Faculty Bibliography
Searched for:
in-biosketch:true
person:wellit01
Total Results:
107
Comprehensive and Integrative Genomic Characterization of Hepatocellular Carcinoma
Liver cancer has the second highest worldwide cancer mortality rate and has limited therapeutic options. We analyzed 363 hepatocellular carcinoma (HCC) cases by whole-exome sequencing and DNA copy number analyses, and we analyzed 196 HCC cases by DNA methylation, RNA, miRNA, and proteomic expression also. DNA sequencing and mutation analysis identified significantly mutated genes, including LZTR1, EEF1A1, SF3B1, and SMARCA4. Significant alterations by mutation or downregulation by hypermethylation in genes likely to result in HCC metabolic reprogramming (ALB, APOB, and CPS1) were observed. Integrative molecular HCC subtyping incorporating unsupervised clustering of five data platforms identified three subtypes, one of which was associated with poorer prognosis in three HCC cohorts. Integrated analyses enabled development of a p53 target gene expression signature correlating with poor survival. Potential therapeutic targets for which inhibitors exist include WNT signaling, MDM4, MET, VEGFA, MCL1, IDH1, TERT, and immune checkpoint proteins CTLA-4, PD-1, and PD-L1.
ISI:000403332400020
ISSN: 1097-4172
CID: 2762962
Non-invasive Liver Ablation Using Histotripsy: Preclinical Safety Study in an in Vivo Porcine Model
This study investigates the safety profile for use of histotripsy, a non-invasive ultrasonic ablation method currently being developed for the treatment of liver cancer, for liver ablation in an in vivo porcine model. Histotripsy treatments were applied to the liver and hepatic veins of 22 porcine subjects, with half of the subjects receiving systemic heparinization. Vital signs (heart rate, blood pressure, temperature, electrocardiogram and SpO2) were monitored throughout the procedure and for 1 h post-treatment. Blood was drawn at six points during the experiment to analyze blood gases, liver function and free hemoglobin levels. All treatments were guided and monitored by real-time ultrasound imaging. After treatment, the tissue was harvested for histological analysis. Results indicated that histotripsy generated well-defined lesions inside the liver and around the treated hepatic veins of all subjects in both treatment groups. Vital signs and blood analysis revealed that animals responded well to histotripsy, with all animals surviving the treatment. One animal in the non-heparinized group had a transient increase in pH and decreases in blood pressure, heart rate and PCO2 during the 15-min vessel treatment, with these changes returning to baseline levels soon after the treatment. Overall, the results indicate that histotripsy can safely be performed on the liver without the need for systemic heparinization, even in regions containing large hepatic vessels, supporting its future use for the treatment of liver cancer.
PMID: 28318889
ISSN: 1879-291x
CID: 2547712
Hepatic transplantation
Philadelphia : Wolters Kluwer, [2017]
pp. ?-?
ISBN: 1469890011
CID: 2762682
Nivolumab (Nivo) in Patients (Pts) With Advanced Hepatocellular Carcinoma (HCC): the CheckMate 040 Study [Meeting Abstract]
ISI:000393900200011
ISSN: 1527-3350
CID: 2548322
Non-Invasive Ultrasound Liver Ablation Using Histotripsy: Chronic Study in an In Vivo Rodent Model
Hepatocellular carcinoma, or liver cancer, has the fastest growing incidence among cancers in the United States. Current liver ablation methods are thermal-based and share limitations due to the heat sink effect from the blood flow through the highly vascular liver. Recently, our group has investigated histotripsy as a non-invasive liver cancer ablation method. Histotripsy is a non-thermal ultrasonic ablation method that fractionates tissue through the control of acoustic cavitation. Previous experiments in an in vivo porcine model show that histotripsy can create well-confined lesions in the liver through ribcage obstruction without damaging the overlying ribs and other tissues. Histotripsy can also completely fractionate liver tissue surrounding major vessels while preserving the vessels. In this study, we investigate the long-term effects of histotripsy liver ablation in a rodent model. We hypothesize that the fractionated histotripsy lesion will be resorbed by the liver, resulting in effective tissue healing. To test this hypothesis, the livers of 20 healthy rats were treated with histotripsy using an 8-element 1-MHz histotripsy transducer. Rats were euthanized after 0, 3, 7, 14 and 28 days (n = 4). In vivo and post mortem results showed histotripsy lesions were successfully generated through the intact abdomen in all 20 rats. Magnetic resonance imaging found primarily negative contrast on day 0, positive contrast on day 3 and rapid normalization of signal intensity thereafter (i.e., signal amplitude returned to baseline levels seen in healthy liver tissue). Histologically, lesions were completely fractionated into an acellular homogenate. The lesions had a maximum cross-sectional area of 17.2 +/- 1.9 mm(2) and sharp boundaries between the lesion and the healthy surrounding tissue after treatment. As the animals recovered after treatment, the histotripsy tissue homogenate was almost completely replaced by regenerated liver parenchyma, resulting in a small fibrous lesion (<1 mm(2) maximum cross-section) remaining after 28 d. The results of this study suggest that histotripsy has potential as a non-invasive liver ablation method for effective tissue removal.
PMCID:4912895
PMID: 27140521
ISSN: 1879-291x
CID: 2547722
GM-CSF Mediates Mesenchymal-Epithelial Cross-talk in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDA) is characterized by a dense stroma consisting of a prevalence of activated fibroblasts whose functional contributions to pancreatic tumorigenesis remain incompletely understood. In this study, we provide the first identification and characterization of mesenchymal stem cells (MSC) within the human PDA microenvironment, highlighting the heterogeneity of the fibroblast population. Primary patient PDA samples and low-passage human pancreatic cancer-associated fibroblast cultures were found to contain a unique population of cancer-associated MSCs (CA-MSC). CA-MSCs markedly enhanced the growth, invasion, and metastatic potential of PDA cancer cells. CA-MSCs secreted the cytokine GM-CSF that was required for tumor cell proliferation, invasion, and transendothelial migration. Depletion of GM-CSF in CA-MSCs inhibited the ability of these cells to promote tumor cell growth and metastasis. Together, these data identify a population of MSCs within the tumor microenvironment that possesses a unique ability, through GM-CSF signaling, to promote PDA survival and metastasis. SIGNIFICANCE: The role of stroma in pancreatic cancer is controversial. Here, we provide the first characterization of MSCs within the human PDA microenvironment and demonstrate that CA-MSCs promote tumorigenesis through the production of GM-CSF. These data identify a novel cytokine pathway that mediates mesenchymal-epithelial cross-talk and is amenable to therapeutic intervention. Cancer Discov; 6(8); 886-99. (c)2016 AACR.This article is highlighted in the In This Issue feature, p. 803.
PMCID:5549011
PMID: 27184426
ISSN: 2159-8290
CID: 2416942
Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6
PURPOSE: The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors. EXPERIMENTAL DESIGN: Initial testing was carried out in the HCT-116 tumor model, which is known to harbor a KRAS mutation. Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models, genomically diverse with respect to KRAS, BRAF, and PIK3CA mutational status. Tolerance, efficacy, and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration. RESULTS: Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib. Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment. Testing of colorectal patient-derived xenograft (PDX) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS(mt) models tested. Stasis was observed in a KRAS/BRAF wild-type and a BRAF(mt) model. CONCLUSIONS: Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested. Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer.
PMCID:4715945
PMID: 26369631
ISSN: 1078-0432
CID: 2547742
Proceedings of SPIE (The International Society for Optical Engineering). 2016:9708.DOI: 10.1117/12.2213001
Photoacoustic physio-chemical analysis of liver conditions in animal and human subjects [Meeting Abstract]
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease affecting 30% of the population in the United States. Biopsy is the gold standard for diagnosing NAFLD. Liver histology assesses the amount of fat, and determines type and extent of cell injury, inflammation and fibrosis. However, liver biopsy is invasive and is limited by sampling error. Current radiological diagnostic modalities can evaluate the 'physical' morphology in liver by quantifying the backscattered US signals, but cannot interrogate the 'histochemical' components forming these backscatterers. For example, ultrasound (US) imaging can detect the presence of fat but cannot differentiate steatosis alone from steatohepatitis. Our previous study of photoacoustic physiochemical analysis (PAPCA) has demonstrated that this method can characterize the histological changes in livers during the progression of NAFLD in animal models. In this study, we will further validate PAPCA with human livers. Ex vivo human liver samples with steatosis, fibrosis and cirrhosis will be scanned using optical illumination at wavelengths of 680-1700 nm and compared to histology results. In vivo study on human subjects with confirmed steatosis is planned using our PA-ultrasound (US) parallel imaging system based on Verasonic US imaging flatform with an L7-4 probe. 10 mJ/cm(2) per pulse optical energy at 755 nm will be delivered to the skin surface, which is under the safety limit of American National Standard Institute. Preliminary study with ex vivo human tissue has demonstrated the potential of the proposed approach in differentiating human liver conditions.
ISI:000378437000052
ISSN: 0277-786x
CID: 2548302
Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction
Aerobic glycolysis regulates T cell function. However, whether and how primary cancer alters T cell glycolytic metabolism and affects tumor immunity in cancer patients remains a question. Here we found that ovarian cancers imposed glucose restriction on T cells and dampened their function via maintaining high expression of microRNAs miR-101 and miR-26a, which constrained expression of the methyltransferase EZH2. EZH2 activated the Notch pathway by suppressing Notch repressors Numb and Fbxw7 via trimethylation of histone H3 at Lys27 and, consequently, stimulated T cell polyfunctional cytokine expression and promoted their survival via Bcl-2 signaling. Moreover, small hairpin RNA-mediated knockdown of human EZH2 in T cells elicited poor antitumor immunity. EZH2(+)CD8(+) T cells were associated with improved survival in patients. Together, these data unveil a metabolic target and mechanism of cancer immune evasion.
PMCID:4684796
PMID: 26523864
ISSN: 1529-2916
CID: 2547732
Gallbladder and biliary tract : anatomy and structural anomalies
Chichester, West Sussex : John Wiley & Sons Inc., 2016
pp. ?-?
ISBN: 1118512065
CID: 2773472
