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  • 1
    In: Clinical Breast Cancer, Elsevier BV, Vol. 23, No. 1 ( 2023-01), p. 38-44
    Type of Medium: Online Resource
    ISSN: 1526-8209
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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  • 2
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    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 1086-1086
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 1086-1086
    Abstract: 1086 Background: Black women are 40% more likely to die from their breast cancer compared to White women. Inadequate representation of Blacks in clinical trials may contribute to health care inequity. Emory’s Winship Cancer Institute (WCI) in Atlanta serves a significant Black population and has a unique opportunity to engage these underrepresented patients in clinical trials. We aimed to assess clinical outcomes in Black versus White women with metastatic breast cancer (MBC) enrolled on investigator-initiated clinical trials (IITs) at Emory. Methods: Black and White women with MBC enrolled on IITs conducted at WCI between 1/2009 and 1/2019 were retrospectively evaluated. Descriptive statistics were generated for all patient characteristics. Univariate analyses and a multiple logistic regression model were used to assess the effect of age and race on clinical response, length of time on trial, number of therapy lines prior to trial enrollment, and toxicity on trial. Overall survival was assessed using Kaplan Meier analysis. Results: Sixty-two women with MBC were included [White, n = 41 (66%), and Black, n = 21 (34%), p = 0.55]. Over 90% of women were enrolled on phase II clinical trials and received targeted therapy. Mean age at clinical trial consent was 53.2 and 55.9 years in Black and White women, respectively (p = 0.36). While the majority of women had hormone-receptor positive disease, a higher percentage of Blacks had triple negative breast cancer (29% vs. 17% in Whites, p = 0.39). Black women had fewer lines of systemic therapy prior to trial enrollment (2.86 vs. 4.3, respectively, p = 0.017) and were enrolled on trial for less time than White women (5.67 mo vs. 7.83 mo, respectively, p = 0.22). There were no differences in toxicity rates among patients enrolled on IITs based on race. Black women were more likely to have progressive disease (PD) on trial (45% in Blacks vs. 20% in Whites, p = 0.05). While there was no significant difference in overall survival (p = 0.482), there was a trend towards shorter survival in Black women (51.3 mos vs. 64 mos, respectively). Conclusions: Black women with MBC who enrolled on IIT trials at Emory had worse treatment response and a trend towards poorer survival compared to White women. More research is needed to determine whether this is due to adverse biology. These results reinforce the need for exploration of biomarkers of response by race and ethnicity and improved representation of Blacks in clinical trials to inform real world efficacy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 3
    In: Cancer, Wiley, Vol. 127, No. 18 ( 2021-09-15), p. 3390-3402
    Abstract: The method of relapse detection (asymptomatic surveillance imaging vs clinically directed assessment) is not associated with improved outcomes for patients with relapsed follicular lymphoma. Radiographic abnormalities identified on asymptomatic surveillance studies are frequently false positive findings.
    Type of Medium: Online Resource
    ISSN: 0008-543X , 1097-0142
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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  • 4
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 3331-3331
    Abstract: Title:Outcomes of Elderly Patients Undergoing Allogeneic Transplantation for Acute Myeloid Leukemia with Fludarabine/Melphalan or Fludarabine/TBI Conditioning Regimen Intro:Acute myeloid leukemia (AML) is an aggressive hematological disorder that primarily occurs in the elderly with an average age of 68 at the time of diagnosis. Allogeneic transplantation provides the only chance for long term survival and several studies have shown that allogeneic transplantation in elderly patients using reduced intensity regimens are safe and well tolerated and lead to long term survival. Fludarabine/melphalan, a reduced intensity conditioning regimen, and fludarabine/total body irradiation (TBI) a non-myeloablative conditioning regimen, are two regimens that are often used for elderly patients. Fludarabine/TBI is considered to be a less intensive conditioning regimen than fludarabine/melphalan. We examined outcomes of allogeneic transplantation in elderly patients with AML that received fludarabine/melphalan or fludarabine/TBI as a conditioning regimen. Methods:Ninety-five (95) patients that had a diagnosis of an AML or secondary AML that were 60 or older and received an allogeneic transplantation between April 2008 and October 2017 at Winship Cancer Institute of Emory University were included in this retrospective analysis. Patients that had active disease relapse at the time of transplant were excluded. Patients were identified using the institutional transplant database and confirmed with our electronic medical record system. Results: Ninety-five patients (95) were included in our study with a median age at transplant of 66. Melphalan was given at a dose of 140mg/m2 in each patient. TBI was given at a dose between 200-300cGy in each patient. Seventy-seven patients (81%) received fludarabine/melphalan conditioning regimen. Twenty patients (21%) were 70 or older. Thirty-two patients (35.6%) patients had unfavorable cytogenetics. Patients that received conditioning regimen with fludarabine and melphalan had a longer 1 year overall survival rate than patients that received fludarabine/TBI (71.2% vs 50.0%, p=0.08). In multivariate analysis, only disease risk score was significantly associated with overall survival (p=0.039). Patients with higher co-morbidity index score (p=0.003) were more likely to receive fludarabine/TBI for conditioning, however the 1 year overall survival rate was higher in the fludarabine/melphalan than the fludarabine/TBI group (69% vs 43.8%, p=0.09). In sub-group analysis, patients between the ages of 60-64 and those with complete remission with incomplete hematological recovery derived the most benefit from fludarabine/melphalan rather than fludarabine/TBI with a 1 year survival rate of 74.3% vs 40.0% (p=0.06) and 61% vs 0%, (p=0.06), respectively. Relapse rates were similar between the two groups (p=.536). Treatment related mortality (TRM) was not significantly different between the two conditioning regimens, with a slightly higher TRM in fludarabine/TBI group (OR= 1.36, 95% CI=0.42-4.35, p=0.60). Conclusions: This retrospective analysis sought to examine the outcomes in elderly patients undergoing allogeneic transplantation for AML with either fludarabine/melphalan or fludarabine/TBI. Fludarabine/TBI is non-myeloablative regimen and considered to a be a less intense regimen than fludarabine/melphalan. There was a trend for better overall survival for the fludarabine/melphalan group in comparison to fludarabine/TBI, even in patients with higher comorbidity index and patients over the age of 70. Thus, fludarabine/melphalan is a reasonable regimen even in elderly and less fit patients that improves overall survival without unacceptable toxicities, including TRM. Disclosures Langston: Astellas Pharma: Other: Research Support; Incyte: Other: Research Support; Jazz Pharmaceuticals: Other: Research Support; Chimerix: Other: Research Support; Takeda: Other: Research Support; Kadmon Corporation: Other: Research Support; Novartis: Other: Research Support; Bristol Myers Squibb: Other: Research Support. Waller:Amgen: Consultancy; Cerus Corporation: Other: Stock, Patents & Royalties; Pharmacyclics: Other: Travel expenses, Research Funding; Cambium Oncology: Patents & Royalties: Patents, royalties or other intellectual property ; Chimerix: Other: Stock; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kalytera: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 5
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. e19504-e19504
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e19504-e19504
    Abstract: e19504 Background: Chimeric antigen receptor (CAR) T-cell therapy is approved for treatment in relapsed/refractory diffuse large B cell lymphoma, penta-refractory multiple myeloma (MM), and acute lymphoblastic leukemia. We evaluated relapse and survival rates by 3 months (mo) in patients (pts) who received BCMA and CD19 CAR-T cell therapies. Methods: We performed a retrospective analysis of pts with RRMM and R/R Non-Hodgkin lymphoma (NHL) who received CAR-T cell therapy from 2012-2023 at the Winship Cancer Institute at Emory University. Pts who relapsed prior to 3mo were excluded. SAS was used for statistical analysis with alpha of 0.05. Grades 3/4 cytopenias were compared at day 0, 1mo, and 3mo per CTCAE criteria with each pt counted once if 〉 1 cytopenia. Hematological recovery was defined as sustained Hgb 〉 8, Plt 〉 50,000, and ANC 〉 1000 without transfusion support. Group differences were evaluated using Chi-Square or Fisher’s exact tests for categorical and ANOVA or Kruskal-Wallis for numerical variables. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method from CAR-T receipt to progression or death, or last known contact for those censored. Univariable and multivariable cox regression were performed. Results: Of 126 pts, 60 had MM and 66 had NHL. Median age at CAR-T receipt was 64yrs (range: 25-85). Fifteen pts had ECOG ≥2. Most pts were male (52.4%) and of white race (61.9%). For R/R NHL, 39.4% received tisa-cel, 33.3% axi-cel, 13.6% brexu-cel, 3.0% liso-cel and 10.6% clinical trial. For RRMM, 91.7% received ide-cel and cilta-cel (8.3%). Bridging therapy, CRS, and ICANS were not associated with severe cytopenias. Overall, 89.7% had grade 3/4 cytopenias at day 0, 54.0% at 1mo, and 34.1% at 3mo. Cytopenia rates, hematological recovery, transfusions, and infectious complications were comparable between groups. Overall, 36.5% required GCSF, 34.9% red cells, 23.0% platelets, and 2.4% TPO. In MM pts, decreased OS was seen with persistence of severe cytopenias (p = 0.009) and decreased PFS with GCSF use ≥2wks (p = 0.007). Time to ANC recovery (days) was more prolonged in MM compared to NHL pts (p = 0.039). Overall median time to recovery (days) was 8, 19, 22.5 for Hgb, ANC, and Plt respectively. On MVA for overall cohort, grade 3/4 cytopenias at 3mo were associated with decreased OS [HR 2.28, 95%CI: (1.22-4.29), p = 0.010) and PFS [HR 1.8, 95%CI: (1.09-2.98), p = 0.022]. On MVA for NHL, decreased OS [HR 2.38, 95%CI: (1.03-5.48), p = 0.043] and PFS [HR 2.11, 95%CI: (1.01-4.41), p = 0.047] were associated with 3mo grade 3/4 cytopenias but not seen in MM pts. Conclusions: We report significant rates of severe cytopenias at 3 months and a potential association with higher relapse and decreased survival rates in pts receiving BCMA and CD19 CAR-T cell therapies. These results are hypothesis generating, and more prospective studies are needed for further confirmation.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 6
    In: Journal of Cell Science, The Company of Biologists, Vol. 132, No. 19 ( 2019-10-01)
    Abstract: Collective invasion, the coordinated movement of cohesive packs of cells, has become recognized as a major mode of metastasis for solid tumors. These packs are phenotypically heterogeneous and include specialized cells that lead the invasive pack and others that follow behind. To better understand how these unique cell types cooperate to facilitate collective invasion, we analyzed transcriptomic sequence variation between leader and follower populations isolated from the H1299 non-small cell lung cancer cell line using an image-guided selection technique. We now identify 14 expressed mutations that are selectively enriched in leader or follower cells, suggesting a novel link between genomic and phenotypic heterogeneity within a collectively invading tumor cell population. Functional characterization of two phenotype-specific candidate mutations showed that ARP3 enhances collective invasion by promoting the leader cell phenotype and that wild-type KDM5B suppresses chain-like cooperative behavior. These results demonstrate an important role for distinct genetic variants in establishing leader and follower phenotypes and highlight the necessity of maintaining a capacity for phenotypic plasticity during collective cancer invasion.
    Type of Medium: Online Resource
    ISSN: 1477-9137 , 0021-9533
    Language: English
    Publisher: The Company of Biologists
    Publication Date: 2019
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. P4-07-31-P4-07-31
    Abstract: Background: Triple-negative breast cancer (TNBC) is a notoriously hard to treat and aggressive breast cancer (BC) subtype. Androgen receptor-positive (AR+) TNBC is characterized by AR overexpression and sensitivity to AR antagonists. In contrast, basal-like TNBC lacking AR expression, also known as quadruple-negative breast cancer (QNBC), is refractory to AR antagonists. Women of African descent are predisposed to TNBC. Moreover, QNBC differences between African American (AA) and European American (EA) patients have been noted, with the former expressing distinct basal and immune signatures and having worse outcomes. Although AR testing is not part of standard BC diagnosis and the QNBC subtype is usually reported as TNBC, QNBC may have distinct biological and clinical characteristics. In this study, we examined the prevalence and clinical characteristics of QNBC.Methods: We immunohistochemically evaluated AR expression in formalin-fixed paraffin-embedded TNBC samples (n=760) from our multi-institutional cohorts across the US and Nigeria. Samples with ≥1% AR-positive nuclei were deemed AR-positive. Descriptive statistics were generated for clinicopathological characteristics. Kaplan-Meier (KM) survival analyses were performed to compare overall survival (OS) between patient groups with a different AR status. Multivariable Cox regression analysis was conducted to select the covariates (a≥0.20 removal criterion). AR mRNA levels in patients with BC were evaluated using RNA-seq data retrieved from The Cancer Genome Atlas (TCGA). The Cancer Proteome Atlas (TCPA) BRCA dataset was used to assess AR protein levels.Results: We found an association between African ancestry and AR loss. QNBC accounted for 92.1% of BCs in Africans, 82.4% in AAs, and only 39.8% in EAs. Similarly, analyses of RNA-seq data from TCGA revealed that tumors in AAs with TNBC (n=32) had lower AR mRNA levels than their EA counterparts (n=67). Consistently, AR protein levels in TNBC tumors were lower in AAs than in EAs. Univariate analyses revealed a significant association between QNBC status and high tumor grade (grade 3: 83.02% vs. 66.41%, p & lt;0.001) and high expression of the proliferation marker Ki-67 (≥14%: 85.41 vs. 75.51%, p=0.022) in patients from our multi-institutional cohorts. Race-wise associations showed a non-significant trend of QNBCs in AAs toward higher tumor grade (85.65% vs. 80.27%, p=0.196) and Ki67 expression levels (87.77% vs. 81.06%, p=0.113) compared with QNBCs in EAs. Compared with EAs with QNBC, a higher proportion of AAs with QNBC aged ≤56 (59.17% AAs vs. 45.7 EAs, p=0.011) and had tumors & gt;2 cm (60.88% AAs vs. 45.65% EAs, p=0.075). KM survival analyses indicated that patients with QNBC had worse outcomes than those with TNBC, with significant differences in women of African descent (p & lt;0.05). Furthermore, a race-wise comparison uncovered that while AA and EA patients with TNBC displayed similar OS, AAs with QNBCs had worse OS than their EA counterparts (p=0.03). Finally, we stratified samples in the TCGA BC dataset (n=920) according to AR mRNA levels into AR-low (n=243) and AR-high groups (n=677) and found that among patients in the AR-low subgroup, AAs (n=90) had significantly worse OS than EAs (n=153; p=0.008). No significant differences in OS were observed within the AR-high group (p=0.93).Conclusion: Our findings suggest a strong association between AR loss and African descent. These data offer compelling evidence to support that racial BC disparities in the US lie within the QNBC subgroup rather than the TNBC subtype. These findings also suggest that the widening BC mortality gap between AAs and EAs essentially whittles down to a failure to characterize the QNBC subtype. Citation Format: Shristi Bhattarai, Geetanjali Saini, Manali Rupji, Justin Luningham, Ravi C. Turaga, Uma Krishnamurti, Xiaoxian (Bill) Li, Johnson Agboola, Murtala Abubakar, Haruna A. Nggada, Abidemi Omonisi, Saad A. Ahmed, Luciane Cavalli, Ritu Aneja. Racial disparities in breast cancer chiefly reside in the lesser-known quadruple-negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-31.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 8
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 247-247
    Abstract: Primary cutaneous melanoma is often successfully treated in early stages in patients with regional disease. While distant metastatic disease, including brain metastasis, that develops in most stage IV melanoma patients, carries a particularly poor prognosis with median overall survival of only 4-5 months. Standard-of-care treatment of brain metastases includes surgery, radiation, and chemotherapy. The fact that melanoma is a radio-resistant cancer, significantly limits treatment options for melanoma that has metastasized to the brain. There is clearly a significant demand for new therapeutic approaches. We have conducted a whole transcriptomic analysis of melanoma brain metastases to provide insight into molecular changes that may contribute to metastasis as well as to identify potential therapeutic targets in the metastasized cancer. Total RNA was extracted from 29 formalin-fixed paraffin-embedded (FFPE) melanoma brain metastatic samples, libraries constructed and enriched for transcript fragments with coding regions. Libraries were subjected to Transcriptome Capture (TCap) targeting 21,415 genes, which represents more than 98% of the total RefSeq exome. Sequencing was performed on the Illumina HiSeq platform. Gene expression analysis of melanoma brain metastatic samples reveals high expression levels of ion channels, including subunits of the ligand-gated neurotransmitter GABAA receptors. We will present differential expression analysis between recent melanoma transcriptomic studies [1, 2] and melanoma brain metastases samples. More than 20% of FDA approved drugs target ion channels. We report that repurposing of one such class of drugs targeting GABAA receptors can impair melanoma cell viability in vitro and reduce tumor volume in vivo. GABAA receptors can serve as a potential therapeutic target for treatment brain metastasis. References 1. Akbani, et al. (The Cancer Genome Atlas Network, TCGA). Genome classification of cutaneous melanoma. Cell 2015; 161(7): 1681-1696. 2. Tirosh, et al. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science 2016; 352 (6282): 189-196. Citation Format: Milota Kaluzova, Tahseen Nasti, Hiao-Rong Chen, Lindsey Lowder, Robert Press, Havi Rosen, Manali Rupji, Laura Kallay, Rikesh Patel, Andre Burnham, Maxwell Xu, Alexandra Ross, Havva Keskin, Erin Connelly, Benjamin Izar, Cory Adamson, Jeffrey Olson, Jing Su, Walter Curran, Ragini Kudchadkar, Matthew Schniederjan, Stewart Neill, David Lawson, Michael Chan, Jeanne Kowalski, Mohammad Khan, Daniel Pomeranz Krummel, Soma Sengupta. Identification of the GABAA receptor in melanoma brain metastases patient tumors and demonstration that it is a viable drug target using benzodiazepine-derivatives [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 247.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 9
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2879-2879
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2879-2879
    Abstract: BACKGROUND: While outcomes for children with acute myeloid leukemia have improved dramatically in recent years, a subset of patients continue to have poor prognosis with & lt;60% 5-year overall survival and the high intensity chemotherapy used to treat these patients is associated with significant short and long-term side effects. New less toxic and more effective treatments are needed. TYRO3, a member of the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases, is overexpressed in many types of cancer and functions to promote tumor cell survival and/or proliferation, metastasis, and resistance to chemotherapy. In addition, higher levels of TYRO3 expression are associated with decreased overall survival in patients with colorectal, hepatocellular or breast cancer. We hypothesize that TYRO3 plays a critical role in survival and proliferation of AML cells and may be a therapeutic target in pediatric AML. METHODS: The TARGET database was utilized to determine expression of mRNAs encoding the TAM family kinases and their ligands, GAS6 and PROS1, in pediatric AML patient samples. Samples (n=145) were categorized into two groups with “high” expression greater than the median or “low” expression less than or equal to the median and overall survival was compared between the two groups using the log-rank test. Expression of TAM family kinases and ligands was determined in AML cell lines by immunoblot. Derivatives of the NB4 AML cell line with shRNA-mediated inhibition of TYRO3 were generated and the impact of TYRO3 inhibition on MERTK levels was determined by immunoblot. RESULTS: High levels of TYRO3 or PROS1 mRNAs in patient samples were independently associated with decreased overall survival in children with AML (p & lt;0.001 and p= 0.042, respectively). Patients with leukemias that expressed higher levels of TYRO3 had a median survival of 870 days with only 40% of patients surviving for 10 years. In contrast, 70% of patients with leukemias that expressed lower levels of TYRO3 were long-term survivors. A hazard ratio of 2.60 (1.56-4.33 95% confidence interval, p & lt;0.001) was associated with high levels of TYRO3. Similarly, patients whose leukemias had higher levels of PROS1 expression had a median survival of 1229 days with 46% 10-year overall survival compared to 62% 10-year survival in patients whose tumors express low levels of PROS1. High levels of PROS1 were associated with a hazard ratio of 1.65 (1.01-2.68, p=0.044). TYRO3 protein was detected in all 9 AML cells lines tested; however, MERTK, GAS6, and PROS1 were differentially expressed. Inhibition of TYRO3 in NB4 cells using shRNA resulted in upregulation of MERTK. CONCLUSIONS: TYRO3 was ubiquitously expressed in all AML cell lines tested and higher levels of TYRO3 and its ligand PROS1 were associated with significantly poorer prognosis in children with AML. These data suggest a role for TYRO3 in pediatric AML and implicate TYRO3 as a therapeutic target in this context. Citation Format: Sherri K. Smart, Manali Rupji, Bhakti Dwivedi, Jeanne Kowalski, Deborah DeRyckere, Douglas K. Graham. TYRO3 is a potential therapeutic target in pediatric acute myeloid leukemia [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 2879.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 14 ( 2019-07-15), p. 3702-3713
    Abstract: Exploitation of the immune system has emerged as an important therapeutic strategy for acute lymphoblastic leukemia (ALL). However, the mechanisms of immune evasion during leukemia progression remain poorly understood. We sought to understand the role of calcineurin in ALL and observed that depletion of calcineurin B (CnB) in leukemia cells dramatically prolongs survival in immune-competent but not immune-deficient recipients. Immune-competent recipients were protected from challenge with leukemia if they were first immunized with CnB-deficient leukemia, suggesting robust adaptive immunity. In the bone marrow (BM), recipients of CnB-deficient leukemia harbored expanded T-cell populations as compared with controls. Gene expression analyses of leukemia cells extracted from the BM identified Cn-dependent significant changes in the expression of immunoregulatory genes. Increased secretion of IL12 from CnB-deficient leukemia cells was sufficient to induce T-cell activation ex vivo, an effect that was abolished when IL12 was neutralized. Strikingly, recombinant IL12 prolonged survival of mice challenged with highly aggressive B-ALL. Moreover, gene expression analyses from children with ALL showed that patients with higher expression of either IL12A or IL12B exhibited prolonged survival. These data suggest that leukemia cells are dependent upon calcineurin for immune evasion by restricting the regulation of proinflammatory genes, particularly IL12. Significance: This report implicates calcineurin as an intracellular signaling molecule responsible for immune evasion during leukemia progression and raises the prospect of re-examining IL12 as a therapeutic in leukemia.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
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