Results: A total of 8,256 patients were included, of them, 4701 (56.9%) underwent BCT, 2862 (34.7%) underwent TM without RT and 693 (8.4%) underwent TM+RT. Patients who underwent TM were younger and were more likely to have larger tumors, positive lymph nodes, higher grade, and HER2-positive tumors. TM rates increased in patients & lt;=50 years old from 2006-2013. At a median follow-up time of 6.1 years, multivariable Cox model showed that patients who underwent BCT had improved OS (HR: 0.8,95%CI: 0.7-0.99, P=0.02) and had a similar DSS, DMFS, and LRR compared to patients who underwent TM without RT. After IPW adjusting, patients undergoing BCT had a slightly worse DSS (RR: 1.2, 95%CI: 1.02-1.4, P=0.03) and similar OS, DMFS and LRR compared to patients underwent TM without RT in the whole cohort. In subset analyses, after IPW adjusting, there were no survival differences in OS, DSS, and DMFS between TM without RT and BCT. Patients with TNBC undergoing BCT had a lower LRR compared to TM (RR: 0.4, 95% CI: 0.3-0.6, P & lt;0.001) regardless of clinical stage. Conclusions: In whole cohort, after IPW adjusting, patients undergoing BCT had a slightly worse DSS compared to patients underwent TM without RT, and those differences in DSS have disappeared in the subset analysis. LRR was lower in patients with TNBC breast cancer undergoing BCT although there as a similar OS, DSS and DMFS compared with TM in subset analysis. These contemporary data may help physicians in surgical decision making for patients who are candidates for either TM or BCT. Table 1. Results from multivariable Cox models for factors associated with survival outcomes and IPW adjusted models for factors associated with survival outcomesCox ModelIPW adjusting modelsFactorsHRP95%CIRRP95% CIOSSurgery typeTM without RTBCT0.80.020.70.991.01.00.9-1.1TM with RT1.00.960.81.31.10.60.9-1.3DSSSurgery typeTM without RTRefBCT1.10.40.81.51.20.031.02-1.4TM with RT1.70.0051.22.61.30.021.04-1.6DMFSSurgery typeTM without RTRefBCT1.10.40.91.41.00.50.9-1.2TM with RT1.70.0021.22.40.90.70.7-1.2 LRRSurgery typeTM without RTRefBCT1.30.11.01.71.00.70.7-1.2TM with RT0.40.020.20.90.80.10.6-1.1Subsets IPW adjusted models for factors associated with LRRBCT vs. TM without RTStage I & HR+/HER2-No. of patientsTM without RT/BCTRRP95% CIStage I & HER2+1469/29451.00.90.8-1.3Stage I & TNBC199/2850.70.30.3-1.5Stage II & HR+/HER2-128/3170.4 & lt;0.0010.3-0.6Stage II & HER2+690/7451.10.70.7-1.8Stage II & TNBC102/1080.90.50.5-1.4Stage I & HR+/HER2-110/1570.50.0480.3-0.99HER2 – human epidermal growth factor receptor 2; HR – hormone receptor; TNBC – triple negative breast cancer Citation Format: Min Yi, Mariana Chavez Mac Gregor, Benjamin Smith, Abigail S Caudle, Sarah M DeSnyder, Henry M Kuerer, Kelly K Hunt. Comparing survival differences between breast-conserving therapy and mastectomy in patients with early-stage breast cancer undergoing upfront surgery [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS1-17.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 3
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 23, No. 12 ( 2017-06-15), p. 2991-3002
    Abstract: Purpose: Low molecular weight cyclin E (LMW-E) detected by Western blot analysis predicts for reduced breast cancer survival; however, it is impractical for clinical use. LMW-E lacks a nuclear localization signal that leads to accumulation in the cytoplasm that can be detected by IHC. We tested the hypothesis that cytoplasmic staining of cyclin E can be used as a predictor of poor outcome in different subtypes of breast cancer using patient cohorts with distinct clinical and pathologic features. Experimental Design: We evaluated the subcellular localization of cyclin E in breast cancer specimens from 2,494 patients from 4 different cohorts: 303 from a prospective study and 2,191 from retrospective cohorts [NCI, MD Anderson Cancer Center (MDA), and the United Kingdom (UK)]. Median follow-up times were 8.0, 10.1, 13.5, and 5.7 years, respectively. Results: Subcellular localization of cyclin E on IHC was associated with full-length (nuclear) and low molecular weight isoforms (cytoplasmic) of cyclin E on Western blot analysis. In multivariable analysis, cytoplasmic cyclin E staining was associated with the greatest risk of recurrence compared with other prognostic factors across all subtypes in three (NCI, MDA, and UK) of the cohorts. In the MDA cohort, cytoplasmic cyclin E staining outperformed Ki67 and all other variables as prognostic factors. Conclusions: Cytoplasmic cyclin E identifies patients with the highest likelihood of recurrence consistently across different patient cohorts and subtypes. These patients may benefit from alternative therapies targeting the oncogenic isoforms of cyclin E. Clin Cancer Res; 23(12); 2991–3002. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1348-1348
    Abstract: Introduction: Cyclin E is an independent predictor of poor outcomes and response to treatment in breast cancer (BrCa). Expression of low-molecular-weight cyclin E (LMW-E) is associated with more aggressive disease in all BrCa subtypes. While tumor infiltrating lymphocytes (TILs) are more abundant in LMW-E+ tumors, high-TIL/LMW-E+ tumors have lower probability of pathological complete response (pCR) to neoadjuvant chemotherapy. We hypothesized that LMW-E induces immune changes that create a permissive microenvironment in the mammary gland for promoting tumor initiation and subsequent growth. We aimed to evaluate the role of mammary epithelial expression of LMW-E in the temporal induction of systemic and local immune responses that ultimately prime the mammary gland for tumor development. Methods: We generated a tri-transgenic mouse model capable of conditionally expressing human LMW-E under the control of the MMTV promoter in a p53 heterozygous background (MPT) upon doxycycline (Dox) administration. Female MPT mice were treated with Dox for 3, 6 and 9 months and age-matched untreated controls were sacrificed at each time point. An independent group of non-transgenic mice in a p53 heterozygous background were maintained +/- Dox as positive and negative controls. Mammary glands and peripheral organs (spleen, lung, bone marrow) were harvested for immune profiling by flow cytometry and multiplex immunofluorescence microscopy (mIF). Serum was also collected for cytokine/chemokine assessment. Immune profiling via flow cytometry was performed using two multi-color panels to assess basic immune and more specialized T-cell subsets. For the mIF experiments, two 5-marker panels were applied to mammary tissue. Results: Histological examination of MPT mammary glands over time showed a temporal increase in acinar proliferation and mitotic figures, which was further confirmed by the co-localization of panCK+ and Ki-67+ markers. We report that although immune cell frequencies changed with age, these specific changes were dependent on LMW-E induction as compared to the non-transgenic cohort of mice. LMW-E+ mammary glands showed a temporal enrichment in B cells, macrophages, T cells (CD4+, PD1+, CD4+Ki67+, and Tregs), cDCs, and panCK+, panCK+vimentin+ populations over time. By contrast, pDCs increased from 3 to 6 months but decreased in the pre-tumorigenic mammary gland of the 9-month old LMW-E+ mice. Conclusions: LMW-E induction mediates an increase in epithelial cell proliferation and epithelial-to-mesenchymal transition events that result in local immune alterations, specifically affecting T-cell subsets. Our findings suggest that the immunological changes driven by LMW-E lead to an immunosuppressive microenvironment that may promote tumor formation at the early stages of breast tumorigenesis. Citation Format: Sofia Mastoraki, Amriti R. Lulla, Sarah Schneider, Karen Clise-Dwyer, Morgan M. Green, Natalie W. Fowlkes, Kelly K. Hunt, Stephanie S. Watowich, Khandan Keyomarsi. LMW-E induction and crosstalk with immune cells potentiates local immune responses leading to an immunosuppressive microenvironment at the early stages of breast tumorigenesis in mouse models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1348.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 315-315
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 315-315
    Abstract: Clinical assessment of breast cancer tumors has shown that androgen receptor (AR) is expressed in more than 75% of cases, independent of molecular subtype. Specifically, clinical studies have shown that estrogen receptor (ER) and AR discordance correlates with endocrine resistance. Preclinical studies show that downregulation of ER results in a lack of estrogen mediated growth which is concurrent with upregulation of AR and its mediated gene targets. In addition, forced expression of AR was shown to induce resistance to tamoxifen, even when estrogen receptor was still expressed. Furthermore, ER positive breast cancer cells made resistant to tamoxifen express higher levels of AR and show sensitivity to abiraterone acetate. Together, these results implicate AR in endocrine resistance and suggest AR as a potential therapeutic target in a subset of these endocrine resistant cancers. The aim of this study was to better understand the role of AR in aromatase inhibitor (AI) resistance through the use of cell lines made resistant to AI through xenograft mouse modeling. In this study, MCF7 cells, MCF7 cells transfected with the human aromatase gene (MCF7Ca), and their aromatase inhibitor (AI) resistant counterparts, were analyzed for changes in AR and ER expression by qPCR and Western blot. Sensitivity of these cells to AR targeting agents was assessed by MTT assay. MCF7Ca cells displayed decreased expression of AR and increased expression of ER when compared to MCF7 cells. AI-resistant cell lines displayed modulation of ER and AR expression when compared to their AI-sensitive counterparts. Upregulation of AR was accompanied with increased AR transcriptional activity, as demonstrated by increased expression of PSA. Treatment of AI-resistant cells with AR targeting agents displayed increased sensitivity when compared to AI-sensitive cells. Together, these results suggest that upregulation of AR may contribute to AI-resistance, and that targeting AR in AI-resistant breast cancer may have therapeutic relevance. Citation Format: Caleb Hunt, Sarah E. Lock, Cynthia E. Shannon, Nichole M. Varela-Gonzalez, Randolph K. Larsen, Amanda J. Schech. Potential role of androgen receptor in aromatase inhibitor resistance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 315.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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