Publications by authors named "Kian-Huat Lim"

44 Publications

CC Chemokine Receptor 2-Targeting Copper Nanoparticles for Positron Emission Tomography-Guided Delivery of Gemcitabine for Pancreatic Ductal Adenocarcinoma.

ACS Nano 2021 01 6;15(1):1186-1198. Epub 2021 Jan 6.

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, United States.

Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with dire prognosis due to aggressive biology, lack of effective tools for diagnosis at an early stage, and limited treatment options. Detection of PDAC using conventional radiographic imaging is limited by the dense, hypovascular stromal component and relatively scarce neoplastic cells within the tumor microenvironment (TME). The CC motif chemokine 2 (CCL2) and its cognate receptor CCR2 (CCL2/CCR2) axis are critical in fostering and maintaining this kind of TME by recruiting immunosuppressive myeloid cells such as the tumor-associated macrophages, thereby presenting an opportunity to exploit this axis for both diagnostic and therapeutic purposes. We engineered CCR2-targeting ultrasmall copper nanoparticles (Cu@CuO) as nanovehicles not only for targeted positron emission tomography imaging by intrinsic radiolabeling with Cu but also for loading and delivery of the chemotherapy drug gemcitabine to PDAC. This Cu-radiolabeled nanovehicle allowed sensitive and accurate detection of PDAC malignancy in autochthonous genetically engineered mouse models. The ultrasmall Cu@CuO showed efficient renal clearance, favorable pharmacokinetics, and minimal toxicity. Systemic administration of gemcitabine-loaded Cu@CuO effectively suppressed the progression of PDAC tumors in a syngeneic xenograft mouse model and prolonged survival. These CCR2-targeted ultrasmall nanoparticles offer a promising image-guided therapeutic agent and show great potential for translation.
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http://dx.doi.org/10.1021/acsnano.0c08185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846978PMC
January 2021

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer.

Signal Transduct Target Ther 2020 10 30;5(1):249. Epub 2020 Oct 30.

Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO, 63110, USA.

Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.
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http://dx.doi.org/10.1038/s41392-020-00341-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596088PMC
October 2020

Deciphering the Role of Innate Immune NF-ĸB Pathway in Pancreatic Cancer.

Cancers (Basel) 2020 Sep 19;12(9). Epub 2020 Sep 19.

Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with no effective treatment option. A predominant hallmark of PDAC is the intense fibro-inflammatory stroma which not only physically collapses vasculature but also functionally suppresses anti-tumor immunity. Constitutive and induced activation of the NF-κB transcription factors is a major mechanism that drives inflammation in PDAC. While targeting this pathway is widely supported as a promising therapeutic strategy, clinical success is elusive due to a lack of safe and effective anti-NF-κB pathway therapeutics. Furthermore, the cell type-specific contribution of this pathway, specifically in neoplastic cells, stromal fibroblasts, and immune cells, has not been critically appraised. In this article, we highlighted seminal and recent literature on molecular mechanisms that drive NF-κB activity in each of these major cell types in PDAC, focusing specifically on the innate immune Toll-like/IL-1 receptor pathway. We reviewed recent evidence on the signaling interplay between the NF-κB and oncogenic KRAS signaling pathways in PDAC cells and their collective contribution to cancer inflammation. Lastly, we reviewed clinical trials on agents that target the NF-κB pathway and novel therapeutic strategies that have been proposed in preclinical studies.
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http://dx.doi.org/10.3390/cancers12092675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564842PMC
September 2020

Antisense oligonucleotide modulation of non-productive alternative splicing upregulates gene expression.

Nat Commun 2020 07 9;11(1):3501. Epub 2020 Jul 9.

Stoke Therapeutics, Inc., Bedford, MA, USA.

While most monogenic diseases are caused by loss or reduction of protein function, the need for technologies that can selectively increase levels of protein in native tissues remains. Here we demonstrate that antisense-mediated modulation of pre-mRNA splicing can increase endogenous expression of full-length protein by preventing naturally occurring non-productive alternative splicing and promoting generation of productive mRNA. Bioinformatics analysis of RNA sequencing data identifies non-productive splicing events in 7,757 protein-coding human genes, of which 1,246 are disease-associated. Antisense oligonucleotides targeting multiple types of non-productive splicing events lead to increases in productive mRNA and protein in a dose-dependent manner in vitro. Moreover, intracerebroventricular injection of two antisense oligonucleotides in wild-type mice leads to a dose-dependent increase in productive mRNA and protein in the brain. The targeting of natural non-productive alternative splicing to upregulate expression from wild-type or hypomorphic alleles provides a unique approach to treating genetic diseases.
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http://dx.doi.org/10.1038/s41467-020-17093-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347940PMC
July 2020

TPL2 enforces RAS-induced inflammatory signaling and is activated by point mutations.

J Clin Invest 2020 09;130(9):4771-4790

Division of Oncology, Department of Internal Medicine, and.

NF-κB transcription factors, driven by the IRAK/IKK cascade, confer treatment resistance in pancreatic ductal adenocarcinoma (PDAC), a cancer characterized by near-universal KRAS mutation. Through reverse-phase protein array and RNA sequencing we discovered that IRAK4 also contributes substantially to MAPK activation in KRAS-mutant PDAC. IRAK4 ablation completely blocked RAS-induced transformation of human and murine cells. Mechanistically, expression of mutant KRAS stimulated an inflammatory, autocrine IL-1β signaling loop that activated IRAK4 and the MAPK pathway. Downstream of IRAK4, we uncovered TPL2 (also known as MAP3K8 or COT) as the essential kinase that propels both MAPK and NF-κB cascades. Inhibition of TPL2 blocked both MAPK and NF-κB signaling, and suppressed KRAS-mutant cell growth. To counter chemotherapy-induced genotoxic stress, PDAC cells upregulated TLR9, which activated prosurvival IRAK4/TPL2 signaling. Accordingly, a TPL2 inhibitor synergized with chemotherapy to curb PDAC growth in vivo. Finally, from TCGA we characterized 2 MAP3K8 point mutations that hyperactivate MAPK and NF-κB cascades by impeding TPL2 protein degradation. Cancer cell lines naturally harboring these MAP3K8 mutations are strikingly sensitive to TPL2 inhibition, underscoring the need to identify these potentially targetable mutations in patients. Overall, our study establishes TPL2 as a promising therapeutic target in RAS- and MAP3K8-mutant cancers and strongly prompts development of TPL2 inhibitors for preclinical and clinical studies.
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http://dx.doi.org/10.1172/JCI137660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456254PMC
September 2020

FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers: A Phase 2 Nonrandomized Clinical Trial.

JAMA Oncol 2020 08;6(8):1231-1240

Sylvester Comprehensive Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Leonard M. Miller School of Medicine, University of Miami, Miami, Florida.

Importance: Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers.

Objective: To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma.

Design, Setting, And Participants: This is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX.

Interventions: Starting doses were fluorouracil, 400 mg/m2 bolus, followed by 2400 mg/m2 over 46 hours; leucovorin, 400 mg/m2; irinotecan, 180 mg/m2; and oxaliplatin, 85 mg/m2. Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease.

Main Outcomes And Measures: The primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response.

Results: From November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects.

Conclusions And Relevance: The FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status.

Trial Registration: ClinicalTrials.gov Identifier: NCT01928290.
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http://dx.doi.org/10.1001/jamaoncol.2020.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260693PMC
August 2020

Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma.

J Gastrointest Oncol 2020 Feb;11(1):61-67

Department of Internal Medicine, Division of Medical Oncology, Washington University in St. Louis, St. Louis, MO, USA.

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC.

Methods: We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m oral twice-daily days 1-14 and oral tosedostat in a dose de-escalation design on days 1-21 of each 21-day cycle. Primary endpoints were the recommended phase 2 dose (RP2D) and progression-free survival (PFS).

Results: Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m oral twice daily was the RP2D. There was one dose-limiting toxicity (DLT) (grade 3 acute coronary syndrome) during phase Ib. The most common treatment-related adverse events were gastrointestinal (nausea, diarrhea), cardiac [QTc prolongation, decreased ejection fraction (EF)], and fatigue. The median PFS was 7.1 months, and the median treatment failure free survival was 3 months. Eight patients experienced stable disease for greater than 3 months. The study was closed early due to lack of drug availability.

Conclusions: Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic cancer.
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http://dx.doi.org/10.21037/jgo.2019.11.06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052765PMC
February 2020

Assessment of Hepatic Arterial Infusion of Floxuridine in Combination With Systemic Gemcitabine and Oxaliplatin in Patients With Unresectable Intrahepatic Cholangiocarcinoma: A Phase 2 Clinical Trial.

JAMA Oncol 2019 Oct 31. Epub 2019 Oct 31.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.

Importance: Unresectable intrahepatic cholangiocarcinoma (IHC) carries a poor prognosis, with a median overall survival (OS) of 11 months. Hepatic arterial infusion (HAI) of high-dose chemotherapy may have potential benefit in these patients.

Objective: To evaluate clinical outcomes when HAI chemotherapy is combined with systemic chemotherapy in patients with unresectable IHC.

Design, Setting, And Participants: A single-institution, phase 2 clinical trial including 38 patients was conducted with HAI floxuridine plus systemic gemcitabine and oxaliplatin in patients with unresectable IHC at Memorial Sloan Kettering Cancer Center between May 20, 2013, and June 27, 2019. A confirmatory phase 1/2 study using the same therapy was conducted during the same time period at Washington University in St Louis. Patients with histologically confirmed, unresectable IHC were eligible. Resectable metastatic disease to regional lymph nodes and prior systemic therapy were permitted. Patients with distant metastatic disease were excluded.

Interventions: Hepatic arterial infusion of floxuridine and systemic administration of gemcitabine and oxaliplatin.

Main Outcomes And Measures: The primary outcome was progression-free survival (PFS) of 80% at 6 months.

Results: For the phase 2 clinical trial at Memorial Sloan Kettering Cancer Center, 42 patients with unresectable IHC were included and, of these, 38 patients were treated (13 [34%] men; median [range] age at diagnosis, 64 [39-81] years). The median follow-up was 30.5 months. Twenty-two patients (58%) achieved a partial radiographic response, and 32 patients (84%) achieved disease control at 6 months. Four patients had sufficient response to undergo resection, and 1 patient had a complete pathologic response. The median PFS was 11.8 months (1-sided 90% CI, 11.1) with a 6-month PFS rate of 84.1% (90% CI, 74.8%-infinity), thereby meeting the primary end point (6-month PFS rate, 80%). The median OS was 25.0 months (95% CI, 20.6-not reached), and the 1-year OS rate was 89.5% (95% CI, 80.2%-99.8%). Patients with resectable regional lymph nodes (18 [47%]) showed no difference in OS compared with patients with node-negative disease (24-month OS: lymph node negative: 60%; 95% CI, 40%-91% vs lymph node positive: 50%; 95% CI, 30%-83%; P = .66). Four patients (11%) had grade 4 toxic effects requiring removal from the study (1 portal hypertension, 2 gastroduodenal artery aneurysms, 1 infection in the pump pocket). Subgroup analysis showed significant improvement in survival in patients with IDH1/2 mutated tumors (2-year OS, 90%; 95% CI, 73%-99%) vs wild-type (2-year OS, 33%; 95% CI, 18%-63%) (P = .01). In the Washington University in St Louis confirmatory cohort, 9 patients (90%) achieved disease control at 6 months; the most common grade 3 toxic effect was elevated results of liver function tests, and median PFS was 12.8 months (1-sided 90% CI, 6.4).

Conclusions And Relevance: Hepatic arterial infusion plus systemic chemotherapy appears to be highly active and tolerable in patients with unresectable IHC; further evaluation is warranted.
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http://dx.doi.org/10.1001/jamaoncol.2019.3718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824231PMC
October 2019

IRAK4 mediates colitis-induced tumorigenesis and chemoresistance in colorectal cancer.

JCI Insight 2019 10 3;4(19). Epub 2019 Oct 3.

Division of Oncology, Department of Internal Medicine, Barnes-Jewish Hospital and The Alvin J. Siteman Comprehensive Cancer Center, Washington University School of Medicine, St. Louis, Missouri, USA.

Aberrant activation of the NF-κB transcription factors underlies chemoresistance in various cancer types, including colorectal cancer (CRC). Targeting the activating mechanisms, particularly with inhibitors to the upstream IκB kinase (IKK) complex, is a promising strategy to augment the effect of chemotherapy. However, clinical success has been limited, largely because of low specificity and toxicities of tested compounds. In solid cancers, the IKKs are driven predominantly by the Toll-like receptor (TLR)/IL-1 receptor family members, which signal through the IL-1 receptor-associated kinases (IRAKs), with isoform 4 (IRAK4) being the most critical. The pathogenic role and therapeutic value of IRAK4 in CRC have not been investigated. We found that IRAK4 inhibition significantly abrogates colitis-induced neoplasm in APCMin/+ mice, and bone marrow transplant experiments showed an essential role of IRAK4 in immune cells during neoplastic progression. Chemotherapy significantly enhances IRAK4 and NF-κB activity in CRC cells through upregulating TLR9 expression, which can in turn be suppressed by IRAK4 and IKK inhibitors, suggesting a feed-forward pathway that protects CRC cells from chemotherapy. Lastly, increased tumor phospho-IRAK4 staining or IRAK4 mRNA expression is associated with significantly worse survival in CRC patients. Our results support targeting IRAK4 to improve the effects of chemotherapy and outcomes in CRC.
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http://dx.doi.org/10.1172/jci.insight.130867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795411PMC
October 2019

Folate Receptor α-Targeted Zr-M9346A Immuno-PET for Image-Guided Intervention with Mirvetuximab Soravtansine in Triple-Negative Breast Cancer.

Mol Pharm 2019 09 16;16(9):3996-4006. Epub 2019 Aug 16.

ImmunoGen, Inc. , Waltham , Massachusetts 02451 , United States.

Folate receptor α (FRα) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody-drug conjugate of FRα-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 (Zr)-radiolabeled M9346A (Zr-M9346A) as an immuno-positron emission tomography (immuno-PET) radiotracer to evaluate FRα expression in triple-negative breast cancer (TNBC) patients, providing a novel means to guide intervention with therapeutic IMGN853. In this study, we verified the binding specificity and immunoreactivity of Zr-M9346A by in vitro studies in FRα cells (HeLa) and FRα cells (OVCAR-3). In vivo PET/computed tomography (PET/CT) imaging in HeLa xenografts and TNBC patient-derived xenograft (PDX) mouse models with various levels of FRα expression demonstrated its targeting specificity and sensitivity. Following PET imaging, the treatment efficiencies of IMGN853, pemetrexed, IMGN853 + pemetrexed, paclitaxel, and saline were assessed in FRα and FRα TNBC PDX models. The correlation between Zr-M9346A tumor uptake and treatment response using IMGN853 in FRα TNBC PDX model suggested the potential of Zr-M9346A PET as a noninvasive tool to prescreen patients based on the in vivo PET imaging for IMGN853-targeted treatment.
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http://dx.doi.org/10.1021/acs.molpharmaceut.9b00653DOI Listing
September 2019

Development of resistance to FAK inhibition in pancreatic cancer is linked to stromal depletion.

Gut 2020 01 10;69(1):122-132. Epub 2019 May 10.

Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.

Objective: We investigated how pancreatic cancer developed resistance to focal adhesion kinase (FAK) inhibition over time.

Design: Pancreatic ductal adenocarcinoma (PDAC) tumours from KPC mice (p48-CRE; LSL-KRas; p53) treated with FAK inhibitor were analysed for the activation of a compensatory survival pathway in resistant tumours. We identified pathways involved in the regulation of signal transducer and activator of transcription 3 (STAT3) signalling on FAK inhibition by gene set enrichment analysis and verified these outcomes by RNA interference studies. We also tested combinatorial approaches targeting FAK and STAT3 in syngeneic transplantable mouse models of PDAC and KPC mice.

Results: In KPC mice, the expression levels of phosphorylated STAT3 (pSTAT3) were increased in PDAC cells as they progressed on FAK inhibitor therapy. This progression corresponded to decreased collagen density, lowered numbers of SMA fibroblasts and downregulation of the transforming growth factor beta (TGF-β)/SMAD signalling pathway in FAK inhibitor-treated PDAC tumours. Furthermore, TGF-β production by fibroblasts in vitro drives repression of STAT3 signalling and enhanced responsiveness to FAK inhibitor therapy. Knockdown of SMAD3 in pancreatic cancer cells abolished the inhibitory effects of TGF-β on pSTAT3. We further found that tumour-intrinsic STAT3 regulates the durability of the antiproliferative activity of FAK inhibitor, and combinatorial targeting of FAK and Janus kinase/STAT3 act synergistically to suppress pancreatic cancer progression in mouse models.

Conclusion: Stromal depletion by FAK inhibitor therapy leads to eventual treatment resistance through the activation of STAT3 signalling. These data suggest that, similar to tumour-targeted therapies, resistance mechanisms to therapies targeting stromal desmoplasia may be critical to treatment durability.
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http://dx.doi.org/10.1136/gutjnl-2018-317424DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167297PMC
January 2020

Pancreatic cancer survival analysis defines a signature that predicts outcome.

PLoS One 2018 9;13(8):e0201751. Epub 2018 Aug 9.

School of Biomedical Engineering, Sciences, and Health Systems, Drexel University, Philadelphia, PA, United States of America.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the US. Despite multiple large-scale genetic sequencing studies, identification of predictors of patient survival remains challenging. We performed a comprehensive assessment and integrative analysis of large-scale gene expression datasets, across multiple platforms, to enable discovery of a prognostic gene signature for patient survival in pancreatic cancer. PDAC RNA-Sequencing data from The Cancer Genome Atlas was stratified into Survival+ (>2-year survival) and Survival-(<1-year survival) cohorts (n = 47). Comparisons of RNA expression profiles between survival groups and normal pancreatic tissue expression data from the Gene Expression Omnibus generated an initial PDAC specific prognostic differential expression gene list. The candidate prognostic gene list was then trained on the Australian pancreatic cancer dataset from the ICGC database (n = 103), using iterative sampling based algorithms, to derive a gene signature predictive of patient survival. The gene signature was validated in 2 independent patient cohorts and against existing PDAC subtype classifications. We identified 707 candidate prognostic genes exhibiting differential expression in tumor versus normal tissue. A substantial fraction of these genes was also found to be differentially methylated between survival groups. From the candidate gene list, a 5-gene signature (ADM, ASPM, DCBLD2, E2F7, and KRT6A) was identified. Our signature demonstrated significant power to predict patient survival in two distinct patient cohorts and was independent of AJCC TNM staging. Cross-validation of our gene signature reported a better ROC AUC (≥ 0.8) when compared to existing PDAC survival signatures. Furthermore, validation of our signature through immunohistochemical analysis of patient tumor tissue and existing gene expression subtyping data in PDAC, demonstrated a correlation to the presence of vascular invasion and the aggressive squamous tumor subtype. Assessment of these genes in patient biopsies could help further inform risk-stratification and treatment decisions in pancreatic cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201751PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084949PMC
January 2019

Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models.

Mol Cancer Ther 2018 10 31;17(10):2144-2155. Epub 2018 Jul 31.

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.

Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting , the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF-MEK-ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with and mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K-AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth and Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-1142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6168412PMC
October 2018

Distinct clinical and magnetic resonance features of metastatic hepatocellular carcinoma treated with pembrolizumab: A case report of late response after pseudoprogression.

Hepatol Commun 2018 02 19;2(2):148-151. Epub 2017 Dec 19.

Division of Oncology, Department of Internal Medicine Washington University School of Medicine St. Louis MO.

There are few effective therapies for unresectable or metastatic hepatocellular carcinoma. Recent data have demonstrated efficacy of immune checkpoint blockade in this difficult to treat disease; however, clinical experience is limited. We report a case of hepatocellular carcinoma displaying pseudoprogression followed by a late response with novel magnetic resonance imaging features following treatment with the anti-programmed cell death protein 1 agent pembrolizumab. ( 2018;2:148-151).
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http://dx.doi.org/10.1002/hep4.1132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796320PMC
February 2018

Tumor-Stroma IL1β-IRAK4 Feedforward Circuitry Drives Tumor Fibrosis, Chemoresistance, and Poor Prognosis in Pancreatic Cancer.

Cancer Res 2018 04 23;78(7):1700-1712. Epub 2018 Jan 23.

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.

Targeting the desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) holds promise to augment the effect of chemotherapy, but success in the clinic has thus far been limited. Preclinical mouse models suggest that near-depletion of cancer-associated fibroblasts (CAF) carries a risk of accelerating PDAC progression, underscoring the need to concurrently target key signaling mechanisms that drive the malignant attributes of both CAF and PDAC cells. We previously reported that inhibition of IL1 receptor-associated kinase 4 (IRAK4) suppresses NFκB activity and promotes response to chemotherapy in PDAC cells. In this study, we report that CAF in PDAC tumors robustly express activated IRAK4 and NFκB. IRAK4 expression in CAF promoted NFκB activity, drove tumor fibrosis, and supported PDAC cell proliferation, survival, and chemoresistance. Cytokine array analysis of CAF and microarray analysis of PDAC cells identified IL1β as a key cytokine that activated IRAK4 in CAF. Targeting IRAK4 or IL1β rendered PDAC tumors less fibrotic and more sensitive to gemcitabine. In clinical specimens of human PDAC, high stromal IL1β expression associated strongly with poor overall survival. Together, our studies establish a tumor-stroma IL1β-IRAK4 feedforward signal that can be therapeutically disrupted to increase chemotherapeutic efficacy in PDAC. Targeting the IL1β-IRAK4 signaling pathway potentiates the effect of chemotherapy in pancreatic cancer. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5890818PMC
April 2018

Pacritinib to inhibit JAK/STAT signaling in refractory metastatic colon and rectal cancer.

J Gastrointest Oncol 2017 Dec;8(6):985-989

Division of Oncology, University of Miami, Miami, FL, USA.

Background: Treatment options for patients with refractory colorectal cancer are limited and typically provide a chance of only modest benefit. The goal of this study was to evaluate the benefit of inhibiting the JAK/STAT inflammatory pathway with single agent pacritinib in patients with metastatic refractory colorectal adenocarcinoma.

Methods: A single arm institutional trial was initiated and enrolled patients with metastatic colorectal cancer refractory to at least two standard lines of treatment. Pacritinib 400 mg daily was administered orally continuously in 28 day cycles.

Results: The trial was discontinued prior to reaching the planned accrual due to an FDA hold on pacritinib and a lack of treatment benefit. Eleven patients were enrolled and seven were evaluated for response. Median baseline C-reactive protein level was 12.1 (2.1-147) mg/L. One patient had stable disease at eight weeks by RECIST criteria and six progressed. There were no grade 4 or 5 adverse events while patients were on study. The grade 2 and lower AE events experienced were consistent with prior pacritinib trials.

Conclusions: In seven evaluable patients there were no objective responses. The trial was discontinued prior to completing planned accrual based on a low likelihood that the progression free survival goal of 4 months would be met.
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http://dx.doi.org/10.21037/jgo.2017.08.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5750170PMC
December 2017

Lack of a Prognostic Impact of the MyD88 L265P Mutation for Diffuse Large B Cell Lymphoma Patients Undergoing Autologous Stem Cell Transplantation.

Biol Blood Marrow Transplant 2017 Dec 26;23(12):2199-2204. Epub 2017 Aug 26.

Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri. Electronic address:

Cell-of-origin determination has emerged as an important prognostic factor for patients initially diagnosed with diffuse large B cell lymphoma (DLBCL). Specifically, the nongerminal center B cell-like (non-GCB) subtype, composed predominantly of the activated B cell-like (ABC) molecular subtype, has been shown to portend poor prognosis because of its more aggressive nature and resistance to standard cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP)-like chemotherapy compared with the GCB subtype. The recurrent MyD88 L265P mutation, present in 29% of ABC DLBCL, was reported as an independent poor prognostic factor for patients with newly diagnosed DLBCL. For patients whose disease relapses or is refractory to first-line chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) is frequently offered as salvage therapy. However, the impact of MyD88 mutation status on post-ASCT outcome has not been reported. Here, we retrospectively analyzed, with up to 20 years of follow-up, 165 patients who underwent ASCT for relapsed/refractory DLBCL at our institution. We found that MyD88 mutation status did not correlate with overall survival (OS), post-ASCT OS, or progression-free survival (PFS). Patients with non-GCB subtype had significantly worse OS from initial diagnosis and after ASCT. Notably, high International Prognostic Index score was predictive of poor pre- and post-transplant PFS and post-transplant OS.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.022DOI Listing
December 2017

Immunotherapy in gastrointestinal cancers.

J Gastrointest Oncol 2017 Jun;8(3):474-484

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO, USA.

Gastrointestinal (GI) cancers such as gastric, esophageal, pancreas, hepatobiliary, colorectal and anal cancers are a major cause of cancer related mortality worldwide. Traditional treatment options such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and anti-angiogenic agents have been the backbone of treatment of GI cancers in various stages. Current cancer research is moving forward to incorporate immunotherapies in the treatment of GI cancers either as single agent or in combination with current available treatment modalities. This review summarizes the existing and ongoing immunotherapies in the treatment of GI cancers.
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http://dx.doi.org/10.21037/jgo.2017.05.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506270PMC
June 2017

Current biologics for treatment of biliary tract cancers.

J Gastrointest Oncol 2017 Jun;8(3):430-440

Division of Oncology, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.

Biliary tract cancers (BTC) is a group of malignancies that arise from the epithelial cells of the biliary tree. These cancers are typically classified by anatomic site of origin: intrahepatic cholangiocarcinoma (IHCC) and extrahepatic cholangiocarcinoma (EHCC), and gallbladder cancer (GBC). To date, complete surgical resection remains the mainstay of treatment especially for earlier stage disease. Unfortunately, most patients present with advanced or metastatic disease, when systemic chemotherapy is the only treatment option. Due to the paucity of effective treatments, BTCs have a dismal prognosis. There is a tremendous need to better understand the disease biology, discover new therapies, and improve clinical outcomes for this challenging disease. Next-generation sequencing has produced a more accurate and detailed picture of the molecular signatures in BTCs. The three BTC histologic subtypes are, in fact, quite molecularly distinct. IHCC commonly contain FGFR2 fusions and IDH 1 and 2 mutations, whereas EHCC and GBC tend to carry mutations in EGFR, HER2, and MAPK pathway. In light of this emerging knowledge, clinical trials have become more biomarker-driven, which allows capturing of subsets of patients that are most likely to respond to certain therapies. Many new and promising targeted therapeutics are currently in the pipeline. Here we review the genetic landscape of BTCs while focusing on new molecular targets and targeted therapeutics currently being investigated in biomarker-driven clinical trials.
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http://dx.doi.org/10.21037/jgo.2017.05.04DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506280PMC
June 2017

Molecular landscape and sub-classification of gastrointestinal cancers: a review of literature.

J Gastrointest Oncol 2017 Jun;8(3):379-386

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, MO 63110, USA.

The historical approach of diagnosing cancer types based entirely on anatomic origin and histologic features, and the "one-size-fit-all" therapeutic approach, are inadequate in modern cancer treatment. From decades of research we now know that cancer is a highly heterogeneous disease driven by complex genetic or epigenetic alterations. The advent of various high throughput molecular tools has now enabled us to view and sub-classify each cancer type based on their distinct molecular features, in addition to histologic classification, with the promise of individualized treatment strategies tailored towards each specific subtype to improve patient outcomes. In this review, we have made an effort to systematically review the most up-to-date, leading literature in molecular analysis and/or subtyping of major gastrointestinal cancers. These include esophageal squamous cell carcinoma (ESCC), gastric cancer (GC) adenocarcinoma, pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), gallbladder cancer (GBC), and colorectal cancer (CRC). For each cancer type we summarized the global mutational landscape, subgroup classification based on genomics, epigenetics, gene expression and/or proteomic analysis, and their salient clinicopathological features. We have highlighted the actionable mutations or mutational pathways that could help guide targeted therapies in the future.
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http://dx.doi.org/10.21037/jgo.2016.11.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506283PMC
June 2017

Entering the molecular era of gastrointestinal oncology: current updates and challenges.

J Gastrointest Oncol 2017 Jun;8(3):377-378

Assistant Professor, Division of Oncology, Department of Internal Medicine, Washington University in Saint Louis, USA (Email:

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http://dx.doi.org/10.21037/jgo.2017.05.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5506275PMC
June 2017

A clinically feasible multiplex proteomic immunoassay as a novel functional diagnostic for pancreatic ductal adenocarcinoma.

Oncotarget 2017 Apr;8(15):24250-24261

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, USA.

To date, targeted therapy for pancreatic ductal adenocarcinoma (PDAC) remains largely unsuccessful in the clinic. Current genomics-based technologies are unable to reflect the quantitative, dynamic signaling changes in the tumor, and require larger tumor samples that are difficult to obtain in PDAC patients. Therefore, a highly sensitive functional tool that can reliably and comprehensively inform intra-tumoral signaling events is direly needed to guide treatment decision. We tested the utility of a highly sensitive proteomics-based functional diagnostic platform, Collaborative Enzyme Enhanced Reactive-immunoassay (CEERTM), on fine-needle aspiration (FNA) samples obtained from 102 patients with radiographically-evident pancreatic tumors. Two FNA passes were collected from each patient, hybridized to customized chips coated with an array of capture antibodies, and detected using two enzyme-conjugated antibodies which emit quantifiable signals. We demonstrate that this technique is highly sensitive in detecting total and phosphorylated forms of multiple signaling molecules in FNA specimens, with reasonable correlation of marker intensities between two different FNA passes. Notably, signals of several markers were significantly higher in PDAC compared to non-cancerous samples. In PDAC samples, we found high total c-Met signal to be associated with poor survival, and confirmed this finding using an independent PDAC tissue microarray.
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http://dx.doi.org/10.18632/oncotarget.15653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421844PMC
April 2017

Utility of a multidisciplinary tumor board in the management of pancreatic and upper gastrointestinal diseases: an observational study.

HPB (Oxford) 2017 02 1;19(2):133-139. Epub 2016 Dec 1.

Department of Surgery, Barnes-Jewish Hospital and the Alvin J. Siteman Cancer Center at Washington University School of Medicine, Saint Louis, MO, USA. Electronic address:

Background & Objectives: Multidisciplinary tumor boards (MDTBs) are frequently employed in cancer centers but their value has been debated. We reviewed the decision-making process and resource utilization of our MDTB to assess its utility in the management of pancreatic and upper gastrointestinal tract conditions.

Methods: A prospectively-collected database was reviewed over a 12-month period. The primary outcome was change in management plan as a result of case discussion. Secondary outcomes included resources required to hold MDTB, survival, and adherence to treatment guidelines.

Results: Four hundred seventy cases were reviewed. MDTB resulted in a change in the proposed plan of management in 101 of 402 evaluable cases (25.1%). New plans favored obtaining additional diagnostic workup. No recorded variables were associated with a change in plan. For newly-diagnosed cases of pancreatic ductal adenocarcinoma (n = 33), survival time was not impacted by MDTB (p = .154) and adherence to National Comprehensive Cancer Network guidelines was 100%. The estimated cost of physician time per case reviewed was $190.

Conclusions: Our MDTB influences treatment decisions in a sizeable number of cases with excellent adherence to national guidelines. However, this requires significant time expenditure and may not impact outcomes. Regular assessments of the effectiveness of MDTBs should be undertaken.
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http://dx.doi.org/10.1016/j.hpb.2016.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5477647PMC
February 2017

Constitutive IRAK4 Activation Underlies Poor Prognosis and Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Clin Cancer Res 2017 Apr 4;23(7):1748-1759. Epub 2016 Oct 4.

Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.

Aberrant activation of the NF-κB transcription factors underlies the aggressive behavior and poor outcome of pancreatic ductal adenocarcinoma (PDAC). However, clinically effective and safe NF-κB inhibitors are not yet available. Because NF-κB transcription factors can be activated by the interleukin-1 receptor-associated kinases (IRAKs) downstream of the Toll-like receptors (TLRs), but has not been explored in PDAC, we sought to investigate the role of IRAKs in the pathobiology of PDAC. We examined the phosphorylation status of IRAK4 (p-IRAK4), the master regulator of TLR signaling, in PDAC cell lines, in surgical samples and commercial tissue microarray. We then performed functional studies using small-molecule IRAK1/4 inhibitor, RNA-interference, and CRISPR/Cas9n techniques to delineate the role of IRAK4 in NF-κB activity, chemoresistance, cytokine production, and growth of PDAC cells and p-IRAK4 staining was detectable in the majority of PDAC lines and about 60% of human PDAC samples. The presence of p-IRAK4 strongly correlated with phospho-NF-κB/p65 staining in PDAC samples and is predictive of postoperative relapse and poor overall survival. Inhibition of IRAK4 potently reduced NF-κB activity, anchorage-independent growth, chemoresistance, and secretion of proinflammatory cytokines from PDAC cells. Both pharmacologic suppression and genetic ablation of IRAK4 greatly abolished PDAC growth in mice and augmented the therapeutic effect of gemcitabine by promoting apoptosis, reducing tumor cell proliferation and tumor fibrosis. Our data established IRAK4 as a novel therapeutic target for PDAC treatment. Development of potent IRAK4 inhibitors is needed for clinical testing. .
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http://dx.doi.org/10.1158/1078-0432.CCR-16-1121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378683PMC
April 2017

Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial.

Lancet Oncol 2016 05 4;17(5):651-62. Epub 2016 Apr 4.

Department of Surgery, University of Rochester Medical Center, Rochester, NY, USA; Center for Tumor Immunology, University of Rochester Medical Center, Rochester, NY, USA; Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY, USA. Electronic address:

Background: In pancreatic ductal adenocarcinoma, the CCL2-CCR2 chemokine axis is used to recruit tumour-associated macrophages for construction of an immunosuppressive tumour microenvironment. This pathway has prognostic implications in pancreatic cancer, and blockade of CCR2 restores anti-tumour immunity in preclinical models. We aimed to establish the safety, tolerability, and recommended phase 2 oral dose of the CCR2 inhibitor PF-04136309 in combination with FOLFIRINOX chemotherapy (oxaliplatin and irinotecan plus leucovorin and fluorouracil).

Methods: We did this open-label, dose-finding, non-randomised, phase 1b study at one centre in the USA. We enrolled treatment-naive patients aged 18 years or older with borderline resectable or locally advanced biopsy-proven pancreatic ductal adenocarcinoma, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1, and normal end-organ function. Patients were allocated to receive either FOLFIRINOX alone (oxaliplatin 85 mg/m(2), irinotecan 180 mg/m(2), leucovorin 400 mg/m(2), and bolus fluorouracil 400 mg/m(2), followed by 2400 mg/m(2) 46-h continuous infusion), administered every 2 weeks for a total of six treatment cycles, or in combination with oral PF-04136309, administered at a starting dose of 500 mg twice daily in a standard 3 + 3 dose de-escalation design. Both FOLFIRINOX and PF-04136309 were simultaneously initiated with a total treatment duration of 12 weeks. The primary endpoints were the safety, tolerability, and recommended phase 2 dose of PF-04136309 plus FOLFIRINOX, with an expansion phase planned at the recommended dose. We analysed the primary outcome by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01413022.

Results: Between April 19, 2012, and Nov 12, 2014, we treated 47 patients with FOLFIRINOX alone (n=8) or with FOLFIRINOX plus PF-04136309 (n=39). One patient had a dose-limiting toxic effect in the dose de-escalation group receiving FOLFIRINOX plus PF-04136309 at 500 mg twice daily (n=6); this dose was established as the recommended phase 2 dose. We pooled patients in the expansion-phase group (n=33) with those in the dose de-escalation group that received PF-04136309 at the recommended phase 2 dose for assessment of treatment-related toxicity. Six (75%) of the eight patients receiving FOLFIRINOX alone were assessed for treatment toxicity, after exclusion of two (25%) patients due to insurance coverage issues. The median duration of follow-up for treatment toxicity was 72·0 days (IQR 49·5-89·0) in the FOLFIRINOX alone group and 77·0 days (70·0-90·5) in the FOLFIRINOX plus PF-04136309 group. No treatment-related deaths occurred. Two (5%) patients in the FOLFIRINOX plus PF-04136309 group stopped treatment earlier than planned due to treatment-related toxic effects. Grade 3 or higher adverse events reported in at least 10% of the patients receiving PF-04136309 included neutropenia (n=27), febrile neutropenia (n=7), lymphopenia (n=4), diarrhoea (n=6), and hypokalaemia (n=7). Grade 3 or higher adverse events reported in at least 10% of patients receiving FOLFIRINOX alone were neutropenia (n=6), febrile neutropenia (n=1), anaemia (n=2), lymphopenia (n=1), diarrhoea (n=2), hypoalbuminaemia (n=1), and hypokalaemia (n=3). Therapy was terminated because of treatment-related toxicity in one (17%) of the six patients receiving FOLFIRINOX alone. 16 (49%) of 33 patients receiving FOLFIRINOX plus PF-04136309 who had undergone repeat imaging achieved an objective tumour response, with local tumour control achieved in 32 (97%) patients. In the FOLFIRINOX alone group, none of the five patients with repeat imaging achieved an objective response, although four (80%) of those patients achieved stable disease.

Interpretation: CCR2-targeted therapy with PF-04136309 in combination with FOLFIRINOX is safe and tolerable.

Funding: Washington University-Pfizer Biomedical Collaborative.
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http://dx.doi.org/10.1016/S1470-2045(16)00078-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407285PMC
May 2016

RNA structure replaces the need for U2AF2 in splicing.

Genome Res 2016 Jan 13;26(1):12-23. Epub 2015 Nov 13.

Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island 02912, USA; Center for Computational Molecular Biology, Brown University, Providence, Rhode Island 02912, USA;

RNA secondary structure plays an integral role in catalytic, ribosomal, small nuclear, micro, and transfer RNAs. Discovering a prevalent role for secondary structure in pre-mRNAs has proven more elusive. By utilizing a variety of computational and biochemical approaches, we present evidence for a class of nuclear introns that relies upon secondary structure for correct splicing. These introns are defined by simple repeat expansions of complementary AC and GT dimers that co-occur at opposite boundaries of an intron to form a bridging structure that enforces correct splice site pairing. Remarkably, this class of introns does not require U2AF2, a core component of the spliceosome, for its processing. Phylogenetic analysis suggests that this mechanism was present in the ancestral vertebrate lineage prior to the divergence of tetrapods from teleosts. While largely lost from land dwelling vertebrates, this class of introns is found in 10% of all zebrafish genes.
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http://dx.doi.org/10.1101/gr.181008.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691745PMC
January 2016

Advanced pancreatic adenocarcinoma: a review of current treatment strategies and developing therapies.

Ther Adv Med Oncol 2015 Mar;7(2):68-84

Division of Oncology, Department of Medicine, Campus Box 8056, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.

Pancreatic adenocarcinoma is one of the deadliest solid malignancies. A large proportion of patients are diagnosed with locally advanced or metastatic disease at the time of presentation and, unfortunately, this severely limits the number of patients who can undergo surgical resection, which offers the only chance for cure. Recent therapeutic advances for patients with advanced pancreatic cancer have extended overall survival, but prognosis still remains grim. Given that traditional chemotherapy is ineffective in curing advanced pancreatic adenocarcinoma, current research is taking a multidirectional approach in the hopes of developing more effective treatments. This article reviews the major clinical trial data that is the basis for the current chemotherapy regimens used as first- and second-line treatments for advanced pancreatic adenocarcinoma. We also review the current ongoing clinical trials, which include the use of agents targeting the oncogenic network signaling of K-Ras, agents targeting the extracellular matrix, and immune therapies.
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http://dx.doi.org/10.1177/1758834014564775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4346211PMC
March 2015

Toll-like receptor signaling.

Cold Spring Harb Perspect Biol 2013 Jan 1;5(1):a011247. Epub 2013 Jan 1.

Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

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http://dx.doi.org/10.1101/cshperspect.a011247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579400PMC
January 2013

Pathogenetic importance and therapeutic implications of NF-κB in lymphoid malignancies.

Immunol Rev 2012 Mar;246(1):359-78

Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Derangement of the nuclear factor κB (NF-κB) pathway initiates and/or sustains many types of human cancer. B-cell malignancies are particularly affected by oncogenic mutations, translocations, and copy number alterations affecting key components the NF-κB pathway, most likely owing to the pervasive role of this pathway in normal B cells. These genetic aberrations cause tumors to be 'addicted' to NF-κB, which can be exploited therapeutically. Since each subtype of lymphoid cancer utilizes different mechanisms to activate NF-κB, several different therapeutic strategies are needed to address this pathogenetic heterogeneity. Fortunately, a number of drugs that block signaling cascades leading to NF-κB are in early phase clinical trials, several of which are already showing activity in lymphoid malignancies.
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http://dx.doi.org/10.1111/j.1600-065X.2012.01105.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4094296PMC
March 2012

Spliceman--a computational web server that predicts sequence variations in pre-mRNA splicing.

Bioinformatics 2012 Apr 10;28(7):1031-2. Epub 2012 Feb 10.

Department of Molecular Biology, Cellular Biology and Biochemistry, Brown University, Providence, RI 02903, USA.

Summary: It was previously demonstrated that splicing elements are positional dependent. We exploited this relationship between location and function by comparing positional distributions between all possible 4096 hexamers around a database of human splice sites. The distance measure used in this study found point mutations that produced higher distances disrupted splicing, whereas point mutations with smaller distances generally had no effect on splicing. Reasoning the idea that functional splicing elements have signature positional distributions around constitutively spliced exons, we introduce Spliceman-an online tool that predicts how likely distant mutations around annotated splice sites were to disrupt splicing. Spliceman takes a set of DNA sequences with point mutations and returns a ranked list to predict the effects of point mutations on pre-mRNA splicing. The current implementation included the analyses of 11 genomes: human, chimp, rhesus, mouse, rat, dog, cat, chicken, guinea pig, frog and zebrafish.

Availability: Freely available on the web at http://fairbrother.biomed.brown.edu/spliceman/

Contact: fairbrother@brown.edu.
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http://dx.doi.org/10.1093/bioinformatics/bts074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315715PMC
April 2012