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  • American Association for Cancer Research (AACR)  (30)
  • 1
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    Online Resource
    Screen to Save: Results from NCI's Colorectal Cancer Outreach and Screening Initiative to Promote Awareness and Knowledge of Colorectal Cancer in Racial/Ethnic and Rural Populations
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 29, No. 5 ( 2020-05-01), p. 910-917
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 29, No. 5 ( 2020-05-01), p. 910-917
    Abstract: The Center to Reduce Cancer Health Disparities (CRCHD), National Cancer Institute (NCI), launched Screen to Save, NCI's Colorectal Cancer Outreach and Screening Initiative to promote awareness and knowledge of colorectal cancer in racial/ethnic and rural populations. Methods: The initiative was implemented through CRCHD's National Outreach Network (NON) and Comprehensive Partnerships to Advance Cancer Health Equity (CPACHE) programs. NON is a national network of Community Health Educators (CHEs), aligned with NCI-designated Cancer Centers (CCs). CPACHE are partnerships between a CC and a minority-serving institution with, among other components, an Outreach Core and a CHE. In phases I and II, the CHEs disseminated cancer-related information and implemented evidence-based educational outreach. Results: In total, 3,183 pre/post surveys were obtained from participants, ages 50 to 74 years, during 347 educational events held in phase I. Results demonstrated all racial/ethnic groups had an increase in colorectal cancer-related knowledge, and each group agreed that the educational event increased the likelihood they would engage in colorectal cancer-related healthful behaviors. For phase II, Connections to Care, participants were linked to screening. Eighty-two percent of participants who were screened during the follow-up period obtained their results. Conclusions: These results suggest that culturally tailored, standardized educational messaging and data collection tools are key elements that can serve to inform the effectiveness of educational outreach to advance awareness and knowledge of colorectal cancer. Impact: Future initiatives should focus on large-scale national efforts to elucidate effective models of connections to care related to colorectal cancer screening, follow-up, and treatments that are modifiable to meet community needs.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-19-0972
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 2
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    EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research ( 2023-09-25)
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), ( 2023-09-25)
    Abstract: NUT carcinoma (NC) is an aggressive carcinoma driven by the BRD4-NUT fusion oncoprotein, which activates chromatin to promote expression of pro-growth genes. BET bromodomain inhibitors (BETi) are a promising treatment for NC that can impede BRD4-NUT’s ability to activate genes, but the efficacy of BETi as monotherapy are limited. Here, we demonstrated that EZH2, which silences genes through establishment of repressive chromatin, is a dependency in NC. Inhibition of EZH2 with the clinical compound tazemetostat (taz) potently blocked growth of NC cells. Epigenetic and transcriptomic analysis revealed that taz reversed the EZH2-specific H3K27me3 silencing mark and restored expression of multiple tumor suppressor genes while having no effect on key oncogenic BRD4-NUT-regulated genes. Indeed, H3K27me3 and H3K27ac domains were found to be mutually exclusive in NC cells. CDKN2A was identified as the only gene among all taz-derepressed genes to confer resistance to taz in a CRISPR-Cas9 screen. Combined inhibition of EZH2 and BET synergized to downregulate cell proliferation genes resulting in more pronounced growth arrest and differentiation than either inhibitor alone. In pre-clinical models, combined taz and BETi synergistically blocked tumor growth and prolonged survival of NC-xenografted mice, with complete remission without relapse in one cohort. Identification of EZH2 as a dependency in NC substantiates the reliance of NC tumor cells on epigenetic dysregulation of functionally opposite, yet highly complementary, chromatin regulatory pathways to maintain NC growth.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-23-1475
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
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    Exposure to Polybrominated Diphenyl Ethers and a Polybrominated Biphenyl and Risk of Thyroid Cancer in Women: Single and Multi-Pollutant Approaches
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 28, No. 10 ( 2019-10-01), p. 1755-1764
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 28, No. 10 ( 2019-10-01), p. 1755-1764
    Abstract: Thyroid cancer incidence is the most rapidly increasing malignancy; rates are three times higher in women than men. Thyroid hormone–disrupting flame-retardant chemicals, including polybrominated diphenyl ethers (PBDE) and polybrominated biphenyls (PBB), may contribute to this trend. Methods: We investigated the relationship between PBDE/PBB exposure and papillary thyroid cancer (PTC) in 250 incident female papillary thyroid cancer cases and 250 female controls frequency-matched on age. Interviews and postdiagnostic serum samples were collected from 2010 to 2013. Serum samples were analyzed for 11 congeners. We calculated ORs and 95% confidence intervals (95% CI) using single-pollutant logistic regression models for continuous and categorical lipid-adjusted serum concentrations of PBDE/PBB, adjusted for age, alcohol consumption, and education. We applied three multi-pollutant approaches [standard multipollutant regression models, hierarchical Bayesian logistic regression modeling (HBLR), principal components analysis (PCA)] to investigate associations with PBDE/PBB mixtures. Results: In single-pollutant models, a decreased risk was observed at the highest ( & gt;90th percentile) versus lowest ( & lt;median) category of BDE-209 concentrations (OR, 0.47; 95% CI, 0.23–0.98); an elevated PTC risk was observed at the highest versus lowest category of BB-153 concentrations (OR, 1.81; 95% CI, 0.96–3.39). In standard multi-pollutant models, an interquartile range increase in BDE-100 concentrations was associated with increased PTC risk (OR, 1.18; 95% CI, 1.01–1.38). HBLR and PCA yielded no statistically significant results. Conclusions: Our results using single- and multi-pollutant modeling do not generally support a positive association with PBDE/PBB and PTC risk. Impact: Prospective studies with more advanced statistical approaches to analyze mixtures and populations with higher exposures could reveal new insights.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-19-0526
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036781-8
    detail.hit.zdb_id: 1153420-5
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  • 4
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    Complement Pathway Is Frequently Altered in Endometriosis and Endometriosis-Associated Ovarian Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 23 ( 2014-12-01), p. 6163-6174
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 23 ( 2014-12-01), p. 6163-6174
    Abstract: Purpose: Mechanisms of immune dysregulation associated with advanced tumors are relatively well understood. Much less is known about the role of immune effectors against cancer precursor lesions. Endometrioid and clear-cell ovarian tumors partly derive from endometriosis, a commonly diagnosed chronic inflammatory disease. We performed here a comprehensive immune gene expression analysis of pelvic inflammation in endometriosis and endometriosis-associated ovarian cancer (EAOC). Experimental Design: RNA was extracted from 120 paraffin tissue blocks comprising of normal endometrium (n = 32), benign endometriosis (n = 30), atypical endometriosis (n = 15), and EAOC (n = 43). Serous tumors (n = 15) were included as nonendometriosis-associated controls. The immune microenvironment was profiled using Nanostring and the nCounter GX Human Immunology Kit, comprising probes for a total of 511 immune genes. Results: One third of the patients with endometriosis revealed a tumor-like inflammation profile, suggesting that cancer-like immune signatures may develop earlier, in patients classified as clinically benign. Gene expression analyses revealed the complement pathway as most prominently involved in both endometriosis and EAOC. Complement proteins are abundantly present in epithelial cells in both benign and malignant lesions. Mechanistic studies in ovarian surface epithelial cells from mice with conditional (Cre-loxP) mutations show intrinsic production of complement in epithelia and demonstrate an early link between Kras- and Pten-driven pathways and complement upregulation. Downregulation of complement in these cells interferes with cell proliferation. Conclusions: These findings reveal new characteristics of inflammation in precursor lesions and point to previously unknown roles of complement in endometriosis and EAOC. Clin Cancer Res; 20(23); 6163–74. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-1338
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 5
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    Online Resource
    Abstract 5020: Potential lifestyle intervention in inner city women with endometrial cancer: A pilot study
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5020-5020
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 5020-5020
    Abstract: Hypothesis: Evidence suggests that modification of diet and exercise practices may prevent cancer recurrence. It may also decrease the risk factors for the leading causes of death in women including heart disease and stroke. Methods: 100 patients with previously diagnosed endometrial cancer were enrolled in a pilot study to collect data regarding current lifestyle, willingness to change and preferred programs of nutrition and exercise. All enrolled subjects were verbally asked to respond to a questionnaire that included validated and novel instruments. Results: Mean age was 64 (39-86 years) and mean body mass index was 34 kg/m2 (17-55). 38% of the responders were Black/African American, 33% were Caucasian, and 21% were Hispanic. Of these, 69% were born in the United States of America. 75% described themselves as “overweight”. The most common mode of current exercise was walking (54%). 89% of the patients responded that they would be interested in participating in a diet or exercise program. The most common reason that women stated they would want to participate was to improve overall health (48%). Only 4% stated that they thought it would prevent recurrence of their cancers. Diabetes mellitus was previously diagnosed in 30% of participants. Eighty three percent of diabetic patients had body mass index over 30 kg/m2 and 30% had body mass index over 40 kg/m2. Eleven patients currently on therapy for diabetes had hemoglobin A1C values greater then 6.5 and are at risk for microvessel damage and end-organ dysfunction including kidney failure and impaired vision Discussion: These data present the opinions of a racially heterogeneous group of women at risk for cancer recurrence, as well as the morbidity and mortality related to obesity and diabetes. These data suggest that women at our center should participate in a dietary and exercise intervention program and our patients would benefit from the additional health education. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5020. doi:10.1158/1538-7445.AM2011-5020
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-5020
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
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    Abstract 2327: Defining the determinants of sensitivity and resistance to BET bromodomain inhibition
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2327-2327
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2327-2327
    Abstract: Selective inhibition of BET bromodomains by small molecule inhibitors has emerged as a promising therapeutic strategy for the treatment of cancer. Accordingly, we have recently initiated clinical trials to assess this mechanism in patients. Recent evidence demonstrates that BET bromodomain inhibition leads to anti-proliferative activity in pre-clinical models of hematological malignancies and solid tumors. This anti-proliferative activity involves down-regulation of the transcription factor MYC, among other cancer-relevant pathways. However, heterogeneity exists in the response to BET bromodomain inhibition at both the molecular and phenotypic level. Given this complexity, the molecular determinants of sensitivity and resistance to BET bromodomain inhibition remains poorly understood. Current efforts are aimed at addressing this key issue by integrating the following: (1) phenotypic endpoints observed upon BET bromodomain inhibition with transcriptional changes, including down-regulation of MYC and other transcription factors important for regulating proliferation and cell death, such as MYB and BCL-2,(2) transcriptional response with BET protein chromatin binding and eviction, and (3) phenotypic endpoints and transcriptional response with genomic context. Our data potentially stratify indications within hematologic malignancies and solid tumors, and provide insight into patient selection strategies. Citation Format: Nicole Follmer, Jennifer Mertz, Andrew Conery, Barbara Bryant, Charlie Hatton, Richard Centore, Hon-Ren Huang, Kerry Spillane, Robert Sims. Defining the determinants of sensitivity and resistance to BET bromodomain inhibition. [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 2327. doi:10.1158/1538-7445.AM2014-2327
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-2327
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
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    Abstract C165: Development of a probody drug conjugate (PDC) against CD166 for the treatment of multiple cancers
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C165-C165
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. C165-C165
    Abstract: Antibody drug conjugates (ADCs) have shown their greatest clinical utility when targeting antigens expressed at very high levels on cancer cells that have coincidentally lower expression in normal tissues. This is exemplified by the approvals of trastuzumab emtansine for her2neu 3+ breast cancer and brentuximab vedotin for Hodgkins Disease and Anaplastic large-cell lymphoma. Both drugs are approved for subsets of specific cancer types where target antigen expression is particularly high relative to expression in normal tissues. There are other cell surface antigens that are highly expressed on cancer cells and normal tissues, but the utility of such antigens as ADC targets is restricted by their corresponding expression in normal tissues. One such target is CD166 (ALCAM), which shows 3+ expression by IHC in most donors of multiple cancer types, e.g., ca. 70% prevalence in breast, prostate, and lung cancers but also expression in multiple normal tissues including lung, GI tissues, and liver. Thus CD166 has not been progressed as a target for ADCs. Probody™ therapeutics are fully recombinant antibody prodrugs that are converted to active antibodies by tumor-associated proteases. Preclinical in vivo studies show that Probody therapeutics remain substantially inactive in normal tissues and in circulation. As such, Probody drug conjugates (PDCs), unlike ADCs, enable targeting of high expression tumor targets that are also expressed in normal tissues. We have developed an anti-CD166 Probody therapeutic selected for specific binding, internalization, and cross reactivity to cynomolgus macaque as a species for toxicology assessments. This therapeutic has been conjugated to spdb-DM4 and tested in preclinical models of efficacy and safety. Treatment with the PDC has led to complete regressions in models of lung and breast cancer at therapeutically relevant doses. These same doses were assessed for safety in cynomolgus monkeys. The safety and efficacy profiles for the anti-CD166 PDC are supportive of progression to clinical development of this anti-CD166 Probody drug conjugate. Citation Format: Annie Yang Weaver, Shweta Singh, Amy DuPage, Jason Sagert, Jeanne Flandez, Elizabeth Menendez, Judi Ford, Michael Krimm, Stephen Moore, Margaret Nguyen, Andrew Jang, Eric Brecht, Yuanhui Huang, Linnea Diep, Nicole Lapuyade, Tereza Sputova, James West, Olga Vasiljeva, Shouchun Liu, Jennifer Richardson, W. Michael Kavanaugh, Jonathan A. Terrett, Luc R. Desnoyers. Development of a probody drug conjugate (PDC) against CD166 for the treatment of multiple cancers. [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 C165.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-C165
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 8
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    Online Resource
    Abstract GS4-04: Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. GS4-04-GS4-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. GS4-04-GS4-04
    Abstract: Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p & lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was & gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was & lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-GS4-04
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Online Resource
    De Novo Lipogenesis Alters the Phospholipidome of Esophageal Adenocarcinoma
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 13 ( 2020-07-01), p. 2764-2774
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 13 ( 2020-07-01), p. 2764-2774
    Abstract: The incidence of esophageal adenocarcinoma is rising, survival remains poor, and new tools to improve early diagnosis and precise treatment are needed. Cancer phospholipidomes quantified with mass spectrometry imaging (MSI) can support objective diagnosis in minutes using a routine frozen tissue section. However, whether MSI can objectively identify primary esophageal adenocarcinoma is currently unknown and represents a significant challenge, as this microenvironment is complex with phenotypically similar tissue-types. Here, we used desorption electrospray ionization-MSI (DESI-MSI) and bespoke chemometrics to assess the phospholipidomes of esophageal adenocarcinoma and relevant control tissues. Multivariate models derived from phospholipid profiles of 117 patients were highly discriminant for esophageal adenocarcinoma both in discovery (AUC = 0.97) and validation cohorts (AUC = 1). Among many other changes, esophageal adenocarcinoma samples were markedly enriched for polyunsaturated phosphatidylglycerols with longer acyl chains, with stepwise enrichment in premalignant tissues. Expression of fatty acid and glycerophospholipid synthesis genes was significantly upregulated, and characteristics of fatty acid acyls matched glycerophospholipid acyls. Mechanistically, silencing the carbon switch ACLY in esophageal adenocarcinoma cells shortened glycerophospholipid chains, linking de novo lipogenesis to the phospholipidome. Thus, DESI-MSI can objectively identify invasive esophageal adenocarcinoma from a number of premalignant tissues and unveils mechanisms of phospholipidomic reprogramming. Significance: These results call for accelerated diagnosis studies using DESI-MSI in the upper gastrointestinal endoscopy suite, as well as functional studies to determine how polyunsaturated phosphatidylglycerols contribute to esophageal carcinogenesis.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-19-4035
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
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    Leukemia Cell of Origin Influences Apoptotic Priming and Sensitivity to LSD1 Inhibition
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Discovery Vol. 10, No. 10 ( 2020-10-01), p. 1500-1513
    Details
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 10, No. 10 ( 2020-10-01), p. 1500-1513
    Abstract: The cell of origin of oncogenic transformation is a determinant of therapeutic sensitivity, but the mechanisms governing cell-of-origin–driven differences in therapeutic response have not been delineated. Leukemias initiating in hematopoietic stem cells (HSC) are less sensitive to chemotherapy and highly express the transcription factor MECOM (EVI1) compared with leukemias derived from myeloid progenitors. Here, we compared leukemias initiated in either HSCs or myeloid progenitors to reveal a novel function for EVI1 in modulating p53 protein abundance and activity. HSC-derived leukemias exhibit decreased apoptotic priming, attenuated p53 transcriptional output, and resistance to lysine-specific demethylase 1 (LSD1) inhibitors in addition to classical genotoxic stresses. p53 loss of function in Evi1lo progenitor-derived leukemias induces resistance to LSD1 inhibition, and EVI1hi leukemias are sensitized to LSD1 inhibition by venetoclax. Our findings demonstrate a role for EVI1 in p53 wild-type cancers in reducing p53 function and provide a strategy to circumvent drug resistance in chemoresistant EVI1hi acute myeloid leukemia. Significance: We demonstrate that the cell of origin of leukemia initiation influences p53 activity and dictates therapeutic sensitivity to pharmacologic LSD1 inhibitors via the transcription factor EVI1. We show that drug resistance could be overcome in HSC-derived leukemias by combining LSD1 inhibition with venetoclax. See related commentary by Gu et al., p. 1445. This article is highlighted in the In This Issue feature, p. 1426
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    URL: Article
    DOI: 10.1158/2159-8290.CD-19-1469
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
    detail.hit.zdb_id: 2607892-2
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