Publications by authors named "Lanlan Zhou"

46 Publications

MEK inhibitors reduce cellular expression of ACE2, pERK, pRb while stimulating NK-mediated cytotoxicity and attenuating inflammatory cytokines relevant to SARS-CoV-2 infection.

Oncotarget 2020 11 17;11(46):4201-4223. Epub 2020 Nov 17.

Brown Experimentalists Against COVID-19 (BEACON) Group, Brown University, Providence, RI 02912, USA.

COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. In serum-deprived and stimulated cells treated with remdesivir and MEKi we observed correlations between pRB, pERK, and ACE2 expression further supporting role of proliferative state and MAPK pathway in ACE2 regulation. We show elevated cytokines in COVID-19-(+) patient plasma ( = 9) versus control ( = 11). TMPRSS2, inflammatory cytokines G-CSF, M-CSF, IL-1α, IL-6 and MCP-1 are suppressed by MEKi alone or with remdesivir. We observed MEKi stimulation of NK-cell killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. Pseudotyped SARS-CoV-2 virus with a lentiviral core and SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope infected human bronchial epithelial cells, small airway epithelial cells, or lung cancer cells and MEKi suppressed infectivity of the pseudovirus. We show a drug class-effect with MEKi to stimulate NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells. MEKi may attenuate SARS-CoV-2 infection to allow immune responses and antiviral agents to control disease progression.
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http://dx.doi.org/10.18632/oncotarget.27799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679035PMC
November 2020

Tandem reassembly of split luciferase-DNA chimeras for bioluminescent detection of attomolar circulating microRNAs using a smartphone.

Biosens Bioelectron 2021 Feb 18;173:112824. Epub 2020 Nov 18.

College of Life Sciences, South-Central University for Nationalities, Wuhan, 430074, PR China. Electronic address:

Detection of dysregulated circulating microRNAs (miRNAs) in human biofluids is a fundamental ability to determine tumor occurrence and metastasis in a minimally invasive fashion. However, the requirements for sophisticated instruments and professional personnel impede the translation of miRNA tests into routine clinical diagnostics, especially for resource-limited regions. Herein, we developed a DNA-guided bioluminescence strategy for the detection of circulating miRNAs. In this strategy, a pair of split luciferase-DNA chimeras was constructed and integrated into the miRNA-triggered rolling circle amplification (RCA) process. The tandem reassembly of split luciferase-DNA chimeras on the RCA products elicited a turn-on bioluminescence response with ultrahigh signal-to-background (S/B) ratio. This strategy enabled smartphone-based assays for different miRNAs with attomolar sensitivity and single-base specificity, as demonstrated here for miR-21. miR-148b, and cel-miR-39. Further application of our approach to the clinical serum samples realized identification of dysregulated miR-21 and miR-148b in the lung cancer patients, showing a satisfactory agreement with the control assays performed with quantitative reverse transcription polymerase chain reaction (qRT-PCR). Therefore, the developed method possesses the benefits of high performance and reliability, offering a potential tool for implementing miRNA-based diagnosis in point-of-care (POC) settings.
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http://dx.doi.org/10.1016/j.bios.2020.112824DOI Listing
February 2021

TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic.

Oncotarget 2020 Oct 20;11(42):3753-3769. Epub 2020 Oct 20.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA.

ONC201 was initially identified as an inducer of cell death through the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway. The compound is currently being tested in patients with hematological malignancies and solid tumors, including those of the breast. We investigated strategies to convert the response of breast cancers to ONC201 from anti-proliferative to apoptotic. ONC201 treatment upregulates TRAIL and primes TRAIL-resistant non-triple negative breast cancer (TNBC) cells to undergo cell death through the extrinsic pathway. Remarkably, the addition of exogenous recombinant human TRAIL (rhTRAIL) converts the response of TRAIL-resistant non-TNBC cells to ONC201 from anti-proliferative to apoptotic in a death receptor 5 (DR5)-dependent manner . Importantly, normal fibroblasts do not undergo apoptosis following rhTRAIL plus ONC201. , MDA-MB-361 tumor growth rate is significantly reduced following treatment with a combination of ONC201 and rhTRAIL as compared to control tumors. Natural killer (NK) cells which use TRAIL to kill DR5-expressing cancer cells, exhibit greater cytotoxicity against ONC201-treated breast cancer cells compared to controls. rhTRAIL also converts the response of cells from other tumor types to ONC201 from anti-proliferative to apoptotic. A monoclonal DR5-agonistic antibody converts the response of non-TNBC cells to ONC201 from anti-proliferative to apoptotic. Our findings describe a novel therapeutic strategy that potently converts the response of a cancer cell to ONC201 from anti-proliferative to apoptotic. This approach may be clinically relevant and has potential to induce tumor regression of patient tumors with relative resistance to ONC201 monotherapy.
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http://dx.doi.org/10.18632/oncotarget.27773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584235PMC
October 2020

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.

Neoplasia 2020 12 23;22(12):725-744. Epub 2020 Oct 23.

Warren Alpert Medical School, Brown University, 70 Ship Street, Room 537, Providence, RI 02912, USA. Electronic address:

ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.
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http://dx.doi.org/10.1016/j.neo.2020.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588802PMC
December 2020

First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2021 Mar 19;20(1):e43-e52. Epub 2020 Aug 19.

Fox Chase Cancer Center, Philadelphia, PA; Penn State Hershey Medical Center, Hershey, PA; The Warren Alpert Medical School, Providence, RI. Electronic address:

Background: Quinacrine plus a fluoropyrimidine has in vivo efficacy against metastatic colorectal cancer (mCRC). This phase 1b trial evaluated the combination of quinacrine plus capecitabine in patients with treatment-refractory mCRC.

Patients And Methods: Using a modified Simon accelerated titration design, adults with treatment-refractory mCRC were treated with capecitabine 1000 mg/m twice daily for 14/21-day cycle, and escalating doses of quinacrine 100 mg daily, 100 mg twice daily, and 200 mg twice daily for 21 days. The primary endpoint was identifying the maximum tolerated dose, determining tolerability and safety. In an expansion cohort, it was overall response rate and time to tumor progression (TTP).

Results: Ten patients (median age of 60 years) were treated in phase 1b. The first 2 quinacrine dosing levels were well tolerated. Dose-limiting toxicities were seen in 3 patients treated with quinacrine 200 mg twice daily. Five additional patients tolerated quinacrine 100 mg twice daily without further dose-limiting toxicities, thus establishing the maximum tolerated dose. Seven additional expansion-cohort patients enrolled onto the study before quinacrine manufacturing ceased within the United States. Five patients experienced stable disease, 1 partial response, and 10 disease progression. Median TTP overall was 2.12 months and median overall survival 5.22 months for the 17 patients.

Conclusion: Capecitabine and quinacrine can be safely administered at the maximum tolerated dose of capecitabine 1000 mg/m by mouth twice daily on days 1-14 and quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients. Although the expansion study was halted early, TTP was in line with other studies of refractory mCRC, suggesting activity of this regimen in heavily pretreated patients.
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http://dx.doi.org/10.1016/j.clcc.2020.08.003DOI Listing
March 2021

Correction: AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing.

Cell Death Discov 2020 7;6:71. Epub 2020 Aug 7.

Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI USA.

[This corrects the article DOI: 10.1038/s41420-020-0292-1.].
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http://dx.doi.org/10.1038/s41420-020-00310-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414103PMC
August 2020

Natural Killer cell activation, reduced ACE2, TMPRSS2, cytokines G-CSF, M-CSF and SARS-CoV-2-S pseudovirus infectivity by MEK inhibitor treatment of human cells.

bioRxiv 2020 Aug 3. Epub 2020 Aug 3.

COVID-19 affects vulnerable populations including elderly individuals and patients with cancer. Natural Killer (NK) cells and innate-immune TRAIL suppress transformed and virally-infected cells. ACE2, and TMPRSS2 protease promote SARS-CoV-2 infectivity, while inflammatory cytokines IL-6, or G-CSF worsen COVID-19 severity. We show MEK inhibitors (MEKi) VS-6766, trametinib and selumetinib reduce ACE2 expression in human cells. Chloroquine or hydroxychloroquine increase cleaved active SP-domain of TMPRSS2, and this is potentiated by MEKi. In some human cells, remdesivir increases ACE2-promoter luciferase-reporter expression, ACE2 mRNA and protein, and ACE2 expression is attenuated by MEKi. We show elevated cytokines in COVID-19- (+) patient plasma (N=9) versus control (N=11). TMPRSS2, inflammatory cytokines G-CSF, M- CSF, IL-1a, IL-6 and MCP-1 are suppressed by MEKi alone or in combination with remdesivir. MEKi enhance NK cell (but not T-cell) killing of target-cells, without suppressing TRAIL-mediated cytotoxicity. We generated a pseudotyped SARS-CoV-2 virus with a lentiviral core but with the SARS-CoV-2 D614 or G614 SPIKE (S) protein on its envelope and used VSV-G lentivirus as a negative control. Our results show infection of human bronchial epithelial cells or lung cancer cells and that MEKi suppress infectivity of the SARS-CoV-2-S pseudovirus following infection. We show a drug class-effect with MEKi to promote immune responses involving NK cells, inhibit inflammatory cytokines and block host-factors for SARS-CoV-2 infection leading also to suppression of SARS-CoV-2-S pseudovirus infection of human cells in a model system. MEKi may attenuate coronavirus infection to allow immune responses and antiviral agents to control COVID-19 disease progression and severity.
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http://dx.doi.org/10.1101/2020.08.02.230839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418728PMC
August 2020

AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing.

Cell Death Discov 2020 6;6:57. Epub 2020 Jul 6.

Joint Program in Cancer Biology, Brown University and Lifespan Health System, Providence, RI USA.

Oncogenic mouse double minute 2 homolog (MDM2) is an E3-ubiquitin ligase that facilitates proteasomal degradation of p53. MDM2 amplification occurs in cancer and has been implicated in accelerated tumor growth, known as hyper-progression, following immune-checkpoint therapy. MDM2 amplification also predicts poor response to immune-checkpoint inhibitors. We sought to evaluate the role of MDM2 in T-cell-mediated immune resistance. Ovarian clear cell carcinoma cell lines carrying wild-type p53 with low/high MDM2 expression were investigated in a T-cell co-culture system evaluating T-cell-mediated tumor killing. Targeting of MDM2 was achieved by siRNA transfection or a selective MDM2 inhibitor, AMG-232 and tumor cells were tested in the T-cell co-culture system. AMG-232 activated p53 signaling in cancer cells and relative resistance to AMG-232 was observed in high MDM2-expressing cell lines. Cell lines with high MDM2 expression were more resistant to T cell-mediated tumor killing. Targeting MDM2 by gene-silencing or pharmacological blockade with AMG-232 enhanced T-cell killing of cancer cells. AMG-232 potentiated tumor cell killing by T-cells in combination with anti-PD-1 antibody treatment, regardless of changes in PD-L1 expression. The AMG-232 was not toxic to the T-cells. MDM2 inhibition lowered expression of Interleukin-6, a pro-inflammatory pro-tumorigenic cytokine. Our data support targeting MDM2 in tumors with overexpression or amplification of MDM2 as a precision therapy approach to overcome drug resistance including hyper-progression in the context of immune checkpoint therapy.
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http://dx.doi.org/10.1038/s41420-020-0292-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338458PMC
July 2020

Ruxolitinib combined with doxorubicin, etoposide, and dexamethasone for the treatment of the lymphoma-associated hemophagocytic syndrome.

J Cancer Res Clin Oncol 2020 Nov 2;146(11):3063-3074. Epub 2020 Jul 2.

Department of Hematology, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangdong, China.

Purpose: Case reports suggest that ruxolitinib-containing treatment could increase the clinical response rate of patients with hemophagocytic syndrome (HPS). This study aimed to explore the effect of ruxolitinib-containing treatment for patients with lymphoma-associated hemophagocytic syndrome (LAHS).

Methods: This was a retrospective study of patients with LAHS hospitalized at the First Affiliated Hospital of Guangdong Pharmaceutical University between October 2017 and September 2019. Patients were treated with HLH-94 (etoposide and dexamethasone) or R-DED regimen (ruxolitinib, doxorubicin, etoposide, and dexamethasone). The clinical characteristics, treatment responses, and overall survival (OS) were compared. The patients were divided into the HLH-94 group (n = 34) and the R-DED group (n = 36).

Results: Compared with HLH-94, R-DED might effectively improve the clinical manifestations, including fever and splenomegaly in patients with LAHS, and control the systemic cytokine storm. The response rate at 2 weeks was 54.8% in the HLH-94 group, which was lower than in the R-DED group (83.3%) (p = 0.011). The OS was significantly prolonged in the R-DED group compared with the HLH-94 group (median, 5 vs. 1.5 months, p = 0.003). The multivariable analysis showed that lower IL-10 levels [hazard ratio (HR)] = 1.000, [95% confidence interval (CI)] 1.000-1.000, p = 0.012), R-DED regimen (HR = 0.196, 95% CI 0.084-0.457, p < 0.001), and non-NK/T-cell lymphoma (HR = 0.254, 95% CI 0.102-0.628, p = 0.003) were associated with better OS. The prognosis of patients with LAHS was generally poor.

Conclusion: Ruxolitinib can be combined with chemotherapy in HPS. It is feasible, with no early signals of increased toxicity.
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http://dx.doi.org/10.1007/s00432-020-03301-yDOI Listing
November 2020

Quassinoid analogs with enhanced efficacy for treatment of hematologic malignancies target the PI3Kγ isoform.

Commun Biol 2020 May 27;3(1):267. Epub 2020 May 27.

Departments of Otorhinolaryngology-Head and Neck Surgery, and Microbiology, and the Tumor Virology Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

Development of novel PI3K inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We investigated the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines. The results demonstrated that the PI3Kγ isoform was identified as a direct target of Brusatol, and inhibition was dramatically reduced on cells with lower PI3Kγ levels. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared comparable or superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. One unique analog had minimal toxicity to normal human cells and in a mouse model. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies.
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http://dx.doi.org/10.1038/s42003-020-0996-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253423PMC
May 2020

Portable and Field-Ready Detection of Circulating MicroRNAs with Paper-Based Bioluminescent Sensing and Isothermal Amplification.

Anal Chem 2019 12 11;91(23):14838-14841. Epub 2019 Nov 11.

Research Center for Micro/Nano System & Bionic Medicine, Institute of Biomedical & Health Engineering , Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences , Shenzhen 518055 , P. R. China.

We present a paper-based system that integrates bioluminescence resonance energy transfer (BRET) and isothermal amplification for the analysis of tumor-associated circulating microRNAs (miRNAs) in clinical serum samples. The analysis procedure could be easily accomplished with two pieces of functionalized paper and a low-cost smartphone-based device, which enables sequence-specific quantification of femtomolar miRNAs, without the need for tedious handling of aqueous reactions and operation of sophisticated equipment. Furthermore, the analytical performance of the proposed paper-based system was highly stable at room temperature, demonstrating its capability for cold-chain-free and remote deployment. These qualities highlight the practical utility of our method for the portable and field-ready miRNA diagnostic tests in resource-limited settings.
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http://dx.doi.org/10.1021/acs.analchem.9b04422DOI Listing
December 2019

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.

J Clin Invest 2018 06 30;128(6):2325-2338. Epub 2018 Apr 30.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program and Department of Hematology/Oncology.

ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.
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http://dx.doi.org/10.1172/JCI96711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5983321PMC
June 2018

Anti-tumor effects of ONC201 in combination with VEGF-inhibitors significantly impacts colorectal cancer growth and survival in vivo through complementary non-overlapping mechanisms.

J Exp Clin Cancer Res 2018 Jan 22;37(1):11. Epub 2018 Jan 22.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program and Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: Small molecule ONC201 is an investigational anti-tumor agent that upregulates intra-tumoral TRAIL expression and the integrated stress response pathway. A Phase I clinical trial using ONC201 therapy in advanced cancer patients has been completed and the drug has progressed into Phase II trials in several cancer types. Colorectal cancer (CRC) remains one of the leading causes of cancer worldwide and metastatic disease has a poor prognosis. Clinical trials in CRC and other tumor types have demonstrated that therapeutics targeting the vascular endothelial growth factor (VEGF) pathway, such as bevacizumab, are effective in combination with certain chemotherapeutic agents.

Methods: We investigated the potential combination of VEGF inhibitors such as bevacizumab and its murine-counterpart; along with other anti-angiogenic agents and ONC201 in both CRC xenograft and patient-derived xenograft (PDX) models. We utilized non-invasive imaging and immunohistochemistry to determine potential mechanisms of action.

Results: Our results demonstrate significant tumor regression or complete tumor ablation in human xenografts with the combination of ONC201 with bevacizumab, and in syngeneic MC38 colorectal cancer xenografts using a murine VEGF-A inhibitor. Imaging demonstrated the impact of this combination on decreasing tumor growth and tumor metastasis. Our results indicate that ONC201 and anti-angiogenic agents act through distinct mechanisms while increasing tumor cell death and inhibiting proliferation.

Conclusion: With the use of both a murine VEGF inhibitor in syngeneic models, and bevacizumab in human cell line-derived xenografts, we demonstrate that ONC201 in combination with anti-angiogenic therapies such as bevacizumab represents a promising approach for further testing in the clinic for the treatment of CRC.
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http://dx.doi.org/10.1186/s13046-018-0671-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778752PMC
January 2018

Platelet glycoprotein receptor Ib blockade ameliorates experimental cerebral ischemia-reperfusion injury by strengthening the blood-brain barrier function and anti-thrombo-inflammatory property.

Brain Behav Immun 2018 03 28;69:255-263. Epub 2017 Nov 28.

Department of Pharmacology, School of Basic Medical Science, Key Laboratory of Anti-inflammatory and Immunopharmacology, Ministry of Education, Anhui Medical University, Hefei 230032, PR China. Electronic address:

Blood-brain barrier (BBB) disruption, thrombus formation and immune-mediated inflammation are important steps in the pathophysiology of cerebral ischemia-reperfusion injury but are still inaccessible to therapeutic interventions. Recent studies have provided increasing evidence that blocking of platelet glycoprotein (GP) receptor Ib might represent a novel target in treating acute ischemic stroke. This research was conducted to explore the therapeutic efficacy and potential mechanisms of GPIbα inhibitor (anfibatide) in a model of brain ischemia-reperfusion injury in mice. Male mice underwent 90 min of right middle cerebral artery occlusion (MCAO) followed by 24 h of reperfusion. Anfibatide (1, 2, 4 ug/kg) or tirofiban were administered intravenously 1 h after reperfusion. The results showed that anfibatide could significantly reduce infarct volumes, increase the number of intact neuronal cells and improve neurobehavioral function. Moreover, anfibatide could reduce post ischemic BBB damage by attenuating increased paracellular permeability in the ischemia hemisphere significantly. Stroke-induced increases in activity and protein expression of macrophage-1 antigen (MAC-1) and P-selectin were also reduced by anfibatide intervention. Finally, anfibatide exerted antithrombotic effects upon stroke by decreased the number of microthrombi formation. This is the first demonstration of anfibatide's efficacy in protecting the BBB integrity and decreasing neutrophil inflammation response mediated by MAC-1 besides microthrombus formation inhibition in the brain during reperfusion. Anfibatide, as a promising anti-thrombo-inflammation agent, could be beneficial for the treatment of ischemic stroke.
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http://dx.doi.org/10.1016/j.bbi.2017.11.019DOI Listing
March 2018

Single agent and synergistic combinatorial efficacy of first-in-class small molecule imipridone ONC201 in hematological malignancies.

Cell Cycle 2018 19;17(4):468-478. Epub 2018 Feb 19.

a Oncoceutics, Inc. , Philadelphia , PA.

ONC201, founding member of the imipridone class of small molecules, is currently being evaluated in advancer cancer clinical trials. We explored single agent and combinatorial efficacy of ONC201 in preclinical models of hematological malignancies. ONC201 demonstrated (GI50 1-8 µM) dose- and time-dependent efficacy in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt's lymphoma, anaplastic large cell lymphoma (ALCL), cutaneous T-cell lymphoma (CTCL), Hodgkin's lymphoma (nodular sclerosis) and multiple myeloma (MM) cell lines including cells resistant to standard of care (dexamethasone in MM) and primary samples. ONC201 induced caspase-dependent apoptosis that involved activation of the integrated stress response (ATF4/CHOP) pathway, inhibition of Akt phosphorylation, Foxo3a activation, downregulation of cyclin D1, IAP and Bcl-2 family members. ONC201 synergistically reduced cell viability in combination with cytarabine and 5-azacytidine in AML cells. ONC201 combined with cytarabine in a Burkitt's lymphoma xenograft model induced tumor growth inhibition that was superior to either agent alone. ONC201 synergistically combined with bortezomib in MM, MCL and ALCL cells and with ixazomib or dexamethasone in MM cells. ONC201 combined with bortezomib in a Burkitt's lymphoma xenograft model reduced tumor cell density and improved CHOP induction compared to either agent alone. These results serve as a rationale for ONC201 single-agent trials in relapsed/refractory acute leukemia, non-Hodgkin's lymphoma, MM and combination trial with dexamethasone in MM, provide pharmacodynamic biomarkers and identify further synergistic combinatorial regimens that can be explored in the clinic.
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http://dx.doi.org/10.1080/15384101.2017.1403689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5927637PMC
September 2019

Circulating tumor cells: silent predictors of metastasis.

F1000Res 2017 14;6. Epub 2017 Aug 14.

Fox Chase Cancer Center, Philadelphia, PA, USA.

Circulating tumor cells (CTCs) were added to the arsenal of clinical testing in 2004 for three cancer types: metastatic breast, prostate, and colorectal cancer. CTCs were found to be an independent prognostic indicator of survival for these three diseases. Multiple enrichment/isolation strategies have been developed and numerous assay applications have been performed using both single and pooled captured/enriched CTCs. We have reviewed the isolation techniques and touched on many analyses. The true utility of a CTC is that it acts as a "silent" predictor of metastatic disease. The mere presence of a single CTC is an indication that disease has spread from the primary site. Comments and suggestions have been set forth for CTCs and cell-free DNA to be used as a screening panel for the early detection of disease recurrence and metastatic spread, providing the opportunity for early intervention with curative intent to treat metastatic disease.
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http://dx.doi.org/10.12688/f1000research.11313.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5558099PMC
August 2017

Analysis of Risk Factors of Peripherally Inserted Central Catheter Induced Catheter-related Infection in Patients with Leukemia.

Iran J Public Health 2017 Apr;46(4):485-490

Dept. of Neurosurgery, People's Hospital of Haiyang City, Haiyang, Shandong, China.

Background: Peripherally inserted central catheter (PICC) is commonly used in nursing for patients with leukemia. The purpose of this study was to investigate the risk factors of Catheter-related infection (CRI) in patients with leukemia and to provide some nursing strategies based on the results.

Methods: Clinical data from 140 patients with leukemia between May 2014 and July 2016 in Haiyang People's Hospital, China were retrospectively analyzed. We employed univariate analysis to explore the relationship of various factors, including leukemia types, puncture times, underlying diseases, Catheter indwelling time, hormones use, chemotherapy use, immune functions and seasons, with the incidence of CRI. Further, multivariate logistic regression analysis was conducted to identify the potential independent risk factors of CRI. Bacterial culture was performed for etiological detection.

Results: Among the 140 patients with leukemia, 25 cases were diagnosed as CRI, with the incidence of 17.9%. Univariate analysis showed that puncture times, underlying diseases, catheter indwelling time, hormones use, chemotherapy use, immune functions and seasons were significantly correlated with the incidence of CRI. Multivariate logistic regression analysis revealed that immune functions, puncture times and seasons were independent risk factors for CRI. Etiological bacterial culture detected 20 strains of bacteria (: n=10, : n=4, : n=2 and other species: n=4) in 25 cases diagnosed with CRI.

Conclusion: Based on risk factors of CRI and its etiological distribution, appropriate nursing measures can be taken to reduce the incidence of CRI in patients with leukemia.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5439037PMC
April 2017

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212.

Cell Cycle 2017 Oct 10;16(19):1790-1799. Epub 2017 May 10.

a Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Molecular Therapeutics Program, Department of Hematology/Oncology, Fox Chase Cancer Center , Philadelphia , PA , USA.

Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.
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http://dx.doi.org/10.1080/15384101.2017.1325046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628644PMC
October 2017

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia.

Cell Cycle 2017 Jun 9;16(12):1193-1200. Epub 2017 May 9.

a Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program , Fox Chase Cancer Center , Philadelphia , PA , USA.

Hypoxia is an inherent impediment to cancer therapy. Palbociclib, a highly selective inhibitor for CDK4/6, has been tested in numerous clinical trials and has been approved by the FDA. We previously reported that CDK inhibitors can destabilize HIF1α regardless of the presence of hypoxia and can sensitize tumor cells to TRAIL through dual blockade of CDK1 and GSK-3β. To translate this knowledge into a cancer therapeutic strategy, we investigated the therapeutic effects and molecular mechanisms of CDK inhibition against colon cancer cells under normoxia and hypoxia. We found that palbociclib sensitizes colon cancer cells to hypoxia-induced apoptotic resistance via deregulation of HIF-1α accumulation. In addition to inhibition of cell proliferation, we observed that palbociclib promotes colon cancer cell death regardless of the presence of hypoxia at a comparatively high concentration via regulating ERK/GSK-3β signaling and GSK-3β expression. Furthermore, palbociclib synergized with irinotecan in a variety of colon cancer cell lines with various molecular subtypes via deregulating irinotecan-induced Rb phosphorylation and reducing HIF-1α accumulation under normoxia or hypoxia. Collectively, our findings provide a novel combination therapy strategy against hypoxic colon cancer cells that may be further translated in the clinic.
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http://dx.doi.org/10.1080/15384101.2017.1320005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499912PMC
June 2017

Tissue TGF-β expression following conventional radiotherapy and pulsed low-dose-rate radiation.

Cell Cycle 2017 Jun 9;16(12):1171-1174. Epub 2017 May 9.

b Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program , Fox Chase Cancer Center , Philadelphia , Pennsylvania.

The release of inflammatory cytokines has been implicated in the toxicity of conventional radiotherapy (CRT). Transforming growth factor β (TGF-β) has been suggested to be a risk marker for pulmonary toxicity following radiotherapy. Pulsed low-dose rate radiotherapy (PLDR) is a technique that involves spreading out a conventional radiotherapy dose into short pulses of dose with breaks in between to reduce toxicities. We hypothesized that the more tolerable toxicity profile of PLDR compared with CRT may be related to differential expression of inflammatory cytokines such as TGF-β in normal tissues. To address this, we analyzed tissues from mice that had been subjected to lethal doses of CRT and PLDR by histology and immunohistochemistry (IHC). Equivalent physical doses of CRT triggered more cellular atrophy in the bone marrow, intestine, and pancreas when compared with PLDR as indicated by hematoxylin and eosin staining. IHC data indicates that TGF-β expression is increased in the bone marrow, intestine, and lungs of mice subjected to CRT as compared with tissues from mice subjected to PLDR. Our in vivo data suggest that differential expression of inflammatory cytokines such as TGF-β may play a role in the more favorable normal tissue late response following treatment with PLDR.
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http://dx.doi.org/10.1080/15384101.2017.1317418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499842PMC
June 2017

Left Ventricular Non-Compaction: A Cardiomyopathy With Acceptable Prognosis in Children.

Heart Lung Circ 2018 Jan 1;27(1):28-32. Epub 2017 Mar 1.

Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Mediacal College, Beijing 100037, China. Electronic address:

Background: Data on children with left ventricular non-compaction (LVNC) is sparse. The purpose of this study was to evaluate its clinical profiles in a population of Chinese children.

Methods: From January 2010 to March 2016, consecutive Chinese children (aged <18 years) with LVNC diagnosed by cardiovascular magnetic resonance (CMR) were prospectively recruited at Fuwai Hospital.

Results: A total of 41 Chinese children (male: 28%; mean age: 14±4years) were included in this study. Left ventricular non-compaction was not detected in 13 (32%) patients at initial echocardiographic evaluation. Congenital heart disease (CHD) was found in 11 (27%) patients. Four (10%) patients had Wolff-Parkinson-White (WPW) syndrome. Mean left ventricular ejection fraction (LVEF) was 41±15%. Late gadolinium enhancement (LGE) was detected in eight (20%) subjects. During a mean follow-up of 2.9 years, four (9%) patients died or received heart transplantation. These patients had lower systolic blood pressure (91±10 vs. 108±14mmHg; p=0.02), diastolic blood pressure (57±7 vs. 68±8mmHg; p=0.007) and LVEF (19±7 vs. 44±12%; p=0.002) than the survivors. In addition, advanced heart failure (100% vs. 16%; p=0.002) and LGE (50% vs. 5%; p=0.04) were detected more in these subjects.

Conclusions: Left ventricular non-compaction is easily overlooked at echocardiographic assessment. Congenital heart disease and WPW syndrome were relatively common in LVNC children. The prognosis of children with LVNC seemed to be better than previous studies reported, and its long-term prognosis needs to be further investigated.
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http://dx.doi.org/10.1016/j.hlc.2017.01.013DOI Listing
January 2018

Discovery and clinical introduction of first-in-class imipridone ONC201.

Oncotarget 2016 Nov;7(45):74380-74392

Fox Chase Cancer Center, Philadelphia, PA, USA.

ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.
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http://dx.doi.org/10.18632/oncotarget.11814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342060PMC
November 2016

Circulating Tumor Cells Versus Circulating Tumor DNA in Colorectal Cancer: Pros and Cons.

Curr Colorectal Cancer Rep 2016 Jun 7;12(3):151-161. Epub 2016 Apr 7.

Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) are emerging noninvasive multifunctional biomarkers in liquid biopsy allowing for early diagnosis, accurate prognosis, therapeutic target selection, spatiotemporal monitoring of metastasis, as well as monitoring response and resistance to treatment. CTCs and ctDNA are released from different tumor types at different stages and contribute complementary information for clinical decision. Although big strides have been taken in technology development for detection, isolation and characterization of CTCs and sensitive and specific detection of ctDNA, CTC-, and ctDNA-based liquid biopsies may not be widely adopted for routine cancer patient care until the suitability, accuracy, and reliability of these tests are validated and more standardized protocols are corroborated in large, independent, prospectively designed trials. This review covers CTC- and ctDNA-related technologies and their application in colorectal cancer. The promise of CTC-and ctDNA-based liquid biopsies is envisioned.
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http://dx.doi.org/10.1007/s11888-016-0320-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4976692PMC
June 2016

Type 2 diabetes mitigation in the diabetic Goto-Kakizaki rat by elevated bile acids following a common-bile-duct surgery.

Metabolism 2016 Feb 26;65(2):78-88. Epub 2015 Sep 26.

Key Laboratory of Human Functional Genomics of Jiangsu Province, Jiangsu Diabetes Center, Nanjing Medical University, Nanjing, Jiangsu, China. Electronic address:

Objective: Elevated plasma bile acids after bariatric surgery are thought to explain type 2 diabetes mellitus (T2DM) remission. Bile acids can bind to and activate the nuclear receptor farnesoid-X receptor (FXR) by regulating lipid and glucose metabolism. We performed a surgical procedure (ligation of the common bile duct and external biliary drainage [LBD]) in the diabetic Goto-Kakizaki (GK) rat in order to investigate its effect on bile acids metabolism and T2DM mitigation.

Material/methods: LBD surgery and sham control surgery were performed on diabetic GK rats. The concentrations of total bile acids and blood glucose were analyzed by an automatic analyzer. Intraperitoneal glucose tolerance test (IPGTT) and insulin tolerance test (ITT) were used to monitor blood glucose level. Expression of genes involved in bile acid metabolism (FXR, CYP7A, et al.) and glycolipid metabolism (G6Pase, PEPCK, et al) was analyzed using qRT-PCR. The protein levels of pAKT, AKT and pGSK3β were tested by western blot. The morphological alterations of the liver and epididymal fat were monitored by H&E staining.

Results: LBD increased plasma total bile acids, improved hepatic insulin sensitivity, and eventually mitigated T2DM, whereas food intake and body weight were unaltered. Post-LBD, the levels of total bile acids were elevated from 24.80±7.12 to 61.44±6.40 and the concentration of fast blood glucose was decreased from 204.7±11.06mg/dL to 109.3±5.4mg/dL. IPGTT and ITT showed that LBD operation improved insulin sensitivity in GK rats. Clusters of FXR signaling target genes were altered in the liver, such as FXR, CYP7A, G6Pase and PEPCK. These contributed to sustained bile acid homeostasis, and they ameliorated hepatic endoplasmic reticulum (ER) stress, increased energy expenditure, and reduced gluconeogenesis, resulting in a substantial improvement in hepatic insulin sensitivity. LBD also significantly reduced epididymal fat tissue and decreased the size of adipocytes.

Conclusion: These results demonstrate that the elevated bile acids observed in LBD-operated GK rats link insulin sensitivity improvement to T2DM mitigation, recapitulating the metabolic effects of bariatric surgery. Our investigation establishes a model for a focused study of bile acids in the context of bariatric surgery that may contribute to the identification of therapeutics for T2DM.
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http://dx.doi.org/10.1016/j.metabol.2015.09.014DOI Listing
February 2016

A multiplexed marker-based algorithm for diagnosis of carcinoma of unknown primary using circulating tumor cells.

Oncotarget 2016 Jan;7(4):3662-76

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Division of Hematology-Oncology, Penn State Hershey Cancer Institute, Hershey, PA, USA.

Real-time, single-cell multiplex immunophenotyping of circulating tumor cells (CTCs) is hypothesized to inform diagnosis of tissue of origin in patients with carcinoma of unknown primary (CUP). In 20 to 50% of CUP patients, the primary site remains unidentified, presenting a challenge for clinicians in diagnosis and treatment. We developed a post-CellSearch CTC assay using multiplexed Q-dot or DyLight conjugated antibodies with the goal of detecting multiple markers in single cells within a CTC population. We adapted our approach to size-based CTC enrichment protocols for capturing CTCs and subsequent immunofluorescence (IF) using a minimal set of markers to predict the primary sites for common metastatic tumors. The carcinomas are characterized with cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor 1 (TTF-1), estrogen receptor (ER) or prostate-specific antigen (PSA. IF has been optimized in cultured tumor cells with individual antibodies, then with conjugated antibodies to form a multiplex antibody set. With IF, we evaluated antibodies specific to these 5 markers in lung, breast, colorectal, and prostate cancer cell lines and blood from metastatic prostate and breast cancer patients. This advanced technology provides a noninvasive, diagnostic blood test as an adjunct to routine tissue biopsy. Its further implementation requires prospective clinical testing.
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http://dx.doi.org/10.18632/oncotarget.6657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4826160PMC
January 2016

Regorafenib with a fluoropyrimidine for metastatic colorectal cancer after progression on multiple 5-FU-containing combination therapies and regorafenib monotherapy.

Cancer Biol Ther 2015 ;16(12):1710-9

a Penn State College of Medicine and Penn State Hershey Cancer Institute ; Hershey , PA 17033 , USA.

We present 2 patients with metastatic colorectal cancer who had progressed despite treatment with first-line FOLFOX and second-line FOLFIRI combination chemotherapy regimens. After failing these fluoropyrimidine-based regimens, both patients received additional cytotoxic and targeted therapies with eventual disease progression. These therapies included capecitabine plus dabrafenib and trametinib, regorafenib monotherapy, and regorafenib with panitumumab. After exhausting available options, both patients were offered regorafenib with either 5-fluorouracil (5-FU) or capecitabine. These therapies are individually approved for the treatment of colorectal cancer but have not yet been studied in combination. This regimen produced stable disease in both patients with acceptable toxicity. One patient continued therapy for 17 months. Although these patients previously progressed during treatment with regorafenib, capecitabine or 5-FU, the combination had some activity in both cases of refractory metastatic colorectal cancer and may be considered in the palliative setting. In bedside-to-bench cell culture experiments performed after the clinical observations, we observed sensitivity of human colorectal cancer cell lines (N = 4) to single agent regorafenib or 5-FU and evidence of synergy with the combination therapy. Synergistic effects were noted in colorectal cancer cells with KRAS mutation, BRAF mutation, and p53 mutation, as well as mismatch repair deficient cells. Regorafenib suppressed Mcl-1 and Bcl-XL in treated cancer cells that may have contributed to the anticancer efficacy including in combination with 5-FU. The safety and efficacy of regorafenib with 5-FU or capecitabine in combination should be further investigated as a therapy for patients with refractory metastatic colorectal cancer, including individuals who had progressed on regorafenib monotherapy.
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http://dx.doi.org/10.1080/15384047.2015.1113355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847811PMC
October 2016

Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53.

Cancer Res 2015 Sep 20;75(18):3842-52. Epub 2015 Aug 20.

Penn State Hershey Cancer Institute, Hershey, Pennsylvania. Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

The tumor-suppressor p53 prevents cancer development via initiating cell-cycle arrest, cell death, repair, or antiangiogenesis processes. Over 50% of human cancers harbor cancer-causing mutant 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 to restore a wild-type p53 signaling pathway provides an attractive strategy for cancer therapy. We demonstrate that small-molecule NSC59984 not only restores wild-type p53 signaling, but also depletes mutant p53 GOF. NSC59984 induces mutant p53 protein degradation via MDM2 and the ubiquitin-proteasome pathway. NSC59984 restores wild-type p53 signaling via p73 activation, specifically in mutant p53-expressing colorectal cancer cells. At therapeutic doses, NSC59984 induces p73-dependent cell death in cancer cells with minimal genotoxicity and without evident toxicity toward normal cells. NSC59984 synergizes with CPT11 to induce cell death in mutant p53-expressing colorectal cancer cells and inhibits mutant p53-associated colon tumor xenograft growth in a p73-dependent manner in vivo. We hypothesize that specific targeting of mutant p53 may be essential for anticancer strategies that involve the stimulation of p73 in order to efficiently restore tumor suppression. Taken together, our data identify NSC59984 as a promising lead compound for anticancer therapy that acts by targeting GOF-mutant p53 and stimulates p73 to restore the p53 pathway signaling.
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http://dx.doi.org/10.1158/0008-5472.CAN-13-1079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573895PMC
September 2015

The relationship between clinical feature, complex immunophenotype, chromosome karyotype, and outcome of patients with acute myeloid leukemia in China.

Dis Markers 2015 7;2015:382186. Epub 2015 Apr 7.

Hematology Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China ; Hematology Department, Kanghua Hospital, Dongguan 523080, China.

Mixed phenotype acute leukemia (MPAL) is a complex entity expressing both lymphoid and myeloid immunophenotyping. In the present study, 47 MPAL, 60 lymphoid antigen-positive acute myeloid leukemia (Ly(+)AML), and 90 acute myeloid leukemia with common myeloid immunophenotype (Ly(-)AML) patients were investigated. We found that, in MPAL patients, there were high proportions of blast cells in bone marrow and incidence of hepatosplenomegaly, lymphadenopathy, and Philadelphia chromosome. The overall survival (OS) and relapse-free survival (RFS) in MPAL patients were significantly shorter than those in Ly(+)AML and Ly(-)AML. With regard to the patients with normal karyotype only, the OS and RFS of MPAL were significantly lower than those of the Ly(+)AML and Ly(-)AML; but there were no significant differences in OS and RFS among the patients with complex karyotype. The OS rates of 3 groups with complex karyotype were lower than those of patients with normal karyotype. In Cox multivariate analysis, complex karyotype was an independent pejorative factor for both OS and RFS. Therefore, MPAL is confirmed to be a poor-risk disease while Ly(+)AML does not impact prognosis. Complex karyotype is an unfavorable prognosis factor in AML patients with different immunophenotype. Mixed immunophenotype and complex karyotype increase the adverse risk when they coexist.
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http://dx.doi.org/10.1155/2015/382186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405022PMC
December 2015

Acoustic separation of circulating tumor cells.

Proc Natl Acad Sci U S A 2015 Apr 6;112(16):4970-5. Epub 2015 Apr 6.

Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA 16802;

Circulating tumor cells (CTCs) are important targets for cancer biology studies. To further elucidate the role of CTCs in cancer metastasis and prognosis, effective methods for isolating extremely rare tumor cells from peripheral blood must be developed. Acoustic-based methods, which are known to preserve the integrity, functionality, and viability of biological cells using label-free and contact-free sorting, have thus far not been successfully developed to isolate rare CTCs using clinical samples from cancer patients owing to technical constraints, insufficient throughput, and lack of long-term device stability. In this work, we demonstrate the development of an acoustic-based microfluidic device that is capable of high-throughput separation of CTCs from peripheral blood samples obtained from cancer patients. Our method uses tilted-angle standing surface acoustic waves. Parametric numerical simulations were performed to design optimum device geometry, tilt angle, and cell throughput that is more than 20 times higher than previously possible for such devices. We first validated the capability of this device by successfully separating low concentrations (∼100 cells/mL) of a variety of cancer cells from cell culture lines from WBCs with a recovery rate better than 83%. We then demonstrated the isolation of CTCs in blood samples obtained from patients with breast cancer. Our acoustic-based separation method thus offers the potential to serve as an invaluable supplemental tool in cancer research, diagnostics, drug efficacy assessment, and therapeutics owing to its excellent biocompatibility, simple design, and label-free automated operation while offering the capability to isolate rare CTCs in a viable state.
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http://dx.doi.org/10.1073/pnas.1504484112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413297PMC
April 2015

Identification of novel molecular markers for prognosis estimation of acute myeloid leukemia: over-expression of PDCD7, FIS1 and Ang2 may indicate poor prognosis in pretreatment patients with acute myeloid leukemia.

PLoS One 2014 8;9(1):e84150. Epub 2014 Jan 8.

Hematology Department of Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.

Numerous factors impact on the prognosis of acute myeloid leukemia (AML), among which molecular genetic abnormalities are developed increasingly, however, accurate prediction for newly diagnosed AML patients remains unsatisfied. For further improving the prognosis evaluation system, we investigated the transcripts levels of PDCD7, FIS1, FAM3A, CA6, APP, KLRF1, ATCAY, GGT5 and Ang2 in 97 AML patients and 30 non-malignant controls, and validated using the published microarray data from 225 cytogenetically normal AML (CN-AML) patients treated according to the German AMLCG-1999 protocol. Real-time quantitative polymerase chain reaction and western blot were carried out, and clinical data were collected and analyzed. High Ang2 and FIS1 expression discriminated the CR rate of AML patients (62.5% versus 82.9% for Ang2, P = 0.011; 61.4% versus 82.2% for FIS1, P = 0.029). In CN-AML, patients with high FIS1 expression were more likely to be resistant to two courses of induction (P = 0.035). Overall survival (OS) and relapse-free survival (RFS) were shorter in CN-AML patients with high PDCD7 expression (P<0.001; P = 0.006), and PDCD7 was revealed to be an independent risk factor for OS in CN-AML (P = 0.004). In the analysis of published data from 225 CN-AML patients, PDCD7 remained independently predicting OS in CN-AML (P = 0.039). As a conclusion, Ang2 and FIS1 seem related to decreased CR rate of AML patients, and PDCD7 is associated with shorter OS and RFS in CN-AML. Hence, PDCD7, Ang2 and FIS1 may indicate a more aggressive form and poor prognosis of AML.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084150PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3885535PMC
September 2014