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  • American Association for Cancer Research (AACR)  (20)
  • 1
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 12 ( 2018-12-01), p. 1548-1565
    Abstract: Malignant pleural mesothelioma (MPM) is a highly lethal cancer of the lining of the chest cavity. To expand our understanding of MPM, we conducted a comprehensive integrated genomic study, including the most detailed analysis of BAP1 alterations to date. We identified histology-independent molecular prognostic subsets, and defined a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity. We also report strong expression of the immune-checkpoint gene VISTA in epithelioid MPM, strikingly higher than in other solid cancers, with implications for the immune response to MPM and for its immunotherapy. Our findings highlight new avenues for further investigation of MPM biology and novel therapeutic options. Significance: Through a comprehensive integrated genomic study of 74 MPMs, we provide a deeper understanding of histology-independent determinants of aggressive behavior, define a novel genomic subtype with TP53 and SETDB1 mutations and extensive loss of heterozygosity, and discovered strong expression of the immune-checkpoint gene VISTA in epithelioid MPM. See related commentary by Aggarwal and Albelda, p. 1508. This article is highlighted in the In This Issue feature, p. 1494
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2106-2106
    Abstract: Introduction: Hepatocellular Carcinoma (HCC) is considered a prototype of inflammation-derived cancer arising from chronic liver injury. The cellular composition of the HCC tumor immune microenvironment (TiME) has a major impact on cancer biology as the TiME can influence tumor initiation, progress, and response to therapy. Mucosal-associated invariant T (MAIT) cells can represent the most abundant T cell subtype in the human liver and have been found to be impaired in both number and function in liver cancer. These innate-like T cells are assigned crucial roles in regulating immunity and inflammation in the context of infection, albeit their role in HCC remains elusive. Methods: High-dimensional flow cytometry was used to analyze MAIT cell phenotypic changes in murine and human liver cancer. Highly multiplexed immunofluorescence microscopy was used to quantify immune cell infiltration in primary human HCC samples. We developed and validated a comprehensive 37-plex antibody panel for immunofluorescence imaging of human fresh frozen HCC samples. We applied co-detection by indexing (CODEX) technology to simultaneously profile in situ expression of 37 proteins at sub-cellular resolution in 15 HCC patient samples using whole slide scanning. Initial image analysis was performed using HALO quantitative image analysis software. Finally, we established an image analysis pipeline to quantify the MAIT cell interaction network at the HCC invasive front. Results: Profiling of human and murine HCC using flow cytometry and highly multiplexed CODEX imaging revealed substantial dysregulation/aberrant activation of MAITs in liver cancer. In situ phenotyping of 4,500,000 single cells (including 1,500,000 CD45+ immune cells) allowed for the quantification of 20 distinct immune cell phenotype clusters, differential analysis of activation markers and spatial features of each individual cell. CODEX imaging revealed detailed composition of the MAIT cell niche in human liver cancer tissue allowing for further distinct spatial analysis including infiltration and nearest-neighbor analysis. Importantly, flow cytometry data of paired samples correlated well with image-based immune phenotyping. Beyond that, whole slide imaging revealed spatial relationships and interactions within the MAIT cell hub localized in distinct tissue regions. Conclusion: Here, we demonstrate that spatially resolved, single-cell analysis of human liver cancer tissue allows for in-depth characterization of interacting immune cellular programs underlying MAIT cell dysfunction in HCC. Citation Format: Benjamin Ruf, Noemi Kedei, Matthias Bruhns, Sepideh Babaei, Bernd Heinrich, Varun Subramanyam, Chi Ma, Simon Wabitsch, Benjamin Green, Kylynda C. Bauer, Yuta Myojin, Jonathan Qi, Amran Nur, Justin McCallen, Layla Greten, William G. Telford, Merrill K. Stovroff, Kesha Oza, Jiman Kang, Alexander Kroemer, Manfred Claassen, Firouzeh Korangy, Tim F. Greten. Spatially resolved immune cell atlas of human liver cancer identifies the cellular interaction network underlying mucosal-associated invariant T (MAIT) cell dysfunction in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2106.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 2582-2582
    Abstract: Background: Checkpoint blockade immunotherapy (CBI) can induce a durable response for some patients with hepatic tumors, but many derive no or incomplete oncologic benefit for unclear reasons. Regulatory T cells (Tregs) in the liver play a central role in maintaining the tolerogenic local immune environment, both in homeostasis and disease. Here we sought to explore the impact of CBI on hepatic Tregs to determine if they play a role in CBI resistance of liver tumors in mice. Methods: High-dimensional flow cytometry was used to examine the ex vivo characteristics of lymphocytes from both tumor-free and orthotopic tumor-bearing livers of mice treated with CBI or other immunomodulatory agents. Results: All hepatic T cell subsets examined displayed higher proliferative and apoptotic indices compared with those of splenic T lymphocytes. We found that hepatic Tregs intensely proliferate and undergo apoptosis compared with splenic Tregs under homeostatic conditions. Hepatic Treg proliferation was enhanced after administration of CBI treatment. This effect was abrogated by co-treatment with sirolimus. CD8, macrophages, and the gut microbiome were found to be dispensable for the in vivo in response to αPD1. Co-treatment of mice with αPD1 and αCD25 sensitized MC38-bearing liver tumors. Conclusion: Murine liver Tregs naturally proliferate and undergo apoptosis due to the mTOR rheostat at homeostasis making them highly responsive to CBI. This behavior potentially explains liver-specific CBI-resistance in tumors. Citation Format: Benjamin L. Green, Chi Ma, Qianfei Zhang, Benjamin Ruf, Umberto Rosato, Jonathan Qi, Simon Wabitsch, Kylynda Bauer, Yuta Myojin, Justin McCallen, John C. McVey, Varun Subramanyam, Vanessa Catania, Amran Nur, Firouzeh Korangy, Changqing Xie, Tim F. Greten. Regulatory T cells restrain efficacy of immunotherapy in murine liver tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2582.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 4
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    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1372-1372
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. 1372-1372
    Abstract: Background: Liver cancer is a leading cause of cancer-related deaths. Non-alcoholic fatty liver disease (NAFLD) has become a burgeoning etiology of liver cancer. Emerging data shows that NAFLD alters adaptive T cell immunity and has a profound influence on both liver cancer development and efficacy of immunotherapy. Tumor antigen-specific T cells recognize tumor and are crucial for controlling malignancy. However, their populations are often low, and detection requires special tools. This study utilized a novel mouse model of HCC to investigate how the tumor antigen-specific T cell response is affected in NAFLD. Methods: We generated a doxycycline-inducible MHC-I OVA257-264 and MHC-II OVA323-339 antigen-expressing HCC cell line which allowed us to investigate tumor antigen-specific T cell responses. The cell line was seeded orthotopically into the livers of diet-induced (methionine choline-deficient [MCD]) and genetic (Ob/Ob [Ob] ) NAFLD mouse models. OVA257-264 specific CD8+ T cells were detected by flow cytometry using H-2Kb/OVA257-264 tetramer. Pharmacological depletion experiments were used to identify additional effector cells. Results: The creation of an inducible MHC-I and -II OVA antigen-expressing HCC cell line was validated in both in-vitro and in-vivo settings. Tumor expression of highly immunogenic OVA antigens caused a strong tumor suppression which was mostly mediated by CD8+ T cells in mice fed with normal diet. The inverse correlation between percentage of OVA257-264 specific CD8+ T cells with tumor size further supported their critical role in tumor control. In contrast, in NAFLD mice fed MCD diet as well as Ob/Ob mice, tumor OVA antigens induction failed to reduce liver tumor growth. The presence of OVA257-264 specific CD8+ T cells in NAFLD mice suggested that NAFLD did not inhibit the generation of tumor antigen-specific T cells. This was supported by the finding that OVA257-264 specific CD8+ T cells from NAFLD mice had similar cytotoxic potential, activation, degranulation, PD-1 expression, and effector memory phenotype compared to controls, suggesting an indirect mechanism for the impaired anti-tumor immunity. Immunoprofiling revealed a drastic increase of macrophages in tumor-bearing NAFLD livers. Depletion of macrophages with clodronate reversed the NAFLD caused resistance to tumor-antigen dependent tumor suppression. It was observed that there were minimal changes to the amount of TAS CD8+ T cells in doxycycline-treated mice irrespective of clodronate depletion. There was, however, higher markers of activation such as CD69 and TNFα in clodronate-depleted mice compared to controls. Conclusions: NAFLD impairs antigen-specific CD8+ T cell immunity against liver tumor. The effect was not due to reduced generation or intrinsic functional changes of tumor antigen-specific CD8+ T cells but caused by accumulated macrophages in the liver environment. Citation Format: John C. McVey, Benjamin L. Green, Benjamin Ruf, Tim F. Greten, Chi Ma. Macrophages impair antigen specific CD8+ T cell response against HCC in NAFLD mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1372.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 21 ( 2020-11-01), p. 4840-4853
    Abstract: Src homology 2 domain-containing phosphatase (SHP2) is a phosphatase that mediates signaling downstream of multiple receptor tyrosine kinases (RTK) and is required for full activation of the MAPK pathway. SHP2 inhibition has demonstrated tumor growth inhibition in RTK-activated cancers in preclinical studies. The long-term effectiveness of tyrosine kinase inhibitors such as the EGFR inhibitor (EGFRi), osimertinib, in non–small cell lung cancer (NSCLC) is limited by acquired resistance. Multiple clinically identified mechanisms underlie resistance to osimertinib, including mutations in EGFR that preclude drug binding as well as EGFR-independent activation of the MAPK pathway through alternate RTK (RTK-bypass). It has also been noted that frequently a tumor from a single patient harbors more than one resistance mechanism, and the plasticity between multiple resistance mechanisms could restrict the effectiveness of therapies targeting a single node of the oncogenic signaling network. Here, we report the discovery of IACS-13909, a specific and potent allosteric inhibitor of SHP2, that suppresses signaling through the MAPK pathway. IACS-13909 potently impeded proliferation of tumors harboring a broad spectrum of activated RTKs as the oncogenic driver. In EGFR-mutant osimertinib-resistant NSCLC models with EGFR-dependent and EGFR-independent resistance mechanisms, IACS-13909, administered as a single agent or in combination with osimertinib, potently suppressed tumor cell proliferation in vitro and caused tumor regression in vivo. Together, our findings provide preclinical evidence for using a SHP2 inhibitor as a therapeutic strategy in acquired EGFRi-resistant NSCLC. Significance: These findings highlight the discovery of IACS-13909 as a potent, selective inhibitor of SHP2 with drug-like properties, and targeting SHP2 may serve as a therapeutic strategy to overcome tumor resistance to osimertinib.
    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: 2020
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  • 6
    In: Cancer Discovery, American Association for Cancer Research (AACR), Vol. 8, No. 9 ( 2018-09-01), p. 1112-1129
    Abstract: Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective, and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient–derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we found that PDO therapeutic profiles paralleled patient outcomes and that PDOs enabled longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Significance: New approaches to prioritize treatment strategies are urgently needed to improve survival and quality of life for patients with pancreatic cancer. Combined genomic, transcriptomic, and therapeutic profiling of PDOs can identify molecular and functional subtypes of pancreatic cancer, predict therapeutic responses, and facilitate precision medicine for patients with pancreatic cancer. Cancer Discov; 8(9); 1112–29. ©2018 AACR. See related commentary by Collisson, p. 1062. This article is highlighted in the In This Issue feature, p. 1047
    Type of Medium: Online Resource
    ISSN: 2159-8274 , 2159-8290
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PD6-06-PD6-06
    Abstract: Background and Purpose:Early and accurate assessment ofbreast cancer response to NAST is important for patient management. In this study, we investigated the value of radiomic phenotypes derived from semi-quantitative and quantitative DCE-MRI parametric maps for early prediction of NASTresponse in TNBC patients. MATERIALS AND METHODS:This IRB approved study included 74 patients with stage I-III TNBC who were enrolled in the prospective ARTEMIS trial (NCT02276443). Pathologic complete response (pCR) and non-pCR were assessed by surgical histopathology after NAST (pCR=34; non-pCR=40).MRI scans were obtained at 3 time points during the NAST treatment with every 2-week anthracycline-based chemotherapy (AC): at baseline (BSL=74), post-2 cycles of AC (C2= 27) and post-4 cycles of AC (C4= 27). Patients went on to receive taxane-based chemotherapy prior to surgery. Tumor regions of interest (ROIs) were segmented by a breast radiologist at the early-phase subtractions of DCE-MRI scans using in-house developed software, followed by co-registration of the ROIs with quantitative (Ktrans, Veand Kep), and semi-quantitative DCE parametric maps (Maximum Slope Increase (MSI), Positive Enhancement Integral (PEI) and Peak Signal Enhancement Ratio (SER)).A total of 93 first order radiomic features were extracted from the tumor ROIs of each time point semi-quantitative DCE parametric map, while a total of 390 extracted radiomic features (first order-histogram features and second order grey-level-co-occurrence matrix) were extracted from each quantitative DCE parametric map using an in-house developed Matlab software.Radiomic features at each time point and changes between the 3 time points were compared between pCR and non-pCR using Wilcoxon Rank Sum test and Fisher’s exact test. Area under the receiver operating characteristics curve (AUC) was used to determine which features predicted pCR.Logistic regression was performed for feature selection, and used to build the radiomic phenotype model. The model performance was assessed by leave-one-out cross validation and 3-fold cross validation. RESULTS:Thirty-three radiomic features from PEI map were significantly different between pCR and non-pCR. The PEI most significant features were changesbetween BSL and C4 in skewness, mean and median (AUC=0.87, 0.85 and 0.87, p= & lt;0.001, 0.001 and 0.002 respectively). Additionally, 31 MSI features were significantly different between pCR and non-pCR. The top 2 features were the interscan-change in skewness between BSL and C2 (AUC=0.80, P=0.007) and C4 standard deviation (AUC=0.80, P=0.006). Four BSL Veradiomic features were statistically significant between pCR and non-pCR with the best being range of difference variance (AUC=0.64, P=0.03). One BSL Kepfeature (Angular-Variance of Information measure of correlation-2) was able to differentiate pCR from non-pCR (AUC=0.64, P=0.04). Five C4-Ktrans features were able to differentiate pCR and non-pCR, with the most significant being mean value (AUC=0.86, P=0.001). BSL-Kepradiomic model built from 24 features (AUC=0.80, p=0.003) and combined (Ktrans, Veand Kep)C2-radiomic model consisting of 20 features (AUC=0.97, p=0.01) showed the best performance for prediction of pCR. CONCLUSIONS:Radiomic phenotypes form DCE-MRI parametric maps were useful for differentiation between pCR and non-pCR and showed promise as noninvasive imaging biomarkers for early prediction of NAST response in TNBC. Potentially, DCE-MRI radiomic features may be used for development of diagnostic predictive model for early noninvasive assessment of NAST treatment response in TNBC patients. Citation Format: Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Abeer H Abdelhafez, Benjamin C Musall, Jia Sun, Medine Boge, Rania M.M Mohamed, Hagar S Mahmoud, Jong Bum Son, Aikaterini Kotrosou, Shu Zhang, Jessica Leung, Deanna Lane, Marion Scoggins, David Spak, Elsa Arribas, Lumarie Santiago, Gary J. Whitman, Huong T Le-Petross, Tanya W Moseley, Jason B White, Elizabeth Ravenberg, Ken-Pin Hwang, Peng Wei, Jennifer K Litton, Lei Huo, Debu Tripathy, Vicente Valero, Alastair M Thompson, Stacy Moulder, Wei T Yang, Mark D Pagel, Jingfei Ma, Gaiane M Rauch. Radiomic phenotypes from dynamic contrast-enhanced MRI (DCE-MRI) parametric maps for early prediction of response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-06.
    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: 2021
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  • 8
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 19, No. 4 ( 2013-02-15), p. 900-908
    Abstract: Purpose: Increased mitogenic signaling and angiogenesis, frequently facilitated by somatic activation of EGF receptor (EGFR; ErbB1) and/or loss of PTEN, and VEGF overexpression, respectively, drive malignant glioma growth. We hypothesized that patients with recurrent glioblastoma would exhibit differential antitumor benefit based on tumor PTEN/EGFRvIII status when treated with the antiangiogenic agent pazopanib and the ErbB inhibitor lapatinib. Experimental Design: A phase II study evaluated the antitumor activity of pazopanib 400 mg/d plus lapatinib 1,000 mg/d in patients with grade 4 malignant glioma and known PTEN/EGFRvIII status not receiving enzyme-inducing anticonvulsants (EIAC). The phase II study used a two-stage Green–Dahlberg design for futility. An independent, parallel phase I component determined the maximum-tolerated regimen (MTR) of pazopanib and lapatinib in patients with grade 3/4 glioma receiving EIACs. Results: The six-month progression-free survival (PFS) rates in phase II (n = 41) were 0% and 15% in the PTEN/EGFRvIII-positive and PTEN/EGFRvIII-negative cohorts, respectively, leading to early termination. Two patients (5%) had a partial response and 14 patients (34%) had stable disease lasting 8 or more weeks. In phase I (n = 34), the MTR was not reached. On the basis of pharmacokinetic and safety review, a regimen of pazopanib 600 mg plus lapatinib 1,000 mg, each twice daily, was considered safe. Concomitant EIACs reduced exposure to pazopanib and lapatinib. Conclusions: The antitumor activity of this combination at the phase II dose tested was limited. Pharmacokinetic data indicated that exposure to lapatinib was subtherapeutic in the phase II evaluation. Evaluation of intratumoral drug delivery and activity may be essential for hypothesis-testing trials with targeted agents in malignant glioma. Clin Cancer Res; 19(4); 900–8. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 9
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 11 ( 2009-06-01), p. 3820-3826
    Abstract: Purpose: Cytogenetic abnormalities are currently the most important predictors of response and clinical outcome for patients with acute myeloid leukemia (AML) or advanced-stage myelodysplastic syndrome (MDS). Because clinical outcomes vary markedly within cytogenetic subgroups, additional biological markers are needed for risk stratification. Experimental Design: We assessed the utility of measuring pretreatment proteasome chymotrypsin-like, caspase-like, and trypsin-like activities in plasma to predict response and survival of patients with AML (n = 174) or advanced-stage MDS (n = 52). Results: All three enzymatic activities were significantly (P & lt; 0.001) increased in the plasma of patients with AML and MDS compared with normal controls. Both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, correlated with outcome. Chymotrypsin-like and caspase-like activities, but not trypsin-like activity, predicted response in univariate analysis (P = 0.002). However, only chymotrypsin-like activity was independent predictor of response from age grouping ( & lt;70 versus ≥70 years), cytogenetics, and blood urea nitrogen in multivariate analysis. Similarly, both chymotrypsin-like and caspase-like activities, but not trypsin-like activity, were predictors of overall survival in univariate analysis (P & lt; 0.0001), but only chymotrypsin-like activity was independent of cytogenetics, age, performance status, blood urea nitrogen, and β2-microglobulin in multivariate Cox regression models. Chymotrypsin-like activity was also a strong independent predictor of survival in patients with intermediate karyotype (n = 124). Conclusions: Measuring plasma chymotrypsin-like activity may provide a powerful biomarker for risk stratification in patients with AML and advanced-stage MDS, including those with normal karyotype.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 10
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2351-2351
    Abstract: CDK4 is a cyclin D dependent kinase that promotes cell cycle progression in a broad range of tumor types by phosphorylating the tumor suppressor retinoblastoma protein (Rb) and releasing transcription factor E2F. Critical involvement of the cyclin D-CDK4-Rb pathway in carcinogenesis is strongly supported by a large amount of genetic evidence. In addition, promoter methylation with consequent silencing of expression of the CDK4 inhibitor, p15, has been reported in 44-60% of acute myeloid leukemia (AML) patients. It is also well established that constitutive activation of the tyrosine kinase FLT3 via mutation contributes to the development of AML, with 30% of AML carrying such activating mutations. FLT3 tyrosine kinase inhibitors used as single agents reduce peripheral blood and bone marrow blasts in only a minority of AML patients, and the effect tends to be transient. This may be due to insufficient FLT3 inhibition, the selection of drug-resistant clones, or the independence of the cell on FLT3 signaling for proliferation and survival. In preclinical models, a synergistic effect of CDK4 inhibition and FLT3 inhibition resulting in increased apoptosis of AML cell lines was reported (Wang et al., Blood, 2007). From a HTS hit through SAR optimization led to AM-5992, a potent and orally bioavailable dual inhibitor of CDK4 and FLT3 including all FLT3 mutants reported to date. AM-5992 inhibits the proliferation of a panel of human tumor cell lines including MDA-MB-435(Rb+), colo-205(Rb+), U937(FLT3WT) and induced cell death in MOLM13(FLT3ITD), MV4-11(FLT3ITD), and even in MOLM13(FLT3ITD, D835Y) which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. In mouse models of leukemia using cells with the FLT3ITD mutation, AM-5992 treatment at 150 mpk qd on days 6-16 after leukemia cell injection significantly reduced the leukemia burden and prolonged survival 11 days over that of vehicle controls. Collectively, these data support the hypothesis that simultaneously inhibition of CDK4 and FLT3 may improve the durability of clinical response in AML; and consequently that this hypothesis should be tested in the clinic. Citation Format: Zhihong Li, Kang Dai, Kathleen Keegan, Ji Ma, Mark Ragains, Jacob Kaizerman, Dustin McMinn, Jiasheng Fu, Benjamin Fisher, Michael Gribble, Lawrence R. McGee, John Eksterowicz, Cong Li, Lingming Liang, Margaret Weidner, Justin Huard, Robert Cho, Timothy Carlson, Grace M. Alba, David Hollenback, John Hill, Darrin Beaupre, Alexander Kamb, Dineli Wickramasinghe, Julio C. Medina. CDK4/FLT3 dual inhibitors as potential therapeutics for acute myeloid leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2351. doi:10.1158/1538-7445.AM2013-2351
    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: 2013
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