GLORIA

GEOMAR Library Ocean Research Information Access

X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • American Association for Cancer Research (AACR)  (11)
  • 2015-2019  (11)
Material
Publisher
  • American Association for Cancer Research (AACR)  (11)
Person/Organisation
Language
Years
  • 2015-2019  (11)
Year
Subjects(RVK)
  • 1
    Online Resource
    Online Resource
    Homologous Recombination DNA Repair Pathway Disruption and Retinoblastoma Protein Loss Are Associated with Exceptional Survival in High-Grade Serous Ovarian Cancer
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 3 ( 2018-02-01), p. 569-580
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 3 ( 2018-02-01), p. 569-580
    Abstract: Purpose: Women with epithelial ovarian cancer generally have a poor prognosis; however, a subset of patients has an unexpected dramatic and durable response to treatment. We sought to identify clinical, pathological, and molecular determinants of exceptional survival in women with high-grade serous cancer (HGSC), a disease associated with the majority of ovarian cancer deaths. Experimental Design: We evaluated the histories of 2,283 ovarian cancer patients and, after applying stringent clinical and pathological selection criteria, identified 96 with HGSC that represented significant outliers in terms of treatment response and overall survival. Patient samples were characterized immunohistochemically and by genome sequencing. Results: Different patterns of clinical response were seen: long progression-free survival (Long-PFS), multiple objective responses to chemotherapy (Multiple Responder), and/or greater than 10-year overall survival (Long-Term Survivors). Pathogenic germline and somatic mutations in genes involved in homologous recombination (HR) repair were enriched in all three groups relative to a population-based series. However, 29% of 10-year survivors lacked an identifiable HR pathway alteration, and tumors from these patients had increased Ki-67 staining. CD8+ tumor-infiltrating lymphocytes were more commonly present in Long-Term Survivors. RB1 loss was associated with long progression-free and overall survival. HR deficiency and RB1 loss were correlated, and co-occurrence was significantly associated with prolonged survival. Conclusions: There was diversity in the clinical trajectory of exceptional survivors associated with multiple molecular determinants of exceptional outcome in HGSC patients. Concurrent HR deficiency and RB1 loss were associated with favorable outcomes, suggesting that co-occurrence of specific mutations might mediate durable responses in such patients. Clin Cancer Res; 24(3); 569–80. ©2017 AACR. See related commentary by Peng and Mills, p. 508
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-1621
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 2
    Online Resource
    Online Resource
    Abstract AP14: POOLED GENOMIC SCREENS IDENTIFY ANTI-APOPTOTIC GENES AS MEDIATORS OF CHEMOTHERAPY RESISTANCE IN OVARIAN CANCER
    American Association for Cancer Research (AACR) ; 2019
    In:  Clinical Cancer Research Vol. 25, No. 22_Supplement ( 2019-11-15), p. AP14-AP14
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 25, No. 22_Supplement ( 2019-11-15), p. AP14-AP14
    Abstract: *Co-senior authors Primary high-grade serous ovarian cancer (HGSOC) is often sensitive to platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. Although alterations in DNA repair function, gene expression, apoptosis, and other pathways have been described that can mediate chemotherapy resistance in HGSOC, the full landscape of HGSOC drug resistance mechanisms and the optimal strategies to eliminate resistant disease have not been fully elucidated. We performed systematic, unbiased near-genome-scale pooled overexpression and CRISPR/Cas9 knockout screens in two BRCA2-mutant HGSOC cell lines to identify genes promoting survival following cisplatin, paclitaxel, or cisplatin/paclitaxel treatment. Anti-apoptotic genes including BCL2L1 (BCL-XL), and BCL2L2 (BCL-W) were among the top hits mediating chemotherapy resistance in the overexpression screen. In the CRISPR/Cas9 screen, loss of pro-apoptotic genes (caspases, APAF1) conferred resistance, and knockout of BCL2L1 sensitized to platinum. A secondary overexpression screen of ~400 genes confirmed anti-apoptotic proteins BCL-XL, BCL-W and BCL-2 as top resistance genes, and validated numerous other candidates. Of note, anti-apoptotic genes BCL2L1 and MCL1 are focally amplified and overexpressed in patients with primary HGSOC. In HGSOC cell lines, overexpression of BCL-XL or BCL-W, and to a lesser extent BCL-2 or MCL1, conferred platinum and taxane resistance and decreased chemotherapy-induced apoptosis in HGSOC cell lines. We systematically tested small molecule inhibitors of BCL-2, BCL-XL, MCL1, or BCL2/BCL-XL as single agents or combined with chemotherapy in HGSOC cell lines. Inhibiting BCL-XL, MCL1, or BCL2/BCL-XL, but not BCL-2, significantly increased cell death when combined with cisplatin or paclitaxel. BCL-XL, MCL1, or BCL2/BCL-XL inhibitors also synergized with olaparib, a poly- ADP-ribose inhibitor. Concomitant overexpression of BCL-XL, BCL-W, or MCL1 abrogated the sensitizing effect of the anti-apoptotic protein inhibitors, depending upon the specific inhibitor. Taken together, unbiased near-genome-scale overexpression screens and patient genomic data highlight the role of the intrinsic pathway of apoptosis in HGSOC chemotherapy resistance. Our studies validate that anti-apoptotic proteins mediate resistance to several clinically relevant drugs in HGSOC, and support that BCL-XL and MCL1 may be therapeutic targets in HGSOC, particularly in combination with DNA-damaging agents. Citation Format: Elizabeth H. Stover, Maria B. Baco, Ofir Cohen, Yvonne Li, Elizabeth Christie, Mukta Bagul, Amy Goodale, Yenarae Lee, Sasha Pantel, Matthew Rees, Guo Wei, Adam Presser, Ioannis Zervantonakis, Patrick Bhola, Jeremy Ryan, Jennifer Guerriero, Felice Liang, Andrew Cherniack, Federica Piccioni, Ursula A. Matulonis, David D. L. Bowtell, Anthony Letai, Kris Sarosiek, Levi Garraway, Cory M. Johannessen, Matthew Meyerson. POOLED GENOMIC SCREENS IDENTIFY ANTI-APOPTOTIC GENES AS MEDIATORS OF CHEMOTHERAPY RESISTANCE IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP14.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1557-3265.OVCASYMP18-AP14
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 3
    Online Resource
    Online Resource
    Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Discovery Vol. 6, No. 2 ( 2016-02-01), p. 154-165
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 6, No. 2 ( 2016-02-01), p. 154-165
    Abstract: Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans cell histiocytosis (LCH) and non-Langerhans cell histiocytosis (non-LCH), respectively. The discovery of BRAFV600E mutations in approximately 50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of patients with BRAFV600E–wild-type non-LCH are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole-exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in patients with BRAFV600E–wild-type non-LCH. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of patients with MAP2K1- and ARAF-mutated non-LCH using MEK and RAF inhibitors, respectively, resulted in clinical efficacy, demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. Significance: We provide the first description of kinase fusions in systemic histiocytic neoplasms and activating ARAF and MAP2K1 mutations in non-Langerhans histiocytic neoplasms. Refractory patients with MAP2K1- and ARAF-mutant histiocytoses had clinical responses to MEK inhibition and sorafenib, respectively, highlighting the importance of comprehensive genomic analysis of these disorders. Cancer Discov; 6(2); 154–65. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 109
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-15-0913
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2607892-2
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 4
    Online Resource
    Online Resource
    Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA
    American Association for Cancer Research (AACR) ; 2016
    In:  Clinical Cancer Research Vol. 22, No. 23 ( 2016-12-01), p. 5772-5782
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 22, No. 23 ( 2016-12-01), p. 5772-5782
    Abstract: Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS. Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible. Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible. Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-16-1231
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 5
    Online Resource
    Online Resource
    Pooled Genomic Screens Identify Anti-apoptotic Genes as Targetable Mediators of Chemotherapy Resistance in Ovarian Cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Molecular Cancer Research Vol. 17, No. 11 ( 2019-11-01), p. 2281-2293
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 17, No. 11 ( 2019-11-01), p. 2281-2293
    Abstract: High-grade serous ovarian cancer (HGSOC) is often sensitive to initial treatment with platinum and taxane combination chemotherapy, but most patients relapse with chemotherapy-resistant disease. To systematically identify genes modulating chemotherapy response, we performed pooled functional genomic screens in HGSOC cell lines treated with cisplatin, paclitaxel, or cisplatin plus paclitaxel. Genes in the intrinsic pathway of apoptosis were among the top candidate resistance genes in both gain-of-function and loss-of-function screens. In an open reading frame overexpression screen, followed by a mini-pool secondary screen, anti-apoptotic genes including BCL2L1 (BCL-XL) and BCL2L2 (BCL-W) were associated with chemotherapy resistance. In a CRISPR-Cas9 knockout screen, loss of BCL2L1 decreased cell survival whereas loss of proapoptotic genes promoted resistance. To dissect the role of individual anti-apoptotic proteins in HGSOC chemotherapy response, we evaluated overexpression or inhibition of BCL-2, BCL-XL, BCL-W, and MCL1 in HGSOC cell lines. Overexpression of anti-apoptotic proteins decreased apoptosis and modestly increased cell viability upon cisplatin or paclitaxel treatment. Conversely, specific inhibitors of BCL-XL, MCL1, or BCL-XL/BCL-2, but not BCL-2 alone, enhanced cell death when combined with cisplatin or paclitaxel. Anti-apoptotic protein inhibitors also sensitized HGSOC cells to the poly (ADP-ribose) polymerase inhibitor olaparib. These unbiased screens highlight anti-apoptotic proteins as mediators of chemotherapy resistance in HGSOC, and support inhibition of BCL-XL and MCL1, alone or combined with chemotherapy or targeted agents, in treatment of primary and recurrent HGSOC. Implications: Anti-apoptotic proteins modulate drug resistance in ovarian cancer, and inhibitors of BCL-XL or MCL1 promote cell death in combination with chemotherapy.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1541-7786.MCR-18-1243
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2097884-4
    SSG: 12
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 6
    Online Resource
    Online Resource
    Abstract 3480: TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3480-3480
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 3480-3480
    Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype worldwide, accounting for 40% of all non-Hodgkin lymphomas. DLBCL presents as an aggressive disease requiring immediate treatment. Although significant improvement in outcome has been achieved, ~40% of patients still experience treatment failure. Here, we characterized the recurrent genetic alterations and transcriptomic signatures in diagnostic biopsies from a population registry-based cohort of 347 patients with de novo DLBCL uniformly treated with R-CHOP. This analysis revealed bi-allelic loss of function mutations of TMEM30A that were associated with favorable treatment outcome. TMEM30A is a chaperone protein, involved in maintaining the asymmetric distribution of phosphatidylethanolamine and phosphatidylserine, an integral component of the plasma membrane and “eat-me” signal recognized by macrophages. Using TMEM30A knockout systems by CRISPR genome editing techniques, we have functionally characterized this loss-of-function mutation in representative human and mouse DLBCL cell line models. We have discovered that TMEM30A loss is associated with increased B-cell signaling following antigen stimulation, including a two-fold increase in the diffusion rate of B-cell receptor (BCR) clustering, using high resolution Single Particle Tracking (SPT) technology. In addition, we have measured three-fold increase in chemotherapeutic drug accumulation in both knockout cell lines and randomly selected patient biopsies with TMEM30A biallelic loss. This observation was validated in a xenograft mouse model, which presented improved survival and limited tumor growth following vincristine treatment in mice injected with TMEM30A null DLBCL cell lines compared with native cell lines. This phenotype explains the improved prognosis observed in DLBCL patients following R-CHOP treatment. Furthermore, we have observed over two fold higher numbers of tumor-associated macrophages in B-cell lymphoma syngeneic mouse models with Tmem30a loss-of-function, prior to any form of treatment, suggesting the existence of “hot” and primed tumors. Our data highlight a multi-faceted role for TMEM30A and plasma membrane physiology in B-cell lymphomagenesis, and characterize intrinsic and extrinsic vulnerabilities of cancer cells that can be therapeutically exploited. Characterization of these mechanisms will address a missing link in the cancer field as related insights in lymphoma will outline therapeutic approaches that can be extended to cancer therapy in general. Citation Format: Shannon Healy, Daisuke Ennishi, Ali Bashashati, Saeed Saberi, Christoffer Hother, Anja Mottok, Fong Chun Chan, Lauren Chong, Robert Kridel, Merrill Boyle, Barbara Meissner, Tomohiro Aoki, Katsuyoshi Takata, Bruce W. Woolcock, Elena Vigano, Libin Abraham, Michael Gold, Adele Telenius, Pedro Farinha, Graham Slack, Susana Ben-Neriah, Daniel Lai, Allen W. Zhang, Sohrab Salehi, Hennady P. Shulha, Derek S. Chiu, Sara Mostafavi, Alina S. Gerrie, Diego Villa, Laurie H. Sehn, Kerry J. J. Savage, Andrew J. J. Mungall, Andrew P. Weng, Marcel Bally, Ryan D. Morin, Gabriela V. Cohen Freue, Joseph M. Connors, Marco A. Marra, Sohrab P. Shah, Randy D. Gascoyne1, David W. Scott, Christian Steidl, Ulrich Steidl. TMEM30A loss-of-function mutations drive lymphomagenesis and confer therapeutically exploitable vulnerability in B-cell lymphoma [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 3480.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-3480
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 7
    Online Resource
    Online Resource
    Abstract B98: Final results of a randomized phase Ib study of fractionated 90Y-clivatuzumab tetraxetan in patients with metastatic pancreatic cancer having at least two prior therapies
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 13_Supplement ( 2015-07-01), p. B98-B98
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 13_Supplement ( 2015-07-01), p. B98-B98
    Abstract: Background: Prior clinical studies in the first and second line setting showed radioimmunotherapy (RAIT) is a promising therapy for pancreatic cancer that avoids the side effects of further chemotherapy. This multicenter study evaluated the contribution of low radiosensitizing doses of gemcitabine (GEM) to fractionated doses of 90Y-clivatuzumab tetraxetan in patients with metastatic pancreatic ductal cancer after having received at least 2 prior systemic therapies. Methods: Fifty-eight patients (33 males, 25 females; median age 63.5 years), 1.6 median years from diagnosis and with a median of 3 (2-7) prior treatments, were randomized to Arm A (N=29, 4-week cycles: 200 mg/m2 GEM, weekly, combined with 6.5 mCi/m2 90Y-clivatuzumab tetraxetan, weekly the last 3 weeks) or Arm B (N=29, 3-week cycles: 6.5 mCi/m2 90Y-clivatuzumab tetraxetan alone, once-weekly), repeating cycles after 4-week delays. Safety and efficacy were evaluated. Results: None of the patients had infusion reactions, and as expected, cytopenias (predominantly thrombocytopenia) were the only significant toxicities, but mostly transient and manageable with infrequent hematologic support and little evidence of increased infection or bleeding. Patients terminated treatment cycles due to disease progression or clinical deterioration, not treatment toxicity. Fifty-three patients (27 Arm A, 26 Arm B, 91% overall) completed ≥1 full treatment cycle and thus were evaluable for efficacy, with 23 (12 Arm A, 11 Arm B; 40%) receiving multiple cycles, including 7 (6 Arm A, 1 Arm B; 12%) given 3-7 cycles. Two patients in Arm A had PRs by RECIST criteria. Karnofsky performance status (90-100 v 70-80), number of prior therapies, and tumor burden estimates (summed length of index lesions, serum CA 19-9 levels) correlated with overall survival (OS), but appear balanced between arms. Kaplan-Meier median OS was 3.9 months (1.0-16.7) in Arm A v 2.8 months (0.9-9.4) in Arm B (hazard ratio 0.54, 95% CI: 0.27-0.87; P=0.020, log-rank). The median OS for Arm A v Arm B increased to 7.9 v 3.4 months with multiple cycles (P= 0.004) and 3 patients in Arm A still being observed (11 – 17 months). Conclusions: This randomized trial demonstrated the feasibility of performing clinical studies in metastatic pancreatic cancer patients after having at least 2 prior therapies (3rd line and beyond). With significant survival advantage and favorable safety profile, fractionated RAIT with 90Y-clivatuzumab tetraxetan and low-dose GEM appears promising in this difficult population, supporting Phase 3 studies of this combination now being initiated. Citation Format: Vincent J. Picozzi, Ramesh K. Ramanathan, Maeve A. Lowery, Allyson J. Ocean, Edith P. Mitchell, Bert H. O'Neil, Michael J. Guarino, Paul R. Conkling, Steven J. Cohen, Nathan Bahary, Richard C. Frank, Tomislav Dragovich, Benjamin B. Bridges, Marie Lee, Ronald L. Korn, Neeta Pandit-Taskar, Stanley J. Goldsmith, Charles M. Intenzo, Arif Sheikh, Timothy C. Manzone, Michael L. Miller, Michael Yu, Judith M. Joyce, Edward B. Strauss, Susan Passalaqua, Ronald V. Dorn, III, Michael J. Anderson, Michael Holt, Fadi S. Braiteh, Fa-Chyi Lee, Thomas E. Gribbin, Donald A. Richards, Alexander N. Starodub, Wegener A. William, Eileen M. O'Reilly, Daniel D. Von Hoff, David M. Goldenberg. Final results of a randomized phase Ib study of fractionated 90Y-clivatuzumab tetraxetan in patients with metastatic pancreatic cancer having at least two prior therapies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B98.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PANCA2014-B98
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 8
    Online Resource
    Online Resource
    Abstract 3845: 24R,25-Dihydroxyvitamin D3 reduces tumor burden and metastasis in ER+ breast cancer in vivo
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3845-3845
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3845-3845
    Abstract: The purpose of this study was to investigate the effects of 24R,25-dihydroxyvitamin D3 (24,25), on tumor growth and metastasis in an in vivo estrogen receptor positive (ER+) orthotopic breast cancer model. 1α,25(OH)2D3 has been shown to have pro-apoptotic effects on breast cancer both in vitro and in vivo. 24,25, a naturally occurring metabolite, is present in human serum at concentrations up to 10 times higher than 1,25. Moreover, 1,25 regulates production of 24,25 by stimulating expression of the 24-hydroxylase. 6-8 week old female nod scid gamma IL2R mice were kept on an ad libitum vitamin D deficient diet. 15 days before surgery, mice were implanted with 1.7mg 0-order release estrogen (E2) pellets. In the first experiment, mice were given a fast-release pellet (45 days). In the second experiment, mice were given a slow-release (90 day) pellet. After 15 days of acclimation (day 0), mice were injected in the T4 mammary fat pad with 1M fluorescently labeled MCF7 cells (an ER+ breast cancer cell line) and cells in 50:50 PBS:Matrigel solution. Tumors were measured once a week starting at day 14 and tracked throughout the course of the study. On day 30, 24,25 treatment was initiated. Each experiment was divided into three groups: 0 ng 24,25, 25 ng 24,25, or 100 ng 24,25 per injection, with n=6-8 mice per group. Treatments were administered three times a week in a 50µL intraperitoneal injection. On day 70, mice were harvested and assessed for tumor burden and metastasis by fluorescence detection microscopy. Fluorescent tissues were marked ‘metastasis positive' and harvested for future immunohistochemical analysis. Mice that were given 24,25 three times weekly showed decreased tumor burden and metastasis as compared to controls. In the first experiment (45 day E2), 25ng and 100ng 24,25 treated mice had significantly lower relative tumor volumes than controls beginning on day 70. These 24,25 treated mice also showed significantly lower rates of left axial lymph node metastasis, and had statistically longer survival rates. The second experiment (90 day E2) had similar results. Mice treated with 25ng and 100ng 24,25 had decreased tumor burden as compared to 0ng controls on day 70. Mice given 24,25 had decreased lung metastasis; however, mice treated with 100ng 24,25 had increased rates of right axial lymph node metastasis. Altogether, mice in both groups that were treated with 100ng of 24,25 had decreased rates of left axial lymph node metastasis and lung metastasis as compared to controls, and statistically longer survival rates. Thus 24,25 could play a role in 1,25's anti-apoptotic effect on breast cancer, potentially via upregulation of 24,25. Citation Format: Anjali Verma, David Joshua Cohen, Chandana Muktipaty, Barbara D. Boyan, Zvi Schwartz. 24R,25-Dihydroxyvitamin D3 reduces tumor burden and metastasis in ER+ breast cancer in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3845.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-3845
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 9
    Online Resource
    Online Resource
    Abstract CT065: Labetuzumab govitecan (IMMU-130), an anti-CEACAM5/SN-38 antibody-drug conjugate, is active in patients (pts) with heavily pretreated metastatic colorectal cancer (mCRC): phase II results
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. CT065-CT065
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. CT065-CT065
    Abstract: Background. There is still an urgent need for better therapies to improve the outcome of mCRC pts. IMMU-130 (labetuzumab govitecan) is a conjugate of a humanized antibody to CEACAM5, coupled site-specifically to the active metabolite of irinotecan, SN-38 (7.6 moles SN-38/IgG), using a proprietary linker. Methods. After initial phase I dose escalation, 4 dose schedules of IMMU-130 were examined in the phase 2 portion of the study (NCT01605318) in irinotecan-refractory/relapsed mCRC pts with an elevated CEA ( & gt;5 ng/mL). Pts were treated with IMMU-130 once- (QW) or twice-weekly (BIW) at 4 to 10 mg/kg doses on weeks 1 and 2 of 3-week cycles. The primary objective of the phase 2 portion of the study was to determine response (by RECIST 1.1) with secondary objectives of progression-free survival (PFS), overall survival (OS), and tolerability. Treatment was continued until disease progression or intolerance. Results. Eighty-six mCRC pts were treated. The majority of patients were male (58%) and had an ECOG performance status of 1 (55%). Median age was 57 yrs (range 30-82) with a median of 5 prior therapies (range, 1-13). All patients had prior irinotecan-containing therapy. Most frequent treatment-related adverse events (AEs) were nausea, fatigue, vomiting, and diarrhea. Grades 3 and 4 AEs included neutropenia (N = 13, 15%), anemia (N = 5, 6%), and diarrhea (N = 2, 2%). Pts who had dose interruptions or reductions due to AEs all recovered without major sequelae. The QW regimen appeared superior based on disease control rate, PFS, and OS. Eleven pts (78%) at 10 mg/kg QW in 21-day cycles (N = 19) had stable disease compared to 7 pts (44%) at 6 mg/kg BIW (N = 19). One pt had a confirmed PR (88% shrinkage) at 6 mg/kg BIW dose, and then maintained PR at 8 mg/kg QW for 3-wk cycles over 2 yrs. Median PFS at 10 mg/kg QW was 4.6 mos compared to 3.7 mos at 6 mg/kg BIW (3-wk cycles). Median OS at 10 mg/kg QW was 9.3 mos compared to 7.4 mos at 6 mg/kg BIW. Exploratory analyses revealed no association between RAS mutation status or baseline CEA and tumor response. There was no significantly higher frequency of grade 3+ neutropenia, febrile neutropenia, or diarrhea for patients with 28*/28* or 1*/28* UGT1A1 genotype (N = 27) vs normal genotype (N = 27). PK profiles demonstrated a shorter half-life for the intact conjugate compared to the antibody. No antibody response to hMN-14-IgG or SN-38 was detected at up to 16 mos. Conclusion. IMMU-130 monotherapy has acceptable toxicity, appearing less than irinotecan. The 10 mg/kg QW x 2 over 3 wks resulted in encouraging median estimates of 4.6 mos for PFS and 9.3 mos for OS in this heavily pre-treated, refractory, mCRC population. Based on this, the 10 mg/kg weekly dosage x 2 of 3-wk cycles was selected for further evaluation. Citation Format: Efrat Dotan, Steven J. Cohen, Alexander N. Starodub, Christopher H. Lieu, Wells A. Messersmith, Michael J. Guarino, John L. Marshall, Richard M. Goldberg, J. Randolph Hecht, Pius Maliakal, William A. Wegener, Robert M. Sharkey, Francois Wilhelm, Lucy Lee, David M. Goldenberg, Jordan D. Berlin. Labetuzumab govitecan (IMMU-130), an anti-CEACAM5/SN-38 antibody-drug conjugate, is active in patients (pts) with heavily pretreated metastatic colorectal cancer (mCRC): phase II results. [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 CT065.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-CT065
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
  • 10
    Online Resource
    Online Resource
    Abstract 2133: 24R,25(OH)2D3 is differentially tumorigenic in ER+ and ER- breast cancer
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2133-2133
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2133-2133
    Abstract: Vitamin D3 (VD3) has long been associated with improved breast cancer prognoses. However, recent clinical trials examining the efficacy of VD3 supplementation on patient prognoses have been largely inconclusive. One reason for this may be that most clinical trials ignore the complex VD3 metabolome and focus solely on 25(OH)D3, the circulating form of VD3. Our study focuses on 24R,25(OH)2D3 (24,25D), a naturally-occurring metabolite of VD3. The aim of the present study was to examine the effect of 2425D on breast cancer tumorigenicity, and to determine if this effect is dependent on estrogen receptor expression in vitro and in vivo.In vivo, MCF7 (an estrogen receptor positive [ER+] breast cancer cell [BCC] line) or HCC38 (ER-) BCCs were implanted in adult female NOD SCID gamma IL2R mice. Mice were supplemented with 24,25D (0, 25, or 100 ng/ IP injection 3X/week). Tumor growth was monitored throughout the study. In vitro, both cells were treated with 0-100nM 24,25D for 15 min or 24h and assayed for phospholipase D (PLD) activity, proliferation (DNA synthesis), apoptosis (BAX, BCL2, p53, TUNEL), epithelial-to-mesenchymal transition (EMT) (SNAI1, MMP1, ERBB2), migration (scratch test), and metastasis (CXCR4/CXCL12, OPG/RANKL). Inhibitors to PLD, caveolin-1, and palmitoylation were used to examine the mechanism of 24,25D. Data were analyzed with one or two-way ANOVA with Tukey’s post-tests.In vivo, mice with ER+ tumors given 24,25D showed decreased tumor burden, metastasis, and increased survival as compared to vehicle-treated controls. Conversely, mice with ER- tumors given 24,25D showed a dose-dependent increase in tumor burden compared to controls. In vitro, both ER+ and ER- cells showed increased proliferation at 24 hours after exposure to 24,25D for 15min but not after exposure for 24h. In ER+ cells, 2425D increased apoptosis and decreased EMT, migration, metastasis, and PLD activity; while in ER- cells, the opposite trend was observed, with 24,25D decreasing apoptosis and increasing EMT, migration, metastatic markers, and PLD activity. The proliferative and apoptotic effects of 24,25D in both cell lines were inhibited by pre-treatment with inhibitors to PLD, caveolin-1, and palmitolyation.24,25D had opposing effects on ER+ and ER- tumor burden in vivo, suggesting that 24,25D is differentially tumorigenic, and observed differences in tumorigenicity are dependent on the expression of ER. In vitro, this ER-associated differential effect was confirmed, with 24,25D decreasing tumorigenic markers in ER+ BCCs and enhancing them in ER- BCCs. Furthermore, 24,25D appears to act at the membrane through a PLD-dependent caveolae-associated mechanism using a palmitoylated transmembrane receptor(s) in both cell types. This study indicates the important role of 24,25D in breast cancer and suggests that ER-status may be an important prognostic marker to consider before prescribing vitamin D3 supplementation to breast cancer patients. Citation Format: Anjali Verma, David J. Cohen, Chandana Muktipaty, Thomas W. Jacobs, Jennifer Koblinski, Barbara D. Boyan, Zvi Schwartz. 24R,25(OH)2D3 is differentially tumorigenic in ER+ and ER- breast cancer [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 2133.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2133
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
    BibTip Others were also interested in ...
    Online Resource
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...