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  • 1
    Online-Ressource
    Online-Ressource
    Abstract LB109: A critical role for SIRT5 in acute myeloid leukemia metabolism
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB109-LB109
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. LB109-LB109
    Kurzfassung: Standard of care for AML includes chemotherapy and stem cell transplant, with 5-year survival rates & lt;30%. We sought to identify genes critical to AML cells, irrespective of mutational status, and performed an shRNA screen targeting 1,287 genes on 12 AML patient samples. This screen identified Sirtuin 5 (SIRT5) as a top candidate. SIRT5 is the only known enzyme with desuccinylase, demalonylase, and/or deglutarylase activity and we are the first to report the dependence of AML cells on SIRT5. Next, we stably transduced a panel of AML cell lines with doxycycline (dox)-inducible shSIRT5 (dox-shSIRT5). SIRT5 knockdown (KD) strongly inhibited cell growth, colony formation and increased apoptosis in 15/22 lines (SIRT5-dependent), while 7/22 lines were SIRT5-independent. SIRT5 dependence did not correlate with AML-related mutations nor basal SIRT5 expression. SIRT5 KD in primary AML samples (N=25) revealed a therapeutic window (~50% reduction), with no effect in CB samples (N=5). We examined the requirement of SIRT5 in vivo using three mouse models of leukemia. In a xenograft model with AML cell lines, SIRT5 KD indefinitely prolonged survival of mice injected with SIRT5-dependent cells with no sign of leukemia. Bone marrow transplant with transduced (MLL-AF9 or BCR-ABL1) SIRT5 null cells showed reduced leukemia cell burden and splenomegaly, and significantly prolonged survival. FLT3-ITD-driven disease was also blunted by the absence of SIRT5 in a genetic knockout mouse model. Mechanically, SIRT5 KD profoundly reduced oxidative phosphorylation (OXPHOS) and glycolysis. Additionally, SIRT5 KD increased mitochondrial superoxide selectively in annexin V-negative, SIRT5-dependent cells. Concomitant, ectopic expression of SOD2 abrogated the increase in superoxide, rescued cells from apoptosis, and rescued the colony formation deficit. Untargeted metabolomics revealed RNA charging and alanine and serine metabolism as top metabolic pathways regulated by SIRT5, with glutaminase (GLS) and α-ketoglutarate identified as potential upstream regulators. Metabolic tracing experiments with [13C5,15N2] -glutamine confirmed disrupted glutamine metabolism in SIRT5-dependent cells. Together, these results indicate that SIRT5 is required to regulate glutamine flux to sustain redox homeostasis and/or anabolism. NRD167, a novel SIRT5 inhibitor, was used to target SIRT5 in AML. NRD167 reduced cell proliferation, induced apoptosis, and reduced OXPHOS in SIRT5-dependent but not SIRT5-independent cells. NRD167 inhibited colony formation from AML patient samples, but not in CB samples. An AML patient-derived xenograft model trended toward prolonged survival following ex vivo treatment with NRD167. Our data suggest that the majority of AML samples are dependent on SIRT5 and that inhibition preferentially targets AML cells, implicating SIRT5 as a therapy target in AML. Citation Format: Dongqing Yan, Anca Franzini, Anthony D. Pomicter, Brayden J. Halverson, Orlando Antelope, Clinton C. Mason, Jonathan M. Ahmann, Anna V. Senina, Courtney L. L. Jones, Matthew S. Zabriskie, Hein Than, Michael J. Xiao, Alexandria van Scoyk, Ami B. Patel, William L. L. Heaton, Shawn C. Owen, Joshua L. Andersen, Christina M. Egbert, Julie A. Reisz, Angelo D'Alessandro, James E. Cox, Kevin C. Gantz, Hannah M. Redwine, Siddharth M. Iyer, Jamshid S. Khorashad, Nima Rajabi, Christian A. Olsen, Thomas O'Hare, Michael W. Deininger. A critical role for SIRT5 in acute myeloid leukemia metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB109.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-LB109
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
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  • 2
    Online-Ressource
    Online-Ressource
    Animal models for COVID-19
    Springer Science and Business Media LLC ; 2020
    In:  Nature Vol. 586, No. 7830 ( 2020-10-22), p. 509-515
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 586, No. 7830 ( 2020-10-22), p. 509-515
    Materialart: Online-Ressource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/s41586-020-2787-6
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2020
    ZDB Id: 120714-3
    ZDB Id: 1413423-8
    SSG: 11
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
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    SIRT5 Is a Druggable Metabolic Vulnerability in Acute Myeloid Leukemia
    American Association for Cancer Research (AACR) ; 2021
    In:  Blood Cancer Discovery Vol. 2, No. 3 ( 2021-05-01), p. 266-287
    Details
    In: Blood Cancer Discovery, American Association for Cancer Research (AACR), Vol. 2, No. 3 ( 2021-05-01), p. 266-287
    Kurzfassung: We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML. Significance: Reducing SIRT5 activity is detrimental to the survival of AML cells regardless of genotype, yet well tolerated by healthy hematopoietic cells. In mouse models, disrupting SIRT5 inhibits AML progression. SIRT5 controls several metabolic pathways that are required for leukemia cell survival. These results identify SIRT5 as a therapeutic target in AML. See related commentary by Li and Melnick, p. 198.
    Materialart: Online-Ressource
    ISSN: 2643-3230 , 2643-3249
    URL: Article
    DOI: 10.1158/2643-3230.BCD-20-0168
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
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    Identification of Novel Combination Therapies Active in BCL2 Inhibitor-Resistant Patient-Derived AML Models
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1273-1273
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 1273-1273
    Kurzfassung: Acute myeloid leukemia (AML) is an aggressive, heterogeneous malignancy. AML patients whose disease relapses on chemotherapy or are unfit for aggressive induction regimens have limited therapeutic options. Many patients benefit from the combination of venetoclax (BCL2i) and a hypomethylating agent (HMA) but this regimen is rarely curative. The addition of novel agents could provide improved benefit for relapsed/refractory patients. To identify such regimens, we screened a panel of 10 AML cell lines with combinations of venetoclax and novel targeted agents. The agents used spanned multiple mechanisms of action (e.g. DNA damage response, kinase signaling, pro-apoptotic agents) and are all in early clinical development. Cells were treated for 72hrs and viability was assessed by CellTiter-Glo. In several of the cell lines that were insensitive or partially sensitive to venetoclax (OCI-AML3, KG1a, MonoMac6, THP1), combinations with inhibitors of MCL1 (AZD5991), AURKB (AZD2811), and BRD4 (AZD5153) showed synergistic activity (Loewe synergy score 〉 5, growth inhibition 〉 180%) (Table 1). We next asked if these combinations were active in patient-derived xenograft (PDX) models of AML. We established an ex vivo co-culture assay using the HS-5 bone marrow stromal cell line. AML PDX cells were isolated from mouse spleens and plated in 96-well format in direct co-culture with HS-5 cells or in HS-5-derived conditioned media. Cells were treated with three doses of each monotherapy and three doses of fixed ratio combination. Replicate screens using cells from individual mice on different days confirmed data were reproducible (r2=0.687) across animals engrafted with the same PDX. Drug response was similar between conditioned media and direct co-culture assays (r2=0.81). Venetoclax sensitivity varied across PDX models ex vivo. Notably, 2/5 PDX models screened (DFAM-68555 and DFAM-10360) were insensitive to both venetoclax and the combination of venetoclax + 5-azacytidine (HMA) ex vivo. Both models were established from untreated/1L patients and harbor TP53 mutations. Combination treatments did not add additional benefit over venetoclax monotherapy in the DFAM-10360 model. However, in DFAM-68555, AZD5153, AZD5991, and AZD2811 showed improved activity over venetoclax alone (67%, 54%, and 67% vs. 26% decrease in viability for venetoclax alone, respectively). Since combination strategies will likely be most impactful in patients refractory to or relapsed after venetoclax, we chose this venetoclax insensitive model to prioritize in vivo. To confirm the translatability of these findings, we designed a pilot in vivo study using DFAM-68555. Mice were randomized to receive vehicle, venetoclax + HMA, or venetoclax + AZD5153 when peripheral blood disease reached ~5% (hCD45+hCD33+ cells by flow cytometry). After two weeks of dosing, animals were sacrificed to evaluate disease burden in bone marrow (sternum), spleen, and peripheral blood. The model remained insensitive to venetoclax + HMA in vivo. The combination of AZD5153 with venetoclax decreased disease burden in blood and spleen compared to vehicle (30% and 42% hCD45+CD33+ cells by flow cytometry vs 70% and 95%, respectively) with similar efficacy seen by immunohistochemistry in the bone. Finally, we screened these venetoclax combinations in additional aggressive AML PDX models which were resistant or only partially responsive to venetoclax in vivo. Addition of AZD2811NP and AZD5991 to venetoclax was more effective than venetoclax alone and venetoclax + HMA in the bone marrow. The most active combination varied from model to model. Efficacy screening in additional models is ongoing to further build ex vivo to in vivo translation and prioritize development of specific combinations. Also ongoing is genomic and transcriptomic profiling of these PDXs to identify potential predictive biomarkers of combination activity. In summary, we developed an ex vivo screening platform to test clinically actionable combinations for activity in clinically relevant models. Using this platform and subsequent in vivo efficacy, we identified venetoclax combinations across multiple mechanisms (pro-apoptotic, cell cycle regulation, transcriptional regulation, DNA damage response) with activity in venetoclax-insensitive models. These results suggest potential therapeutic options to explore clinically for AML patients. Disclosures Andersen: AstraZeneca: Employment. Christie:AstraZeneca: Employment. Rosen:Astrazeneca: Employment. Maratea:AstraZeneca: Employment. Hattersley:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Cidado:AstraZeneca: Employment. Pulukuri:AstraZeneca: Employment. Saeh:AstraZeneca: Employment. Clark:AstraZeneca: Employment, Equity Ownership. Reimer:AstraZeneca: Employment. Mettetal:AstraZeneca: Employment.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-129475
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2019
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
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  • 5
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    Abstract 2957: A novel circulating tumor DNA (ctDNA) assay enables monitoring of disease progression and treatment response in disseminated preclinical hematologic cancer models
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2957-2957
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 2957-2957
    Kurzfassung: We have established a novel assay to assess circulating tumor DNA (ctDNA) in mice engrafted with disseminated cell line and patient-derived xenografts (PDX) of hematologic malignancies. Disseminated models recapitulate many features of human disease, but engraftment in multiple tissues makes monitoring of disease and treatment response difficult. Existing assays also lack the sensitivity required to assess minimal residual disease (MRD). This novel ddPCR assay targets highly conserved human-specific regions of LINE-1 and HERV-K repeat elements resulting in exceptionally sensitive detection of shed human ctDNA. Initial data shows sensitivity of 0.8 haploid genome equivalents (one haploid genome is ~3.3pg of human DNA), whereas ctDNA monitoring assays currently on the market require 1,000 times more input DNA to reach a sensitivity of just 2-9 genome equivalents. Serial dilution experiments confirm this assay is suitable to detect increases in ctDNA over several orders of magnitude, while also establishing a minimum plasma input of 40uL. To validate the assay we assessed the ability of ctDNA to detect disease alongside traditional histology, bioluminescence imaging, and flow cytometry assays in 10 leukemia and lymphoma models. Levels of ctDNA correlated well with disease progression across models engrafting in bone marrow, spleen, liver, blood and other tissues. In all cases where early stage disease was analyzed, the ctDNA assay was able to detect disease earlier relative to other methods due to its increased sensitivity, and these data can be effectively used for randomization into treatment groups. We also assessed the utility of ctDNA for determining drug treatment response in mice engrafted with a disseminated mantle cell lymphoma PDX. Baseline ctDNA assessment was completed on day 11 post-engraftment confirming ctDNA levels above baseline, at which point mice were divided into 7 treatment groups: Vehicle, Acalabrutinib, and 5 combination arms of Acalabrutinib plus clinically used agents. After 4 weeks of treatment disease burden was assessed by flow cytometry of the bone marrow (femur) compared to ctDNA detected in plasma. Efficacy readouts from both assays agreed for all groups, while the ctDNA assay was able to identify a significant difference between the two best responding arms which appeared to have near complete responses when assessed by flow cytometry alone. The fold difference between the two best responding arms was 1.1 fold by flow cytometry and 3.6 fold by ctDNA, illuminating a greater disparity in MRD and relapse potential between these 2 groups. This novel ctDNA assay allows for robust experimental designs to answer questions about the depth and durability of treatment responses, as well as to identify early stage disease. Work is ongoing to explore extended monitoring for relapse and application to solid tumor models. Citation Format: Amanda L. Christie, Paul Labrousse, Courtney L. Andersen, Justine E. Roderick, Jacob Gordon, Deborah Lawson, Denise Hughes, Kimberly Maratea, Daniel Stetson, Brandon Willis, Andrew Bloecher, Corinne Reimer, Brian Dougherty. A novel circulating tumor DNA (ctDNA) assay enables monitoring of disease progression and treatment response in disseminated preclinical hematologic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2957.
    Materialart: Online-Ressource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-2957
    RVK:
    XA 36000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Association for Cancer Research (AACR)
    Publikationsdatum: 2021
    ZDB Id: 2036785-5
    ZDB Id: 1432-1
    ZDB Id: 410466-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
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    Genomic identification of intergeneric hybrids in New World wood-warblers (Aves: Parulidae)
    Oxford University Press (OUP) ; 2020
    In:  Biological Journal of the Linnean Society Vol. 131, No. 1 ( 2020-08-26), p. 183-191
    Details
    In: Biological Journal of the Linnean Society, Oxford University Press (OUP), Vol. 131, No. 1 ( 2020-08-26), p. 183-191
    Kurzfassung: The documentation of hybrids between distantly related taxa can illustrate an initial step to explain how genes might move between species that do not exhibit complete reproductive isolation. In birds, some of the most phylogenetically distant hybrid combinations occur between genera. Traditionally, morphological and plumage characters have been used to assign the identity of the parental species of a putative hybrid, although recently, nuclear introns also have been used. Here, we demonstrate how high-throughput short-read DNA sequence data can be used to identify the parentage of a putative intergeneric hybrid, in this case between a blue-winged warbler (Vermivora cyanoptera) and a cerulean warbler (Setophaga cerulea). This hybrid had mitochondrial DNA of a cerulean warbler, indicating the maternal parent. For hundreds of single nucleotide polymorphisms within six regions of the nuclear genome that differentiate blue-winged warblers and golden-winged warblers (Vermivora chrysoptera), the hybrid had roughly equal ancestry assignment to blue-winged and cerulean warblers, suggesting a blue-winged warbler as the paternal parent species and demonstrating that this was a first generation (F1) hybrid between these species. Unlike other recently characterized intergeneric warbler hybrids, this individual hybrid learned to song match its maternal parent species, suggesting that it might have been the result of an extra-pair mating and raised in a cerulean warbler nest.
    Materialart: Online-Ressource
    ISSN: 0024-4066 , 1095-8312
    URL: Article
    DOI: 10.1093/biolinnean/blaa085
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2020
    ZDB Id: 1461865-5
    ZDB Id: 220623-7
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
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    Hormone response in ovarian cancer: time to reconsider as a clinical target?
    Bioscientifica ; 2012
    In:  Endocrine-Related Cancer Vol. 19, No. 6 ( 2012-10-8), p. R255-R279
    Details
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 19, No. 6 ( 2012-10-8), p. R255-R279
    Kurzfassung: Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence from in vitro studies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response.
    Materialart: Online-Ressource
    ISSN: 1351-0088 , 1479-6821
    URL: Article
    DOI: 10.1530/ERC-12-0175
    Sprache: Unbekannt
    Verlag: Bioscientifica
    Publikationsdatum: 2012
    ZDB Id: 2010895-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
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    Cardiac Arrest Following the Administration of Intravenous Diphenhydramine for Sedation to an Infant With Congenital Heart Disease
    Pediatric Pharmacy Advocacy Group ; 2021
    In:  The Journal of Pediatric Pharmacology and Therapeutics Vol. 26, No. 3 ( 2021-03-01), p. 311-314
    Details
    In: The Journal of Pediatric Pharmacology and Therapeutics, Pediatric Pharmacy Advocacy Group, Vol. 26, No. 3 ( 2021-03-01), p. 311-314
    Kurzfassung: Diphenhydramine (Benadryl) is a first-generation antihistamine that is used primarily to treat allergic reactions including anaphylaxis, urticaria, and allergic rhinitis. Despite its availability as an over-the-counter medication, toxicity may occur with its use especially when administered in large doses or via the intravenous route. We present a 3-month-old infant with Trisomy 21 who suffered a cardiac arrest immediately following administration of a single 1.25 mg/kg dose of intravenous diphenhydramine, prescribed for sedation in the Pediatric ICU setting. The potential cardiovascular and respiratory effects of diphenhydramine are presented, previous reports of life-threatening adverse effects reviewed, and options to limit these effects discussed.
    Materialart: Online-Ressource
    ISSN: 1551-6776
    URL: Article
    URL: Article
    DOI: 10.5863/1551-6776-26.3.311
    DOI: 10.5863/1551-6776-26.3.311.S
    Sprache: Englisch
    Verlag: Pediatric Pharmacy Advocacy Group
    Publikationsdatum: 2021
    ZDB Id: 3028543-4
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
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    Combination Therapy of Bcl-2/X L dual Inhibitor AZD0466 with Acalabrutinib to Overcome Therapeutic Resistance in Aggressive R/R Mantle Cell Lymphoma
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1867-1867
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1867-1867
    Kurzfassung: Introduction As a rare form of non-Hodgkin's lymphoma, mantle cell lymphoma (MCL) is an aggressive subtype. This is largely due to frequent relapses after therapies including paradigm shifting therapies BTK inhibitors (BTKi), such as ibrutinib and acalabrutinib, and Bcl-2 inhibitor (Bcl-2i) venetoclax after long-term treatment in the clinic. Dysregulation of Bcl-2 and Bcl-X L, contributes to therapeutic resistance in MCL. AZD0466 is a novel and highly potent Bcl-2/X L dual inhibitor with active moiety AZD4320. Our preliminary data showed AZD4320 is potent in inhibiting cell viability of MCL cells (IC 50 = 1.6-78 nM). In this study, we assessed the combination efficacy of AZD4320/AZD0466 and acalabrutinib on preclinical MCL models. Methods Cell viability assay was performed to assess the in vitro efficacy of AZD4320 and acalabrutinib alone or in combination in a panel of ibrutinib/venetoclax-sensitive and -resistant MCL cell lines. Cell apoptosis assay was also performed to determine if AZD4320 and acalabrutinib enhanced cell death by cell apoptosis in MCL cell lines. Protein expression profiles of a panel of pro- and anti-apoptotic proteins and other relevant proteins were detected by immunoblotting. Since AZD4320 is limited in preclinical model due to physicochemical properties and dose limiting cardiovascular toxicity, AZD0466, the drug-dendrimer conjugate of AZD4320, was used for in vivo experiment. In vivo efficacy of AZD0466 (34 mg/kg, weekly, iv) and acalabrutinib (20 mg/kg, BID, oral) alone or in combination was evaluated using a Mino-venetoclax-R (Mino-R) cell xenograft model and a PDX model derived from an ibrutinib-CAR-T dual-resistant MCL patient. Results AZD4320 in combo with acalabrutinib inhibited cell proliferation synergistically in both ibrutinib/venetoclax-sensitive and -resistant cell lines (combination index = 0.17-0.93). Compared to vehicle or either single agent, the combination enhanced cell apoptosis by increasing pro-apoptotic markers cleaved caspase 3 and cleaved PARP. In the xenograft mouse model derived from venetoclax-resistant Mino-R cells, co-treatment of AZD0466 and acalabrutinib decreased tumor size significantly compared to vehicle (n = 5, p & lt; 0.0001) or either single agent (n = 5, p = 0.0118 and 0.0070, respectively). Furthermore, in the PDX mouse model derived from a patient relapsed subsequently from ibrutinib and CAR T therapy, the combination of AZD0466 and acalabrutinib inhibited tumor growth compared to vehicle or either single agent. Acalabrutinib or AZD0466 improved survival compared with vehicle by 14 days or 32 days, respectively. Compared to Acalabrutinib or AZD0466, the combination therapy extended survival by 25 days and 7 days, respectively. All mice tolerated the treatment dose without any weight loss compared to the vehicle or either single agent group. Conclusion Compared to AZD4320/AZD0466 and acalabrutinib, combination therapy demonstrated anti-MCL synergy both in vitro and in vivo. These findings suggest that targeting Bcl-2/X L and BTK is promising to overcome multiple acquired resistance phenotypes, including CD19 CAR T-cell therapy. Disclosures Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Wang: DTRM Biopharma (Cayman) Limited: Consultancy; BeiGene: Consultancy, Honoraria, Research Funding; Physicians Education Resources (PER): Honoraria; Anticancer Association: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; CAHON: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Epizyme: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; BGICS: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria; Celgene: Research Funding; Genentech: Consultancy; Loxo Oncology: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; VelosBio: Consultancy, Research Funding; BioInvent: Research Funding; Oncternal: Consultancy, Research Funding; OMI: Honoraria; Newbridge Pharmaceuticals: Honoraria; Scripps: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Chinese Medical Association: Honoraria; Pharmacyclics: Consultancy, Research Funding; Juno: Consultancy, Research Funding; CStone: Consultancy; Bayer Healthcare: Consultancy; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding; Dava Oncology: Honoraria; Moffit Cancer Center: Honoraria; Mumbai Hematology Group: Honoraria.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-151609
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2021
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
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    AZD4573 Effectively Induces Apoptosis in r/r MCL As a Monotherapy or in Combination with Acalabrutinib
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2255-2255
    Details
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2255-2255
    Kurzfassung: Mantle cell lymphoma (MCL) is an aggressive form of NHL where frequent relapse following standard therapies remains a serious concern, even for promising new treatments such as combinations of a BTK inhibitor with the selective Bcl2 inhibitor venetoclax. Previous studies have also shown that MCL cells develop resistance through tumor microenvironment interactions that increase levels of Mcl1, BclxL, and/or Bfl1. Given the ability of CDK9 inhibition to deplete Mcl1 and Bfl1 (Boiko et al 2021), we explored the potential of clinical-stage inhibitor AZD4573 to induce apoptosis in MCL cell lines and PDX models as a monotherapy or in combination with acalabrutinib. Currently, AZD4573 is being evaluated as a monotherapy in a first-in-human study for relapsed or refractory hematological malignancies (NCT03263637) as well as in combination with the BTK inhibitor, acalabrutinib, in patients with non-Hodgkin lymphoma (NHL) (NCT04630756). CDK9 is a serine/threonine kinase that mediates transcription elongation via phosphorylation of serine 2 of the RNA polymerase II carboxyl-terminal domain (pSer2-RNAP2). As previously shown, potent and selective inhibition of CDK9 by AZD4573 results in reduction of pSer2-RNAP2 levels leading to preferential depletion of labile proteins, including the Bcl2 family anti-apoptotic proteins Mcl1 and Bfl1 (as well as other known oncoproteins like Myc). This in turn drives rapid induction of apoptosis in a broad range of preclinical cancer models, particularly those derived from hematologic malignancies (Cidado et al 2020). Here, we used 7 MCL cell lines and 1 PDX organoid to assess the rapid apoptogenic potential of AZD4573 in vitro. Cleaved caspase-3 (CC3), a hallmark of apoptosis, was measured immediately following acute treatment (6h) using Caspase-Glo 3/7. Four models were sensitive to CDK9 inhibition (EC 50 & lt; 100nM; max. CC3 & gt; 50%) while 1 cell line exhibited intermediate sensitivity (EC 50 & lt; 100nM; max. CC3 & lt; 50%) and 3 others were resistant (EC 50 & gt; 100nM; max. CC3 & lt; 50%). Regardless of sensitivity, AZD4573 caused a dose- and time-dependent reduction of pSer2-RNAP2, Mcl1, and Myc, consistent with our prior reports. Most MCL cell lines are not responsive to BTK inhibition and, therefore, did not show combination benefit with AZD4573. We, therefore, chose to evaluate the in vivo activity of AZD4573 +/- acalabrutinib in 3 disseminated r/r MCL PDX models. In DFBL-44685, an acalabrutinib-unresponsive model harboring a CARD11 mutation, AZD4573 showed moderate activity, reducing MCL cells in all compartments analyzed (peripheral blood, bone marrow, and spleen) by & gt;40% two weeks into treatment and increasing overall survival benefit (P & lt;0.01). In an acalabrutinib-responsive MCL PDX, DFBL-96069, the combination of AZD4573 with acalabrutinib reduced tumor burden in all compartments analyzed by & gt;80% and significantly increased survival over vehicle as well as monotherapy treatments (P & lt;0.001). The third model, DFBL-98848, expresses high Bfl1. In this model, AZD4573 monotherapy reduced disease burden in all compartments analyzed by & gt;50% and significantly increased survival over vehicle (P & lt;0.001). Additionally, AZD4573 plus acalabrutinib further reduced disease burden and increased survival in this model compared to AZD4573 alone, although this did not reach statistical significance. Our findings show that targeting CDK9 with AZD4573 can effectively induce apoptosis in a range of MCL cell lines and PDX models, including acalabrutinib-sensitive and -insensitive models as well as those expressing high levels of Bfl1. In 3 r/r MCL PDX models, single agent AZD4573 significantly reduced the tumor burden in the peripheral blood, bone marrow, and spleen of the affected mice, resulting in increased survival. Combination of AZD4573 with acalabrutinib resulted in greater anti-tumor activity than either monotherapy. Altogether, these data suggest that AZD4573, alone or in combination with acalabrutinib, could be an effective therapy for patients with r/r MCL. Figure 1 Figure 1. Disclosures Boiko: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Andersen: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Liang: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Dowdell: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Reimer: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Drew: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Townsley: AstraZeneca: Current Employment, Current equity holder in publicly-traded company. Cidado: AstraZeneca: Current Employment, Current equity holder in publicly-traded company.
    Materialart: Online-Ressource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2021-151725
    RVK:
    XA 33000
    RVK:
    XA 10000
    Sprache: Englisch
    Verlag: American Society of Hematology
    Publikationsdatum: 2021
    ZDB Id: 1468538-3
    ZDB Id: 80069-7
    Standort Signatur Einschränkungen Verfügbarkeit
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