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  • 1
    Online Resource
    Online Resource
    Abstract 1750: Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1750-1750
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 1750-1750
    Abstract: Our ongoing efforts to validate kinases for cancer therapy led to the novel finding that ectopic expression of JAK2 and Aurora A together is more effective than each alone at inducing normal cells to grow in an anchorage-independent manner and to invade. In addition, siRNA silencing or pharmacological inhibition of JAK2 and Aurora A with Ruxolitinib and Alisertib, respectively, is more effective than blocking each kinase alone at suppressing anchorage-dependent and -independent growth and invasion as well as at inducing apoptosis. This led us to develop dual Aurora and JAK inhibitors, AJI-214 and AJI-100, which potently inhibit the activities of Aurora A, Aurora B and JAK2 in vitro. In human cancer cells, these dual inhibitors block the auto-phosphorylation of Aurora A (Thr-288) and the phosphorylation of the Aurora B substrate histone H3 (Ser-10) and the JAK2 substrate STAT3 (Tyr-705). Furthermore, AJI-214 and AJI-100 inhibit anchorage dependent and independent cell growth and invasion and induce G2/M cell cycle accumulation and apoptosis. Finally, the more soluble AJI-100 was effective at inducing tumor regression of human xenografts in mice. Taken together, our genetic and pharmacological studies indicate that targeting Aurora A and JAK2 together is a more effective approach than each alone at inhibiting malignant transformation and warrant further advanced pre clinical investigations of dual Aurora A/JAK2 inhibitors as potential anti tumor agents. Citation Format: Said M. Sebti, Hua Yang, Harshani Lawrence, Aslamuzzaman Kazi, Harsukh Gervaria, Ronil Patel, Yunting Luo, Uwe Rix, Ernst Schonbrunn, Nicholas Lawrence. Combined blockade of Aurora A and JAK2 kinase is highly effective at inhibiting malignant transformation. [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 1750. doi:10.1158/1538-7445.AM2014-1750
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-1750
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 2
    Online Resource
    Online Resource
    Abstract 1362: Discovery of a novel structural class of compounds: HLM-030376 and its analogs as potent chymotrypsin-like proteasome inhibitors
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1362-1362
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1362-1362
    Abstract: The ubiquitin-proteasome pathway plays a critical role in the regulated degradation of proteins involved in cell cycle control and tumor growth. Proteasome inhibitors cause selective apoptosis of malignant cells and represent a new class of antineoplastic agents. In 2003 Bortezomib (peptide boronate), a proteasome inhibitor was approved by FDA for treatment of multiple myeloma. Toxicity and tumor cell resistance against Bortezomib demand development of less toxic proteasome inhibitors with broader spectrum of tumor activity. Our aim is to develop non-peptidic small drug-like molecules as proteasome inhibitors. To this end, we have identified through in-house screening efforts HLM-030376 as a small molecule proteasome inhibitor with phenanthridine pharmacophore. HLM-030376 showed in-vitro chymotrypsin like, trypsin like and PGPH inhibitory activities with IC50 values 0.26, 0.19 and 2.07 µM respectively. Extensive synthetic modifications around the HLM-030376 pharmacophore were undertaken to aid the cell activity of this class of compounds. We will describe the synthesis and activity of analogs of HLM-030376 as potent proteasome inhibitors. The analogs of HLM-030376 showed in-vivo CT-L inhibitory activities (IC50 between 0.6-6.0 µM) against MDA-MB 468 breast cancer cell line as well as improved (IC50 between 70-200 nM) in-vitro CT-L inhibitory activities. The detailed in-vitro structure activity relationship (SAR) data of HLM-030376 and analogs will be discussed to understand the structural moieties responsible for proteasome activity. The whole cell activity data of HLM-030376 as well as in-silico docking studies will be presented as potential proteasome inhibitors for further development. 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 1362. doi:10.1158/1538-7445.AM2011-1362
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1362
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 3
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    Online Resource
    Abstract B35: Dual inhibitors of FT and GGT-1 as novel therapeutic agents for K-Ras-dependent tumors
    American Association for Cancer Research (AACR) ; 2014
    In:  Molecular Cancer Research Vol. 12, No. 12_Supplement ( 2014-12-01), p. B35-B35
    Details
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 12_Supplement ( 2014-12-01), p. B35-B35
    Abstract: Inhibition of mutant H-Ras farnesylation with farnesyltransferase inhibitors (FTIs) blocks its binding to membranes and its ability to activate oncogenic signaling. In contrast, inhibition of K-Ras farnesylation with FTIs leads to its prenylation by geranylgeranyltransferase I (GGT-1), and therefore, inhibition of K-Ras prenylation and oncogenic function requires blocking both FT and GGT-1. Furthermore, several proteins downstream of K-Ras that mediate its malignant transforming activity also require farnesylation (e.g.Rheb) or gernaylgeranylation (e.g. Ral). In addition, the ability of mutant K-Ras to induce lung cancer in mouse models is severely hampered when both FT and GGT-1 are conditionally deficient. These observations prompted us to design small molecule dual FT and GGT-1 inhibitors. In this presentation, the development of FGTI-2734 as a novel therapeutic for K-Ras dependent cancers will be described. The presentation will focus on the effect of this dual inhibitor as compared to the selective FTI-2148 and GGTI-2418 on K-ras prenylation, oncogenic signaling and malignant transformation in cancer cells that depend on K-Ras. Citation Format: Kazi Aslamuzzaman, Xiaolei Zhang, Yunting Luo, Ronil Patel, Steven Fletcher, Christopher Cummings, Harshani Lawrence, Andrew Hamilton, Said M. Sebti. Dual inhibitors of FT and GGT-1 as novel therapeutic agents for K-Ras-dependent tumors. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B35. doi: 10.1158/1557-3125.RASONC14-B35
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    URL: Article
    DOI: 10.1158/1557-3125.RASONC14-B35
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
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    Phase II Trial of Tipifarnib plus Neoadjuvant Doxorubicin-Cyclophosphamide in Patients with Clinical Stage IIB-IIIC Breast Cancer
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 8 ( 2009-04-15), p. 2942-2948
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 8 ( 2009-04-15), p. 2942-2948
    Abstract: Purpose: Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified. Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (α = 0.05, β = 0.10). Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01). Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-2658
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 5
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    Online Resource
    Association of mitochondrial calpain activation with increased expression and autolysis of calpain small subunit in an early stage of apoptosis
    Spandidos Publications ; 2003
    In:  International Journal of Molecular Medicine ( 2003-08-01)
    Details
    In: International Journal of Molecular Medicine, Spandidos Publications, ( 2003-08-01)
    Type of Medium: Online Resource
    ISSN: 1107-3756 , 1791-244X
    URL: Journal
    URL: Article
    DOI: 10.3892/ijmm
    DOI: 10.3892/ijmm.12.2.247
    Language: Unknown
    Publisher: Spandidos Publications
    Publication Date: 2003
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  • 6
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    Online Resource
    CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Immunology Research Vol. 9, No. 1 ( 2021-01-01), p. 62-74
    Details
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 9, No. 1 ( 2021-01-01), p. 62-74
    Abstract: An obstacle to the development of chimeric antigen receptor (CAR) T cells is the limited understanding of CAR T-cell biology and the mechanisms behind their antitumor activity. We and others have shown that CARs with a CD28 costimulatory domain drive high T-cell activation, which leads to exhaustion and shortened persistence. This work led us to hypothesize that by incorporating null mutations of CD28 subdomains (YMNM, PRRP, or PYAP), we could optimize CAR T-cell costimulation and enhance function. In vivo, we found that mice given CAR T cells with only a PYAP CD28 endodomain had a significant survival advantage, with 100% of mice alive after 62 days compared with 50% for mice with an unmutated endodomain. We observed that mutant CAR T cells remained more sensitive to antigen after ex vivo antigen and PD-L1 stimulation, as demonstrated by increased cytokine production. The mutant CAR T cells also had a reduction of exhaustion-related transcription factors and genes such as Nfatc1, Nr42a, and Pdcd1. Our results demonstrated that CAR T cells with a mutant CD28 endodomain have better survival and function. This work allows for the development of enhanced CAR T-cell therapies by optimizing CAR T-cell costimulation.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    URL: Article
    DOI: 10.1158/2326-6066.CIR-20-0253
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Online Resource
    The GTPase KRAS suppresses the p53 tumor suppressor by activating the NRF2-regulated antioxidant defense system in cancer cells
    Elsevier BV ; 2020
    In:  Journal of Biological Chemistry Vol. 295, No. 10 ( 2020-03), p. 3055-3063
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 295, No. 10 ( 2020-03), p. 3055-3063
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.RA119.011930
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
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    SSG: 12
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  • 8
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    Online Resource
    Discovery of PI-1840, a Novel Noncovalent and Rapidly Reversible Proteasome Inhibitor with Anti-tumor Activity
    Elsevier BV ; 2014
    In:  Journal of Biological Chemistry Vol. 289, No. 17 ( 2014-04), p. 11906-11915
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 289, No. 17 ( 2014-04), p. 11906-11915
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.M113.533950
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
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    detail.hit.zdb_id: 1474604-9
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  • 9
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    Online Resource
    Mutation of the CD28 Co-Stimulatory Domain Confers Enhanced CAR T Cell Function
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 248-248
    Details
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 248-248
    Abstract: An obstacle with continued clinical development of CAR T cells is the limited understanding of their biology and mechanisms of anti-tumor immunity. We and others have shown that CARs with a CD28 co-stimulatory domain drive high levels of T cell activation that also lead to exhaustion and shortened persistence. The CD28 domain includes 3 intracellular subdomains (YMNM, PRRP, and PYAP) that regulate signaling pathways post TCR-stimulation, but it is unknown how they modulate activation and/or exhaustion of CAR T cells. A detailed understanding of the mechanism of CD28-dependent exhaustion in CAR T cells will allow the design of a CAR less prone to exhaustion and reduce relapse rates. This led us to hypothesize that by incorporating null mutations of CD28 subdomains (Fig 1A) we could optimize CAR T cell signaling and reduce exhaustion. In vitro, we found mutated CAR T cells with only a functional PYAP (mut06) subdomain secrete significantly less IFNγ, IL6, and TNFα after 24hr stimulation compared to non-mutated CD28 CAR T cells, but greater than the 1st generation m19z CAR. Also, cytotoxicity was enhanced compared to non-mutated CARs (Fig 1B). Using a pre-clinical immunocompetent mouse tumor model, we found the mut06 CAR T cell treated mice had a significant survival advantage compared to non-mutated CD28 CAR T cells (Fig 1C). To examine exhaustion, we ex vivo stimulated CAR T cells with target cells expressing CD19 and PDL1 and found mut06 CAR T cells had increased IFNγ (42%), TNFα (62%) and IL2 (73%) secretion compared to exhausted non-mutated CD28 CAR T cells. This suggests that mut06 CAR T cells are more resistant to exhaustion. To find a mechanistic explanation for this observation we examined CAR T cell signaling. After 24hr stimulation with CD19 target cells mut06 CAR T cells had a significant reduction in pAkt compared to m1928z CAR T cells, which is a critical signaling mediator in the NFAT and NR4A1 transcription factor pathways. Additionally, mut06 had decreased p-NFAT compared to m1928z when examined by western blot. To determine how optimized CAR signaling affected T cell exhaustion we looked at 22 genes that are upregulated when NFAT is constitutively active and overlap with genes identified as important for T cell exhaustion. We found that most of the exhaustion related genes were upregulated in m1928z CAR T cells while they were decreased in m19hBBz. The mut06 CAR T cell gene expression pattern was more similar to m19hBBz with exhaustion related genes downregulated compared to m1928z (Fig 1D). To examine differences in the accessibility of exhaustion related genes we performed ATAC-seq and found NFAT (Nfatc1) and NR4A2 (Nr4a2) had lower chromatin accessibility profiles in mut06 compared to m1928z (Fig 1E). We also found that exhaustion related genes Havcr2 (TIM3), Pdcd1 (PD1), and Lag3 (LAG3) all had greatly reduced chromatin accessibility in mut06 CAR T cells compared m1928z. Overall, these genomic studies support our findings that mut06 optimizes CAR T cell signaling by lowering transcription factors that regulate exhaustion. Figure 1 Disclosures Li: ImmuneBro Therapeutics: Other: sole shareholder . Davila:Atara: Research Funding; Celgene: Research Funding; GlaxoSmithKline: Consultancy; Novartis: Research Funding; Anixa: Consultancy; Bellicum: Consultancy; Adaptive: Consultancy; Precision Biosciences: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2019-122954
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
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  • 10
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    Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers
    Elsevier BV ; 2023
    In:  iScience Vol. 26, No. 3 ( 2023-03), p. 106082-
    Details
    In: iScience, Elsevier BV, Vol. 26, No. 3 ( 2023-03), p. 106082-
    Type of Medium: Online Resource
    ISSN: 2589-0042
    URL: Article
    DOI: 10.1016/j.isci.2023.106082
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
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