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  • 1
    In: Cell Cycle, Informa UK Limited, Vol. 16, No. 19 ( 2017-10-02), p. 1790-1799
    Type of Medium: Online Resource
    ISSN: 1538-4101 , 1551-4005
    Language: English
    Publisher: Informa UK Limited
    Publication Date: 2017
    detail.hit.zdb_id: 2102687-7
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  • 2
    In: Oncogenesis, Springer Science and Business Media LLC, Vol. 10, No. 5 ( 2021-05-14)
    Abstract: Salivary gland cancers (SGCs) are rare yet aggressive malignancies with significant histological heterogeneity, which has made prediction of prognosis and development of targeted therapies challenging. In majority of patients, local recurrence and/or distant metastasis are common and systemic treatments have minimal impact on survival. Therefore, identification of novel targets for treatment that can also be used as predictors of recurrence for multiple histological subtypes of SGCs is an area of unmet need. In this study, we developed a novel transgenic mouse model of SGC, efficiently recapitulating the major histological subtype (adenocarcinomas of the parotid gland) of human SGC. CDK2 knock out (KO) mice crossed with MMTV-low molecular weight forms of cyclin E (LMW-E) mice generated the transgenic mouse models of SGC, which arise in the parotid region of the salivary gland, similar to the common site of origin seen in human SGCs. To identify the CDK2 independent catalytic partner(s) of LMW-E, we used LMW-E expressing cell lines in mass spectrometric analysis and subsequent biochemical validation in pull down assays. These studies revealed that in the absence of CDK2, LMW-E preferentially binds to CDK5. Molecular targeting of CDK5, using siRNA, resulted in inhibition of cell proliferation of human SGCs overexpressing LMW-E. We also provide clinical evidence of significant association of LMW-E/CDK5 co-expression and decreased recurrence free survival in human SGC. Immunohistochemical analysis of LMW-E and CDK5 in 424 patients representing each of the four major histological subtypes of human salivary cancers (Aci, AdCC, MEC, and SDC) revealed that LMW-E and CDK5 are concordantly (positive/positive or negative/negative) expressed in 70% of these patients. The co-expression of LMW-E/CDK5 (both positive) robustly predicts the likelihood of recurrence, regardless of the histological classification of these tumors. Collectively, our results suggest that CDK5 is a novel and targetable biomarker for the treatment of patients with SGC presenting with LMW-E overexpressing tumors.
    Type of Medium: Online Resource
    ISSN: 2157-9024
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2674437-5
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  • 3
    Online Resource
    Online Resource
    F1000 Research Ltd ; 2014
    In:  F1000Research Vol. 3 ( 2014-8-19), p. 198-
    In: F1000Research, F1000 Research Ltd, Vol. 3 ( 2014-8-19), p. 198-
    Type of Medium: Online Resource
    ISSN: 2046-1402
    Language: English
    Publisher: F1000 Research Ltd
    Publication Date: 2014
    detail.hit.zdb_id: 2699932-8
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  • 4
    In: Neoplasia, Elsevier BV, Vol. 20, No. 1 ( 2018-01), p. 80-91
    Type of Medium: Online Resource
    ISSN: 1476-5586
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 2008231-9
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  • 5
    In: Neoplasia, Elsevier BV, Vol. 23, No. 3 ( 2021-03), p. 304-325
    Type of Medium: Online Resource
    ISSN: 1476-5586
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2008231-9
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  • 6
    In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 5237-5237
    Abstract: ONC201/TIC10 is a potent small molecule anti-tumor agent in several types of solid tumors and lymphomas. ONC201/TIC10 is on track to enter clinical trials for patients with advanced cancer in 2014, with IND issued by the FDA in March, 2014. Early trials will evaluate the safety and efficacy of ONC201/TIC10 as a monoagent in hematological malignancies. In the current study, we evaluated the anti-cancer effects of the small molecule in Acute Lymphoblastic Leukemia (ALL). Analysis of cell viability by the CellTiter-Glo method revealed that ONC201/TIC10 treatment reduces the viability of three ALL cell lines (Reh, Jurkat, MOLT-4) in a dose- (2.5/5/10 μM) and time-dependent manner (24/48/72 h). We have previously reported that ONC201/TIC10-mediated reduction in cell viability and apoptosis in various types of solid tumors occurs at 60/72 h. Interestingly, ONC201/TIC10 reduces the viability of ALL cell lines within 24/48 h at the indicated doses. An inactive TIC10 isomer compound synthesized by Medkoo Biosciences with a structure related to the active ONC201/TIC10 compound does not reduce the viability of ALL cells. Sub-G1 analysis indicated that ONC201/TIC10 induces apoptosis in ALL cells and a pan-caspase inhibitor reduces ONC201/TIC10-mediated apoptosis. Western blot analysis was used to further investigate the mechanism of ONC201/TIC10-mediated apoptosis. ONC201/TIC10-mediated apoptosis involves PARP cleavage and caspase-9 activation. Anti-apoptotic Bcl-2 family members Bcl-2 and Bcl-xl are downregulated while the pro-apoptotic Bcl-2 family member Bim is upregulated in response to ONC201/TIC10 treatment. ONC201/TIC10 also downregulates the inhibitor of apoptosis (IAP) family proteins cIAP1 and cIAP2. We have previously shown that the anti-tumor effect of ONC201/TIC10 involves inhibition Akt and ERK phosphorylation resulting in Foxo3a activation and TRAIL-gene transcription. We observed inhibition of Akt phosphorylation upon ONC201/TIC10 treatment of ALL cells. Thus, ONC201/TIC10 holds promise as a novel agent for the treatment of ALL based on its robust activity in preclinical models of the disease. Our ongoing studies are evaluating the impact of this novel therapy on ALL cells with different translocations, and are introducing combination therapy with ONC201/TIC10 for ALL. Figure 1 Figure 1. Disclosures Allen: Oncoceutics: Employment, Equity Ownership, Patents & Royalties. El-Deiry:Oncoceutics, Inc.: Equity Ownership, Patents & Royalties.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1215-1215
    Abstract: Tumor suppressor p53 is frequently mutated or inactivated in colorectal cancer while p53 family member p73 is rarely mutated in cancer cells. Small molecules that activate p73 can elicit a p53-like tumor suppressive function and represent a novel approach for p53 pathway restoration. Colorectal tumors contain a small population of cancer stem cells (CSCs) capable of self-renewal that contributes to tumor maintenance and resistance to therapy. Targeting CSCs could improve treatment response and prolong patient survival. We have previously shown that small molecule Prodigiosin restores the p53 pathway via activation of p73 and inhibition of the mutant p53-p73 interaction (Hong et al., Cancer Research 74:1153-1165, 2014). We now demonstrate that prodigiosin targets 5-Fluorouracil-resistant CSCs along with bulk tumor cells. Prodigiosin prevents colonosphere formation of CRC cell lines independent of p53 status of the cells. Prodigiosin reduces the viability of both CSCs and non-CSCs while 5-Fluorouracil only targets non-CSCs. Prodigiosin significantly reduces the growth of xenograft tumors initiated in mice with CSCs without toxic effects and prevents the passage of these tumors. In a p53-reponsive luciferase reporter assay, prodigiosin induces p53-pathway transcription in colonospheres and CSC-initiated xenograft tumors. Stable shRNA knockdown of p73 revealed that prodigiosin inhibits the self-renewal of CSCs in a p73-dependent manner. Next, we explored the mechanisms of prodigiosin-mediated p53-pathway restoration and anti-CSC effects upstream of p73 activation. The oncogenic N-terminally truncated isoform ΔNp73 is a dominant negative inhibitor of p73 and p53. ΔNp73 levels correlate with poor overall survival in colorectal cancer patients. Western blot analysis revealed that prodigiosin increases protein levels of p73 and its target genes and reduces levels of the oncogenic isoform ΔNp73. Prodigiosin has been previously shown to increase the expression of c-Jun, a member of the AP-1 family of transcription factors. c-Jun is known to regulate the induction of p73 and degradation of ΔNp73 in response to cellular stress. We hypothesized that prodigiosin mediated p53-pathway restoration involves c-Jun upregulation resulting in ΔNp73 inhibition and p73 activation. Western blot analysis revealed that prodigiosin induces levels of c-Jun and phospho-c-Jun. siRNA knockdown of c-Jun protein levels reduced prodigiosin-mediated ΔNp73 downregulation. Thus, we have characterized a previously unrecognized mechanism of prodigiosin-mediated p73 activation via c-Jun-dependent ΔNp73 inhibition. Ongoing experiments involve further validation of the mechanism by studying the effects of c-Jun knockdown and ΔNp73 overexpression on Prodigiosin-mediated effects on apoptosis, CSC self-renewal and p53 pathway restoration. Citation Format: Varun Vijay Prabhu, Shengliang Zhang, Bo Hong, Joshua E. Allen, Amriti Lulla, David T. Dicker, Wafik S. El-Deiry. Small molecule Prodigiosin-mediated p53 pathway restoration and inhibition of self-renewal in colorectal cancer involves c-Jun-mediated ΔNp73 inhibition and p73 activation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1215. doi:10.1158/1538-7445.AM2015-1215
    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: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1020-1020
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 1020-1020
    Abstract: The development of novel agents including the proteasome inhibitor bortezomib (Btz) has significantly improved treatment outcomes in multiple myeloma (MM). Despite these advances, resistance to therapy invariably emerges and MM remains an incurable disease. The objective of this study was to identify new therapeutic agents and combinations with the ability to overcome resistance to Btz in MM cells. We developed a high throughput drug screening (HTS) assay system to discover small molecules that selectively target Btz resistant MM cells as single agents and/or re-sensitize resistant cells to Btz. For HTS we used isogenic pairs of Btz sensitive (595 P) and resistant (595 VR) cells derived from iMycCα/Bcl-xL transgenic mouse model of MM. Cell viability was the HTS assay read-out, and 3 treatment groups (595 P, 595 VR, and 595 VR + Btz) were included to identify compounds with selective activity against Btz resistant cells as single agents, and compounds that restore Btz sensitivity in the presence of Btz. Our screening of multiple publically-available compound libraries identified several chemical structures with selective activity against Btz resistant cells. One compound in particular showed modest but significant selectivity for Btz resistant cells as a single agent, and most notably, exhibited potent Btz re-sensitizing activity when the 2 drugs were combined. We named this compound Velcade Re-sensitizing Compound 2, or VRC-2 for short. The Btz re-sensitizing activity of VRC-2 was confirmed using multiple human and mouse cell lines that had been selected for Btz resistance in vitro. IC50s for VRC-2 in normal mouse and human fibroblasts were 100-fold higher than that observed in MM cells, suggesting it may have a low toxicity profile in vivo. We are currently evaluating the activity of VRC-2 in animal models of MM, alone and in combination with Btz, and conducting molecular studies to identify its precise mechanism of action. This study establishes the proof-of-principal for our HTS approach and demonstrates the potential of VRC-2 in Btz refractory MM. Citation Format: Amriti Lulla, Holly Stessman, David Dicker, Brian Van Ness, Wafik El-Deiry, Nathan G. Dolloff. VRC2, a novel bortezomib re-sensitizing compound for the treatment of multiple myeloma. [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 1020. doi:10.1158/1538-7445.AM2013-1020
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1825-1825
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 1825-1825
    Abstract: Prostate cancer is the most common cancer and the second leading cause of cancer related death among men in the United States. Current therapy for advanced prostate cancer is mainly based on androgen deprivation, though in many cases tumors become androgen-independent and resistant to available treatments. Thus, accessing novel therapies for prostate cancer and resistant tumors remains an important goal in the field. ONC201 is a first-in-class small molecule anti-cancer drug, shown to selectively induce cell death in most cancer cells tested in contrast to matched normal cells. In this study we investigated the single-agent and combination efficacy of ONC201 on a panel of prostate cancer cell lines with varied androgen receptor (AR) and receptor tyrosine kinases (RTKs) expression status. Our preliminary data suggests that the pro-apoptotic effects of ONC201 correlate with expression of androgen receptor and other receptor tyrosine kinases (RTKs). Specifically, high AR and low RTK (c-MET, EGFR, HER2 and IGFR) expression demonstrated higher sensitivity to ONC201 as compared to low AR and high RTK expression as evaluated by cell viability using the Cell-Titer Glo assay. We further modeled these findings in ONC201-sensitive 22Rv1 and ONC201-resistant DU145 cell lines. ONC201 induced robust apoptosis (cleaved PARP) in ONC201-sensitive 22Rv1 cells as compared to ONC201-resistant DU145 cells In addition, ONC201-sensitive 22RV1 cells showed abrogation of total AR expression 72 hours following treatment with ONC201. Thus, AR and RTK status seem to be emerging efficacy markers for response of ONC201 in prostate cancer cells. We are further investigating the involvement of ONC201 in the signal transduction pathway of AR and other RTKs in prostate cancer. Lastly, our initial screening for treatment of cells with a combination of ONC201 and FDA-approved therapies for prostate cancer showed synergistic potential of ONC201 with everolimus and docetaxel in both AR-dependent and independent cells. As expected, synergism of anti-androgen MDV3100 (enzalutamide) with ONC201 was restricted to AR positive prostate cancer cell lines. Our results indicate that ONC201 has therapeutic potential both as a single agent and in combination therapy for prostate cancer. Our long-term goal is to integrate our pre-clinical studies and translate the findings to single agent/combination trials of ONC201 for prostate cancer patients. Citation Format: Avital Lev, Amriti R. Lulla, David T. Dicker, Wafik S. El-Deiry. ONC201 induces cell death in androgen receptor positive prostate cancer cells and shows synergistic effect with anti-prostate cancer drugs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1825.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 10
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Molecular Cancer Research Vol. 16, No. 5 ( 2018-05-01), p. 754-766
    In: Molecular Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 5 ( 2018-05-01), p. 754-766
    Abstract: Androgen receptor (AR) signaling plays a key role in prostate cancer progression, and androgen deprivation therapy (ADT) is a mainstay clinical treatment regimen for patients with advanced disease. Unfortunately, most prostate cancers eventually become androgen-independent and resistant to ADT with patients progressing to metastatic castration-resistant prostate cancer (mCRPC). Constitutively activated AR variants (AR-V) have emerged as mediators of resistance to AR-targeted therapy and the progression of mCRPC, and they represent an important therapeutic target. Out of at least 15 AR-Vs described thus far, AR-V7 is the most abundant, and its expression correlates with ADT resistance. ONC201/TIC10 is the founding member of the imipridone class of small molecules and has shown anticancer activity in a broad range of tumor types. ONC201 is currently being tested in phase I/II clinical trials for advanced solid tumors, including mCRPC, and hematologic malignancies. There has been promising activity observed in patients in early clinical testing. This study demonstrates preclinical single-agent efficacy of ONC201 using in vitro and in vivo models of prostate cancer. ONC201 has potent antiproliferative and proapoptotic effects in both castration-resistant and -sensitive prostate cancer cells. Furthermore, the data demonstrate that ONC201 downregulates the expression of key drivers of prostate cancer such as AR-V7 and downstream target genes including the clinically used biomarker PSA (KLK3). Finally, the data also provide a preclinical rationale for combination of ONC201 with approved therapeutics for prostate cancer such as enzalutamide, everolimus (mTOR inhibitor), or docetaxel. Implications: The preclinical efficacy of ONC201 as a single agent or in combination, in hormone-sensitive or castration-resistant prostate cancer, suggests the potential for immediate clinical translation. Mol Cancer Res; 16(5); 754–66. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1541-7786 , 1557-3125
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2097884-4
    SSG: 12
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