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  • American Association for Cancer Research (AACR)  (19)
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  • American Association for Cancer Research (AACR)  (19)
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  • 1
    Online Resource
    Online Resource
    NF-κB Activation in Breast Cancer Occurs Via Different Mechanisms in Triple Negative and HER2+ Tumors with Lymphocytic Infiltrate.
    American Association for Cancer Research (AACR) ; 2009
    In:  Cancer Research Vol. 69, No. 24_Supplement ( 2009-12-15), p. 1164-1164
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 69, No. 24_Supplement ( 2009-12-15), p. 1164-1164
    Abstract: NF-κB transcription factors regulate expression of genes involved in immune response, inflammation, apoptosis and cancer. NF-κB is known to be regulated via two main mechanisms: (i) through the IκB kinase complex (via the canonical pathway), and (ii) through the IKKα and NIK kinases (via the alternative pathway). Recently, NF-κB has also been shown to be activated by the IKBKE kinase. In breast cancer the level of NF-κB was found elevated only in triple negative (basal) and in HER2+ tumors. Inhibition of NF-κB has been shown to block cell proliferation and tumor formation, and therefore, genes that activate NF-κB might be potential drug targets in the treatment of cancer. Our study aims to identify the mechanisms of activation of NF-κB in various breast cancer subtypes.We analyzed several breast cancer gene expression microarray datasets from public repositories (GSE 2034, 4922, 7390) and used our molecular classification of breast cancer proposed in (Can Res 2007 67: 10669-76) to identify the subtypes of breast cancer in which the NF-κB pathway is altered. The NF-κB activity was evaluated based on upstream and downstream events for the canonical and the alternative pathways, and quantified through a consensus of geneset enrichment scores. We found that the NF-κB downstream genes are upregulated only in triple negative (subtype basal BA) and Her2+ tumors having an immune signature provided by the presence of a lymphocytic infiltrate (subtype Her2I).In order to identify the pathways involved in NF-κB activation, we analyzed the expression of the upstream genes in the canonical, alternative, IKBKE and PI3K/AKT pathways. We found that AKT1 -- an AKT isoform that activates IKKα -- is overexpressed in Her2I, while other AKT isoforms, AKT2 and AKT3, are overexpressed in BA. PI3K is overexpressed in BA, but not in Her2I. We also found that PDK1, which phosphorylates and activates AKT, is overexpressed in Her2I but not in BA. TNFα -- an activator of the NF-κB canonical pathway -- was found overexpressed in BA. However, in BA the components of the IKK complex have low expression apart from IKKγ. IKBKE was found upregulated in both BA and Her2I subtypes.In Her2I, the absence of high expression of TRAF2/5, which recruits the IKK complex, and also the low expression of IKKβ, indicates that NF-κB is not activated by the canonical pathway. Combined with the overexpression of the NIK gene in Her2I, this leads to the hypothesis that in Her2I, NF-κB is being activated by IKBKE and the alternative pathway.In BA, the overexpression of TRAF3 -- an inhibitor of the alternative pathway, suggests that the activation of NF-κB may also occur via the canonical pathway.In summary, we hypothesize that the activation of NF-κB in Her2I tumors is initiated by the IKBKE oncogene and the alternative pathway, while the activation of NF-κB in BA tumors is initiated by IKBKE and the canonical pathway. Boehm et al (Cell, 2007) shown that NF-κB can be inhibited by simultaneously targeting AKT and IKBKE. Combined with our findings, this raises the interesting possibility of developing a targeted therapy for the BA and Her2I breast tumors. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1164.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS-09-1164
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 2
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    Online Resource
    Abstract PR05: Exceptional Response to PD-1 antibody treatment in a POLE-mutant endometrial cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. PR05-PR05
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. PR05-PR05
    Abstract: Genomic assessment of exceptional responders is a promising approach to identify predictors of response to antibody therapy directed against the immune checkpoint programmed death 1 (PD-1) receptor, which has been shown to yield prolonged and deep responses in multiple types of human cancer. We identified a patient with endometrial cancer who experienced an exceptional response to pembrolizumab, an antibody to programmed death 1 (PD-1) receptor. The primary endometrial cancer specimen and the biopsy from the recurrent supraclavicular lymph node (LN) metastasis obtained prior to treatment were analyzed by hybrid-capture based genomic profiling at a commercial CLIA-certified laboratory, Foundation Medicine, targeting all exons of 315 cancer-related genes. In the patient's pre-treatment endometrial cancer specimens we identified a mutation in DNA polymerase epsilon gene (POLE), which is associated with disruption of the exonuclease activity required for proofreading function and results in a high mutation burden or “ultramutator” phenotype. This tumor did harbor a large number of mutations: 32 likely pathogenic sequence variants and 116 variants of unknown significance (VUS). We next reviewed genomic alterations in 252 deidentified endometrioid endometrial cancers that underwent genomic profiling with the FoundationOne assay and determined that 23 (9.1%) had sequence variants in POLE. The cancers with POLE sequence variants had a mean of 21.2 +/-4.1 mutations identified as likely pathogenic and 82.2 +/-25 variants identified as VUS, compared with a mean of 7.5+/-0.5 likely pathogenic variants and 12.8 +/- 2.6 VUS in POLE wt cases (mean +/- S.E.; p & lt;0.005 and P = 0.015, respectively). This is consistent with TCGA data showing that POLE mutant cancers typically harbor an extremely high mutational burden. To determine if POLE mutant cancers were associated with an immune signature, analysis of RNA sequencing data from endometrioid endometrial cancers in TCGA was performed. POLE mutant cancers have higher expression of several genes encoding for immune checkpoint-related proteins, including PD-L1 and PD-L2, than either MSI or MSS endometrioid cancers. POLE mutant cancers also showed higher expression of T-cell markers such as CD8A, CD3G, PD-1 and CTLA-4, suggesting the presence of a pre-existing T-cell infiltrate. Analysis of histologic image data from TCGA confirmed that POLE mutant cancers had presence of a robust lymphocytic infiltrate. These data suggest that endometrial cancers harboring POLE mutations are associated with expression of immune checkpoint genes and evidence of lymphocytic infiltration. Thus, these tumors may be exceptionally vulnerable to treatment with immune checkpoint inhibitor therapy. We propose further clinical investigation with immunotherapy in endometrial and other cancers with POLE mutations. Citation Format: Janice M. Mehnert, Anshuman Panda, Hua Zhong, Kim M. Hirshfield, Sherri Damare, Katherine Stiles, Levi Sokol, Mark N. Stein, Lorna Rodriguez-Rodriguez, Howard L. Kaufman, Siraj Ali, Jeffery Ross, Dean C. Pavlick, Gyan Bhanot, Eileen P. White, Robert S. DiPaola, Ann Lovell, Jonathan Cheng, Shridar Ganesan. Exceptional Response to PD-1 antibody treatment in a POLE-mutant endometrial cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PR05.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-PR05
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 3
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    Abstract 212: Identification by mass spectrometry of unique phosphoproteins subsequent to signaling through c-ErbB2
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 212-212
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 212-212
    Abstract: The receptor tyrosine kinase c-ErbB2 is amplified in breast and ovarian cancer. The linear pathways through which signals by c-ErbB2 are transduced is well known. However, second generation questions that address spatial aspects of signaling remain. To address this, we have undertaken a mass spectrometry approach to identify phosphoproteins. We have used two tyrosine kinase inhibitors, Lapatinib and CP724714, that inhibit phosphorylation of c-ErbB2 to identify phosphoproteins. SKOV-3, an ovarian cancer cell line that endogenously overexpresses c-ErbB2 was grown in culture without serum for 72 hrs. Cells were then stimulated in the presence or absence of inhibitor with EGF (100ng/ml) as a ligand for 60 mins. Subsequently, cells were lysed and evaluated by western blotting with anti-phosphotyrosine antibody (4G10). Following stimulation of cells with EGF, maximal phosphorylation of c-ErbB2 was observed at 60 minutes. Lapatinib (10μM) and CP724714 (15μM) completely inhibited phosphorylation of c-ErbB2, which was confirmed by immunoprecipitation. This was further confirmed by the inhibition of downstream effectors (Erk1/2, Akt). Lapatinib (10 μM) also completely inhibited phosphorylation of EGFR while CP724714 (15μM) only inhibited partially. Cellular lysates were prepared from quiescent cells (grown without serum), after stimulation with EGF in the presence or absence of inhibitors. Purified phosphoproteins from all three samples following digestion with trypsin were subjected to mass spectrometry (Nano LC ESI MS/MS). We identified totally 62 phosphoproteins. Twenty seven phosphoproteins were observed in all the 3 samples while 17 phosphoproteins were identified both in the EGF stimulated and lapatinib treated samples. Eighteen unique phosphoproteins were observed only in the EGF stimulated sample suggesting that they are specific to signaling by c-ErbB2. The novel phosphoproteins included the proteins that partcipate in carbohydrate metabolism,cytoskeleton, cell migration and proliferation. We have evaluated two phosphoproteins, LASP-1 and Aldose reductase that has not been previously described following phosphorylation of c-ErbB2. LASP-1 is an oncogene and is located as the same arm 17q21 as c-ErbB2. It was not expressed in the normal ovary or fallopian tube. However, it was over-expressed in 17% of tumours (n=85) from patients with ovarian cancer. c-ErbB2 was not expressed in tumours that expressed LASP1. Aldose reductase is a cytosolic NADPH dependent oxidoreductase that catalyzes the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism. The activity of aldose reductase in reducing NADPH as a substrate was significantly higher in lysates from EGF stimulated as compared to the starved cells. Identification of phosphoproteins by using mass spectrometry is promising in identifying novel substrates and pathways following phosphorylation of c-ErbB2. Citation Format: C Sidhanth, Manoj Garg, P Manasa, S Krishna Priya, S Bindhya, S Sneha, R.P. Nagare, S Shirley, M Kanchan, Trivadi S. Ganesan. Identification by mass spectrometry of unique phosphoproteins subsequent to signaling through c-ErbB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 212. doi:10.1158/1538-7445.AM2017-212
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2017-212
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2017
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  • 4
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    Abstract 4463: Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4463-4463
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 4463-4463
    Abstract: Metabotropic glutamate receptor 1 (GRM1) has an established oncogenic role in melanoma. Growing evidence supports a similar role in breast cancer. We have previously shown that GRM1 is not only expressed in human breast cancers, but that levels of expression correlate with clinical outcomes with tamoxifen treatment, and that GRM1 knockdown reduces breast cancer cell viability and growth. Others have shown that GRM1 modulating drugs also reduce viability and growth of estrogen receptor (ER) negative breast cancer cell lines. Riluzole, a postulated inhibitor of glutamate release, has been evaluated in pre-clinical studies in melanoma. Early clinical trials have shown promising results for this disease. However, the mechanistic effects of riluzole have not been well-defined. Therefore, we evaluated the functional activity of riluzole in breast cancer. A molecularly diverse set of ER+ and ER- breast cancer cell lines with variable GRM1 expression were evaluated. Cell lines were treated with either riluzole or BAY 36-7620 (non-competitive GRM1 antagonist) or their combination. Treatment with either drug reduces cell number and viability, inhibits cell proliferation, and alters expression of cell cycle and apoptotic pathway genes as determined by gene microarray analysis. Drug treatment produces cell line-dependent effects on markers for proliferation, cell cycle, DNA damage, and apoptosis. Riluzole induces G2/M arrest in all cell lines tested. More specifically, riluzole induces mitotic arrest as demonstrated by changes in histone H3 phosphorylation at serine 10 and cyclin B level. Treatment with BAY 36-7620 induces a modest G2/M arrest and increase in the sub G1 population in a subset of cell lines. However, BAY 36-7620 does not induce mitotic arrest. The combination of riluzole and BAY 36-7620 results in increased cell death and decreased proliferation in all cell lines tested. Our data suggest that either riluzole or BAY 36-7620 induce breast cancer cell death. However, riluzole may modulate the activity of intracellular targets independent of GRM1. As riluzole is an FDA-approved drug, it could be quickly moved into a clinical trial and may provide a novel therapeutic approach in the treatment of breast cancer. Citation Format: Sonia C. Dolfi, Daniel J. Medina, Shridar Ganesan, Alexei Vazquez, Kim M. Hirshfield. Riluzole effectively modulates cell cycle and cell death in a molecularly diverse set of breast cancer cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4463. doi:10.1158/1538-7445.AM2015-4463
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-4463
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Abstract 182: Cancer stem cells and tumor angiogenesis in serous adenocarcinoma of ovary
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 182-182
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 182-182
    Abstract: The traditional view of tumour vascularization is that tumours acquire blood supply from the neighbouring normal stroma. However, recently the origin of tumour endothelial cells or pericytes in part has been shown to be derived from cancer stem cells (CSCs) in glioblastoma. In high grade serous ovarian cancer (HGSOC), the origin of endothelial cells is not known. Our objective was to determine if components of a tumour blood vessel and lymphatic vessel are derived from CSCs in ovarian cancer. Using spheroids as an in vitro model, we have evaluated the role of CSCs in primary malignant cells (PMCs) from patients with serous adenocarcinoma of ovary cultured under specific conditions. The expression of endothelial, pericyte and lymphatic endothelial markers was evaluated by flow cytometry. In addition, functional assays were performed to assess the endothelial phenotype. Further, the ability of CSCs to express endothelial markers under appropriate growth conditions was also evaluated with Bevacizumab which antagonize VEGF. PMCs grown in endothelial growth medium (EGM) showed significantly higher expression of CD105 (n=32, p = 0.002) and CLEC14A (n=10, p = 0.012) and co-expression of CD105/CLEC14A (n=10, p= 0.012) than that of spheroids. Primary malignant cells when grown in pericyte and lymphatic endothelial specific conditions, showed significantly higher expression of desmin (n=10, p=0.03), Smooth muscle actin (SMA) (n=10, p=0.017) and VEGFR3 (n=10, p=0.028) than that of the spheroids. When the PMCs were grown as spheroids in endothelial conditions in the presence or absence of Bevacizumab (1 μg/μl), there was a reduction in the co-expression of CD105 and CLEC14A (P=0.04). The cells grown in endothelial conditions showed formation of tubes, uptake of Dil-ac-LDL and expressed eNOS, confirming their endothelial phenotype. GFP transduced spheroids from PMCs formed tumours in mice and the blood vessels in the tumour co-expressed CD31, SMA, VEGFR3 and GFP, suggesting that these cells are derived from CSCs. These results prove that a proportion of endothelial cells, pericytes and lymphatic endothelial cells are derived from CSCs in serous ovarian carcinoma and the VEGF pathway has a key role. This property of CSCs to contribute to tumour angiogenesis can be inhibited. Citation Format: S Krishnapriya, C Sidhanth, P Manasa, S Sneha, S Bindhya, R P. Nagare, T S. Ganesan. Cancer stem cells and tumor angiogenesis in serous adenocarcinoma of ovary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 182.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-182
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
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    A Phase II Study of Etanercept (Enbrel), a Tumor Necrosis Factor α Inhibitor in Patients with Metastatic Breast Cancer
    American Association for Cancer Research (AACR) ; 2004
    In:  Clinical Cancer Research Vol. 10, No. 19 ( 2004-10-01), p. 6528-6534
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 10, No. 19 ( 2004-10-01), p. 6528-6534
    Abstract: Purpose: Tumor necrosis factor (TNF) α is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-α and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer. Experimental Design: We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression. Results: Sixteen patients were recruited [median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received ≥12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-α was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84). Conclusions: Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-04-0730
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2004
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  • 7
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    Abstract P1-15-14: Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of triple negative breast cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 4_Supplement ( 2019-02-15), p. P1-15-14-P1-15-14
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 4_Supplement ( 2019-02-15), p. P1-15-14-P1-15-14
    Abstract: Background: The use of neoadjuvant platinum with taxane for triple negative breast cancer (TNBC) has gained increased attention for improving rates of pathologic complete response (pCR). Our prior trial combining carboplatin (CAR) with liposomal doxorubicin (DOX) for metastatic TNBC showed good response rates with minimal side effects while allowing for greater platinum dosing compared to a taxane combination. We hypothesized that the doublet of DOX+CAR is effective and tolerable in the neoadjuvant setting for TNBC and that tumor genomics may aid in determining those patients most likely to benefit. Methods: A phase II single arm trial was conducted for patients (pts) diagnosed with stage II-III TNBC. Patients received 4 cycles of neoadjuvant carboplatin (AUC 5) and liposomal doxorubicin (30mg/m2) administered every 28 days, then underwent definitive breast surgery followed by 12 weeks of adjuvant paclitaxel 80 mg/m2 administered weekly. Primary and secondary clinical endpoints were rate of pCR and two year recurrence free survival (RFS) and overall survival (OS), respectively. Cardiac safety of the combination was assessed. Fresh residual tumor samples were obtained at time of surgery for generation of patient derived xenografts (PDX). Tumor genomic profiling was done to determine the mutational spectrum, association of this spectrum in primary tumors with achieving pCR, and identifying alternative treatment strategies for PDX evaluation for patients with resistant disease. Results: From 2/2015 to 5/2018, 36 pts were enrolled and 32 completed treatment; 4 pts await definitive surgery; 12 (33%) are two years from diagnosis. Median age of the cohort was 53 years. There was high participation by under-represented groups: 23% African American, 20% Asian, 14% Hispanic. Most histologies were invasive ductal but included apocrine, pleomorphic lobular, and metaplastic subtypes. Of the 32 pts who completed surgery, 34% (11) achieved pCR and 64% (23) had clinical response on serial physical exam. At 2 years, there were 2 distant and 1 local recurrence. The most common toxicities during DOX+CAR were grade 1 nausea in 19 pts (53%), grade 3/4 neutropenia occurred in 10 pts (28%); these pts received GCSF support with subsequent cycles; febrile neutropenia occurred in 1 pt (3%) in this group. Grade 3 thrombocytopenia (2 pts), pruritis (1 pt), and mucositis (1 pt) were observed. Only 6 pts (17%) had grade 1 alopecia. There were no delays in treatment due to cardiotoxicity or complications from surgical healing. TP53 (93%), PI3K/PTEN (26.6%), and NOTCH (20%) were the most commonly altered pathways. Structural variants, such as amplifications, rearrangements, and frameshifts were the most frequent alterations detected. Of the 25 pts who had residual disease, PDX was attempted from 14 pts, and 10 (71%) PDX were established, including those for all 3 patients experiencing recurrence. Conclusion: Neoadjuvant DOX+CAR demonstrated good efficacy and tolerability. Post-chemotherapy PDX is feasible and may help identify targeted approaches for patients with resistant disease. These results warrant further evaluation of this combination for early stage TNBC. Citation Format: Chan N, Riedlinger GM, Lu S-e, Pham KT, Kirstein LJ, Eladoumikdachi FG, George MA, Potdevin LB, Kowzun MJ, Desai SA, Tang DM, Omene CO, Wong ST, Rodriguez-Rust L, Kumar S, Kearney TJ, Liu C, Ganesan S, Toppmeyer DL, Hirshfield KM. Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-14.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS18-P1-15-14
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 8
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    Abstract P4-03-04: Computer extracted image measurements of nuclear shape and texture from H&E images appear to stratify low and high risk ER+ breast cancers assessed via oncotype DX
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 24_Supplement ( 2013-12-15), p. P4-03-04-P4-03-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 24_Supplement ( 2013-12-15), p. P4-03-04-P4-03-04
    Abstract: Background: In this study we investigate the ability of computer extracted image features (nuclear morphology and texture) from digitized H & E tissue slides to stratify women with lymph node negative (LN-), estrogen receptor positive (ER+) breast cancer (BCa) as low or high risk as determined by Oncotype DX (ODX), a 21 gene-expression assay. Each year, over 120,000 women in the United States (1 million worldwide) are diagnosed with ER+ BCa. Treatment guidelines recommend hormone therapy (HT) plus chemotherapy (CT); however, up to 85% of ER+ BCa patients will not benefit from CT, yet will still suffer its side effects. ODX yields a numeric risk score (RS) ranging from 1-100; RS & lt;18 suggests patients will respond to HT alone while RS & gt;30 indicates need for adjuvant CT. Unfortunately, this test is expensive ( & gt;$4000), time-consuming, and involves destructive tissue testing. The goal of this study is to show that quantitative features calculated from H & E images can accurately predict risk stratification as determined by ODX in women with LN-, ER+ BCa, suggesting a histologic image based classifier could serve as a low-cost alternative. Methods: Digitized H & E-stained ER+ BCa tissue sampled from 111 patients (34 high and 77 low-risk as determined by ODX) were obtained from the University of Pennsylvania, the University of Medicine and Dentistry of NJ, and Case Western Reserve University. Regions of cancer were annotated manually by an expert pathologist, and representative fields of view (FOV) were chosen at 20x magnification (2000 by 2000 pixels) for each patient. A selection of nuclear boundaries was annotated manually in each FOV. For each nucleus, a set of 2343 features was extracted, including 21 morphological (size, shape, and boundary) and 2322 texture (Gabor, Local Binary Pattern, Greylevel, and Laws filter features). Using Minimum Redundancy Maximum Relevance (mRMR) feature selection, the 3 features best able to separate low and high ODX risk categories were identified and used to build a supervised Bayesian classifier. Classifier training employed a randomized 3-fold cross-validation scheme; in each trial, two-thirds of the dataset were randomly selected for training, and the remaining one-third employed for independent testing. Classifier performance was evaluated using area under the receiver operating characteristic curve (AUC), positive predictive value (PPV), and negative predictive value (NPV) with respect to low and high ODX risk categorization. Performance metrics were averaged over 100 trials of 3-fold cross-validation (see table). Results: The mRMR method selected one morphological feature (nuclear area) and two Laws-based texture features as being highly discriminating between risk categories. The Bayesian classifier trained with these 3 features yielded high AUC, PPV, and NPV measures with low variance in distinguishing ODX risk categories. The supervised classification results indicate that quantitative image features from H & E-stained histopathology are able to accurately discriminate between low and high risk patients as determined by ODX. Classification PerformancePerformance MetricAverage (100 Trials)Standard DeviationAUC0.870.018PPV0.810.039NPV0.880.017 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-03-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.SABCS13-P4-03-04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
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    Abstract 3330: Tumor angiogenesis and cancer stem cells in serous adenocarcinoma of the ovary
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3330-3330
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 3330-3330
    Abstract: Angiogenesis is required for tumor growth and metastasis. The conventional view of tumour angiogenesis is that tumours get their blood supply from the neighbouring normal stroma. However, recently the origin of tumour endothelial cells or pericytes in part has been shown to be derived from cancer stem cells (CSC) in glioma. The spread of ovarian cancer (SOC) is different and the origin of endothelial cells in the tumor is not known. Using spheroids as an in vitro model (which is enriched for CSC), we have evaluated the role of CSC in primary malignant cells (PMCs) from patients with serous adenocarcinoma of ovary (n = 30) cultured under endothelial conditions. The expression of endothelial markers (CD31, CD105, and CLEC14a) was evaluated by flow cytometry. Further, the ability of CSC to express endothelial markers under appropriate growth conditions was also evaluated with Bevacizumab (Avastin) or Cediranib which antagonize VEGF or its receptor (VEGFR2) respectively. In addition, functional assays such as uptake of Dil labelled acetylated low density lipoprotein (Dil-ac-LDL) and expression of endothelial nitric oxide synthase (e-NOS) was performed to assess the endothelial phenotype. The localization of tumour blood vessels and CSC in primary ovarian tumors was examined by double immunohistochemistry of CD31/CD105/CLEC14a and ALDH1a1. Primary malignant cells (n = 30) grown in endothelial growth medium (EGM) showed significantly higher expression of CD105 (mean 20.8%, p = 0.001) and CLEC14a (mean 5.3%, p = 0.012) and a co-expression of CD105/CLEC14a (mean 1.6%, p = 0.012) than that of control (mean, 12.5%, 2.5% and 0.95% respectively). The co-expression of ALDH1a1 with endothelial markers, CD31, (mean, 1.58%), CD105, (mean 0.7%), CLEC14a (mean 0.44%) in primary malignant cells (n = 5), denovo, suggest that there is a small proportion of cells which are in transit to form endothelial cells. When the primary malignant cells were grown as spheroids in endothelial conditions in the presence or absence of Avastin (1 μg/μl), there was reduction in the expression of CD105 (mean, 12.5% (EGM) and 7.9% (Avastin), P = 0.056) and CLEC14a (mean. 5.5% (EGM) and 1.5% (Avastin), P = 0.04). However, when the spheroids were cultured in presence of cediranib (10 nM), the expression of CD105 was not reduced (Mean, 2.53% (EGM) and 4% (cediranib). The cells grown in endothelial conditions showed uptake of Dil-ac-LDL (n = 3) and expressed e-NOS (n = 3), confirming their endothelial phenotype. The double immunostaining with ALDH1a1 and CD31/CD105 demonstrated that the blood vessels were in proximity to ALDH1A1+ cells in primary serous adenocarcinoma of the ovary (n = 5). These results suggest that a proportion of endothelial cells (probably 20%) could be derived from CSC in serous ovarian carcinoma and the VEGF pathway has an important role. This property of CSC to contribute to tumour angiogenesis can be inhibited. Citation Format: Syama Krishna Priya, Rohit P. Nagare, V S. Sneha, C Sidhanth, S Bindhya, P Manasa, Trivadi S. Ganesan. Tumor angiogenesis and cancer stem cells in serous adenocarcinoma of the ovary. [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 3330.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-3330
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 10
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    TGFβ Promotes Genomic Instability after Loss of RUNX3
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 1 ( 2018-01-01), p. 88-102
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 1 ( 2018-01-01), p. 88-102
    Abstract: Studies of genomic instability have historically focused on intrinsic mechanisms rather than extrinsic mechanisms based in the tumor microenvironment (TME). TGFβ is the most abundantly secreted cytokine in the TME, where it imparts various aggressive characteristics including invasive migration, drug resistance, and epithelial-to-mesenchymal transition (EMT). Here we show that TGFβ also promotes genomic instability in the form of DNA double strand breaks (DSB) in cancer cells that lack the tumor suppressor gene RUNX3. Loss of RUNX3 resulted in transcriptional downregulation of the redox regulator heme oxygenase-1 (HO-1 or HMOX1). Consequently, elevated oxidative DNA damage disrupted genomic integrity and triggered cellular senescence, which was accompanied by tumor-promoting inflammatory cytokine expression and acquisition of the senescence-associated secretory phenotype (SASP). Recapitulating the above findings, tumors harboring a TGFβ gene expression signature and RUNX3 loss exhibited higher levels of genomic instability. In summary, RUNX3 creates an effective barrier against further TGFβ-dependent tumor progression by preventing genomic instability. These data suggest a novel cooperation between cancer cell–extrinsic TGFβ signaling and cancer cell–intrinsic RUNX3 inactivation as aggravating factors for genomic instability. Significance: RUNX3 inactivation in cancer removes an antioxidant barrier against DNA double strand breaks induced by TGFβ expressed in the tumor microenvironment. Cancer Res; 78(1); 88–102. ©2017 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-17-1178
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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