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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: 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
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    detail.hit.zdb_id: 410466-3
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  • 3
    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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  • 4
    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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  • 5
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2017
    In:  Cancer Research Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2154-2154
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 77, No. 13_Supplement ( 2017-07-01), p. 2154-2154
    Abstract: We recently reported that P01 is a potent p53 pathway-restoring small molecule that acts through increasing levels of TAp73. Further, it also interferes with the p73-mutant p53 protein-protein interaction and by downregulation of ΔNp73 (Tian, Zhang and El-Deiry, abstract# 3830, AACR 2016). P01 is a member of the natural products that have been shown to have potent anti-cancer activity against tumors with mutated p53. Based on the structure of the pharmacophore of compound P01, we designed and synthesized new analogs based on published structure-activity relationship and organic synthesis papers. The newly synthesized analogs were potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines such as HT29, SW480, DLD-1, MDA-MB-231and H1975 with EC50s in the range of 0.16 μM to 0.26 μM. We are currently evaluating the anti-cancer effects of three analogs P301, P304 and P306, of which only two of these analogs induce TAp73 as assayed by western blot. We are currently characterizing the analog P306, which is the most potent compound among them. P306 engages the apoptosis pathway by upregulation of pro-apoptotic proteins like PUMA, DR5, and BIM and downregulation of anti-apoptotic markers such as Mcl-1 in a time-and dose-dependent manner in colorectal cancer cell lines. P306 treatment also downregulates both mRNA and protein level of MET and EGFR in HT29 cells that overexpress MET and EGFR receptors. We are currently investigating the mechanisms of induction of both PUMA and DR5 in mutant p53 cells and determining whether either gene is necessary for the apoptotic effects of P306 in colorectal cancer cells. Our preliminary data indicates that upregulation of DR5 is through the ATF4/CHOP pathway post-P306 treatment. It has been reported that Puma is a target gene of ATF4, CHOP and p73, however, we found that none of them is responsible for P306-induced upregulation of PUMA in p53 mutated DLD1, SW480 or HCT116 p53-null cell lines. Thus, our ongoing in vitro studies are focused on further understanding the mechanism of action of P306 in mutant p53 cells and potentially exploring combinations with FDA-approved therapies. We are also in the process of conducting, first-in animal studies of P306 as single agent or in combination with chemotherapy or targeted therapy. Citation Format: Xiaobing Tian, Shengliang Zhang, Amriti Lulla, wafik S. El-Deiry. P53 pathway restoring compound P306 inhibits colorectal cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2154. doi:10.1158/1538-7445.AM2017-2154
    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: 2017
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 10 ( 2018-05-15), p. 2770-2771
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 10 ( 2018-05-15), p. 2770-2771
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 7
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3954-3954
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 3954-3954
    Abstract: The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or anti-angiogenesis processes. Over 50% of human cancers harbor cancer-causing mutations in p53. p53 mutations not only abrogate its tumor-suppressor function, but also endow mutant p53 with a gain of function (GOF), creating a proto-oncogene that contributes to tumorigenesis, tumor progression, and chemo- or radiotherapy resistance. Thus, targeting mutant p53 and/or restoring a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We previously showed that P01, a natural product, has potent anti-cancer activity against tumors with mutated p53. Based on the structure of the pharmacophore of the P01 family, we designed and synthesized new analogues. The novel synthetic analogue, P306, is potent in reducing both short-term and long-term proliferation in a broad panel of mutant p53 cell lines, including HT29, SW480, DLD-1, MDA-MB-231, MDA-MB-468, U251, FaDu, CAL-27, PANC-1, ASPC-1 and H1975, with IC50 values in the range of 33.9 to 242 nM. In this study, we have characterized a distinct mechanism of P306 that engages the apoptosis pathway by upregulating pro-apoptotic proteins including PUMA in a time-and dose-dependent manner in colorectal cancer cell lines. PUMA is necessary for the apoptotic effects of P306 in colorectal cancer cells with PUMA-mediated caspase 8 activation mediating P306-induced apoptosis. P306 not only restores p53 pathway but also depletes mutant p53 protein in various mutant p53-expressing cancer cells regardless of what kinds of mutation. P306 treatment potently downregulates c-Myc protein level, and apoptosis induced by P306 is dependent on the c-Myc-PUMA pathway. Our results provide novel mechanistic insights into the tumor cell death promoting activity of a candidate therapeutic agent for cancer. Citation Format: Xiaobing Tian, Amriti R. Lulla, Shengling Zhang, Avital Lev, Philip Abbosh, Rahmat Sikder, David T. Dicker, Wafik S. El-Deiry. Anti-cancer agent P306 restores p53 pathway through PUMA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3954.
    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: 2018
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), ( 2023-10-5)
    Abstract: Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways by NE. These NE-regulated pathways are critical for cell-to-cell contact and motility and consistent with the delay in metastasis in NE-/- mice. To evaluate whether pharmacological inhibition of NE inhibited pulmonary metastasis and phenotypically mimicked PyMT NE-/- mice, we utilized AZD9668, a clinically available and specific NE inhibitor. We found AZD9668 treated PyMT-NE+/+ mice showed significantly reduced lung metastases, improved recurrence-free, metastasis-free and overall survival, and their tumors showed similar molecular alterations as those observed in PyMT-NE-/- tumors. Lastly, we identified a NE-specific signature that predicts recurrence and metastasis in breast cancer patients. Collectively, our studies suggest that genetic ablation and pharmacological inhibition of NE reduces metastasis and extends survival of mouse models of breast cancer, providing rationale to examine NE inhibitors as a treatment strategy for the clinical management of metastatic breast cancer patients.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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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:
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    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
    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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