Faculty Bibliography
Searched for:
in-biosketch:true
person:wellit01
Total Results:
108
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
Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial
BACKGROUND: For patients with advanced hepatocellular carcinoma, sorafenib is the only approved drug worldwide, and outcomes remain poor. We aimed to assess the safety and efficacy of nivolumab, a programmed cell death protein-1 (PD-1) immune checkpoint inhibitor, in patients with advanced hepatocellular carcinoma with or without chronic viral hepatitis. METHODS: We did a phase 1/2, open-label, non-comparative, dose escalation and expansion trial (CheckMate 040) of nivolumab in adults (>/=18 years) with histologically confirmed advanced hepatocellular carcinoma with or without hepatitis C or B (HCV or HBV) infection. Previous sorafenib treatment was allowed. A dose-escalation phase was conducted at seven hospitals or academic centres in four countries or territories (USA, Spain, Hong Kong, and Singapore) and a dose-expansion phase was conducted at an additional 39 sites in 11 countries (Canada, UK, Germany, Italy, Japan, South Korea, Taiwan). At screening, eligible patients had Child-Pugh scores of 7 or less (Child-Pugh A or B7) for the dose-escalation phase and 6 or less (Child-Pugh A) for the dose-expansion phase, and an Eastern Cooperative Oncology Group performance status of 1 or less. Patients with HBV infection had to be receiving effective antiviral therapy (viral load <100 IU/mL); antiviral therapy was not required for patients with HCV infection. We excluded patients previously treated with an agent targeting T-cell costimulation or checkpoint pathways. Patients received intravenous nivolumab 0.1-10 mg/kg every 2 weeks in the dose-escalation phase (3+3 design). Nivolumab 3 mg/kg was given every 2 weeks in the dose-expansion phase to patients in four cohorts: sorafenib untreated or intolerant without viral hepatitis, sorafenib progressor without viral hepatitis, HCV infected, and HBV infected. Primary endpoints were safety and tolerability for the escalation phase and objective response rate (Response Evaluation Criteria In Solid Tumors version 1.1) for the expansion phase. This study is registered with ClinicalTrials.gov, number NCT01658878. FINDINGS: Between Nov 26, 2012, and Aug 8, 2016, 262 eligible patients were treated (48 patients in the dose-escalation phase and 214 in the dose-expansion phase). 202 (77%) of 262 patients have completed treatment and follow-up is ongoing. During dose escalation, nivolumab showed a manageable safety profile, including acceptable tolerability. In this phase, 46 (96%) of 48 patients discontinued treatment, 42 (88%) due to disease progression. Incidence of treatment-related adverse events did not seem to be associated with dose and no maximum tolerated dose was reached. 12 (25%) of 48 patients had grade 3/4 treatment-related adverse events. Three (6%) patients had treatment-related serious adverse events (pemphigoid, adrenal insufficiency, liver disorder). 30 (63%) of 48 patients in the dose-escalation phase died (not determined to be related to nivolumab therapy). Nivolumab 3 mg/kg was chosen for dose expansion. The objective response rate was 20% (95% CI 15-26) in patients treated with nivolumab 3 mg/kg in the dose-expansion phase and 15% (95% CI 6-28) in the dose-escalation phase. INTERPRETATION: Nivolumab had a manageable safety profile and no new signals were observed in patients with advanced hepatocellular carcinoma. Durable objective responses show the potential of nivolumab for treatment of advanced hepatocellular carcinoma. FUNDING: Bristol-Myers Squibb.
PMID: 28434648
ISSN: 1474-547x
CID: 2762952
Hepatic transplantation
Philadelphia : Wolters Kluwer, [2017]
pp. ?-?
ISBN: 1469890011
CID: 2762682
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
Gallbladder and biliary tract : anatomy and structural anomalies
Chichester, West Sussex : John Wiley & Sons Inc., 2016
pp. ?-?
ISBN: 1118512065
CID: 2773472
Gallbladder and biliary tract : anatomy and structural anomalies
Chichester, West Sussex ; Hoboken, NJ : Wiley Blackwell, 2016
pp. ?-?
ISBN: 9781118512012
CID: 2764002
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
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
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
Nivolumab (Nivo) in Patients (Pts) With Advanced Hepatocellular Carcinoma (HCC): the CheckMate 040 Study [Meeting Abstract]
ISI:000393900200011
ISSN: 1527-3350
CID: 2548322
