Yeup Yoon

Spatiotemporal Evolution of the Primary Glioblastoma Genome

Tumor recurrence following treatment is the major cause of mortality for glioblastoma multiforme (GBM) patients. Thus, insights on the evolutionary process at recurrence are critical for improved patient care. Here, we describe our genomic analyses of the initial and recurrent tumor specimens from each of 38 GBM patients. A substantial divergence in the landscape of driver alterations was associated with distant appearance of a recurrent tumor from the initial tumor, suggesting that the genomic profile of the initial tumor can mislead targeted therapies for the distally recurred tumor. In addition, in contrast to IDH1-mutated gliomas, IDH1-wild-type primary GBMs rarely developed hypermutation following temozolomide (TMZ) treatment, indicating low risk for TMZ-induced hypermutation for these tumors under the standard regimen.

Adeno‐associated virus‐mediated expression of apolipoprotein (a) kringles suppresses hepatocellular carcinoma growth in mice

Hepatocellular carcinoma (HCC) constitutes more than 90% of all primary liver cancers. HCC is a hypervascular tumor that develops from dedifferentiation of small avascular HCC and is therefore a good target for anti‐angiogenic gene therapy. Recent studies have identified apolipoprotein(a) [apo(a)] kringles LK68 and LK8 (LKs) as having a potential anti‐angiogenic and anti‐tumor activity, and the current study evaluates the therapeutic potential of gene therapy with recombinant adeno‐associated virus carrying genes encoding LKs (rAAV‐LK) in the treatment of hypervascular HCC. We generated rAAV‐LK to obtain persistent transgene expression in vivo, which is essential for anti‐angiogenic therapy. The rAAV‐produced LKs substantially inhibited proliferation and migration of human umbilical vein endothelial cells (HUVECs) in vitro, validating their anti‐angiogenic potential. Intramuscular administration of rAAV‐LK gave 60% to 84% suppression (P < .05) of tumor growth in mice bearing subcutaneously transplanted HCC derived from Huh‐7 and Hep3B cells, respectively. Histological and immunohistochemical analyses of HCC tumor sections showed that a single administration of rAAV‐LK gave rise to persistent expression of LKs that inhibited tumor angiogenesis and triggered tumor apoptosis, and, thus, significantly suppressed tumor growth. The administration of rAAV‐LK provided a significant survival benefit (P < .05), and 3 of 10 rAAV‐LK–treated mice were still alive without visible tumors and without clinical symptoms 188 days after treatment. In conclusion, rAAV‐LK is a potential candidate for anti‐angiogenic gene therapy in the treatment of HCC. (HEPATOLOGY 2006;43:1063–1073.)

Natural killer (NK) cells inhibit systemic metastasis of glioblastoma cells and have therapeutic effects against glioblastomas in the brain

BackgroundGlioblastoma multiforme (GBM) is characterized by extensive local invasion, which is in contrast with extremely rare systemic metastasis of GBM. Molecular mechanisms inhibiting systemic metastasis of GBM would be a novel therapeutic candidate for GBM in the brain.MethodsPatient-derived GBM cells were primarily cultured from surgical samples of GBM patients and were inoculated into the brains of immune deficient BALB/c-nude or NOD-SCID IL2Rgammanull (NSG) mice. Human NK cells were isolated from peripheral blood mononucleated cells and expanded in vitro.ResultsPatient-derived GBM cells in the brains of NSG mice unexpectedly induced spontaneous lung metastasis although no metastasis was detected in BALB/c-nude mice. Based on the difference of the innate immunity between two mouse strains, NK cell activities of orthotopic GBM xenograft models based on BALB/c-nude mice were inhibited. NK cell inactivation induced spontaneous lung metastasis of GBM cells, which indicated that NK cells inhibit the systemic metastasis. In vitro cytotoxic activities of human NK cells against GBM cells indicated that cytotoxic activity of NK cells against GBM cells prevents systemic metastasis of GBM and that NK cells could be effective cell therapeutics against GBM. Accordingly, NK cells transplanted into orthotopic GBM xenograft models intravenously or intratumorally induced apoptosis of GBM cells in the brain and showed significant therapeutic effects.ConclusionsOur results suggest that innate NK immunity is responsible for rare systemic metastasis of GBM and that sufficient supplementation of NK cells could be a promising immunotherapeutic strategy for GBM in the brain.

Translational Validation of Personalized Treatment Strategy Based on Genetic Characteristics of Glioblastoma

Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. The Cancer Genome Atlas (TCGA) Research Network has been established the comprehensive genomic abnormalities of GBM, which sub-classified GBMs into 4 different molecular subtypes. The molecular subtypes could be utilized to develop personalized treatment strategy for each subtype. We applied a classifying method, NTP (Nearest Template Prediction) method to determine molecular subtype of each GBM patient and corresponding orthotopic xenograft animal model. The models were derived from GBM cells dissociated from patients surgical sample. Specific drug candidates for each subtype were selected using an integrated pharmacological network database (PharmDB), which link drugs with subtype specific genes. Treatment effects of the drug candidates were determined by in vitro limiting dilution assay using patient-derived GBM cells primarily cultured from orthotopic xenograft tumors. The consistent identification of molecular subtype by the NTP method was validated using TCGA database. When subtypes were determined by the NTP method, orthotopic xenograft animal models faithfully maintained the molecular subtypes of parental tumors. Subtype specific drugs not only showed significant inhibition effects on the in vitro clonogenicity of patient-derived GBM cells but also synergistically reversed temozolomide resistance of MGMT-unmethylated patient-derived GBM cells. However, inhibitory effects on the clonogenicity were not totally subtype-specific. Personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs, although more sophisticated classifying techniques and subtype specific drugs need to be further elucidated.

T2 mapping of the articular cartilage in the ankle: Correlation to the status of anterior talofibular ligament

AIM To evaluate differences in T2 relaxation time of ankle cartilage using magnetic resonance imaging (MRI) according to the status of the anterior talofibular ligament (ATFL). MATERIALS AND METHODS The talar trochlear cartilage (TTC) was evaluated in 52 patients with ankle pain that were categorized according to the status of ATFL; normal (NL; n = 23, mean age 40 years); partial tear (PT; n = 21, mean age 39 years); or complete tear (CT; n = 8, mean age 33 years). The TTC was divided into six compartments (medial anterior, medial centre, medial posterior, lateral anterior, lateral centre, and lateral posterior). The mean T2 value of each compartment was obtained using the multi-echo sequence. Data were analysed with parametric and non-parametric statistical tests. RESULTS The mean T2 values of the TTC showed significant differences between the three groups; NL, PT, and CT (p < 0.001). The T2 value between the three ligamentous groups were significantly different in the medial anterior, lateral anterior, and lateral centre compartments (p = 0.003, 0.002, 0.002, respectively). T2 values of the PT and CT groups were significantly higher than those of the NL group in the medial anterior compartment (p = 0.015, 0.002) and lateral anterior compartment (p = 0.026, <0.001). The T2 value of the CT group was significantly higher than that of NL and PT groups in the lateral centre compartment (p < 0.001, 0.031). CONCLUSION The T2 value of the TTC in patients with ATFL injury increased at the medial anterior, lateral anterior, and lateral centre compartments.

Pharmacogenomic landscape of patient-derived tumor cells informs precision oncology therapy

Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive intertumoral heterogeneity. The fundamental tenet of precision oncology defines molecular characterization of tumors to guide optimal patient-tailored therapy. Towards this goal, we have established a compilation of pharmacological landscapes of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared with the traditional long-term cultured cancer cell line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. Here, we provide insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors, and the potential repurposing of ibrutinib (currently used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present a potential implementation of PDC-derived drug sensitivities for the prediction of clinical response to targeted therapeutics using retrospective clinical studies.Analysis of genomic and transcriptomic data from 462 patient-derived tumor cell (PDC) samples across 14 cancer types, along with pharmacological responses to 60 agents, indicates that PDC-derived drug sensitivities might be predictive of clinical response to targeted therapies.

GC1118, an anti-EGFR antibody with a distinct binding epitope and superior inhibitory activity against high-affinity EGFR ligands

The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR–GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251–63. ©2015 AACR.

Multiparametric approach with diffusion-weighted imaging and dynamic contrast-enhanced MRI: a comparison study for differentiating between benign and malignant bone lesions in adults

AIM To evaluate and compare the diagnostic performance of quantitative parameters derived from diffusion-weighted imaging (DWI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in differentiating benign and malignant bone tumours. MATERIALS AND METHODS Fifty-five patients (age range, 21-82 years; mean age, 55 years) underwent pretreatment MRI. Apparent diffusion coefficient (ADC) values were calculated by DWI. The DCE-MRI data were analysed for the volume transfer constant (Ktrans), extravascular extracellular volume fraction (Ve), and volume rate constant (Kep), and Ktrans/ADC ratio. Each parameters performance was evaluated using the area under the receiver operating characteristic (ROC) curv (AUC), and their AUCs were compared. ROC curves were analysed and each parameters optimal cut-off value was determined, from which each parameter was evaluated for sensitivity, specificity, accuracy, and positive and negative predictive values. The odds ratio (OR) with 95% confidence interval for detecting malignant bone lesions after adjusting the age factor of each parameter was estimated. RESULTS All parameter values (except Ve) were significantly different between benign and malignant bone tumours (p<0.05). The Ktrans had a significantly greater AUC than Ve (p=0.03). The Ktrans/ADC and Kep had the best sensitivity (0.917) and specificity (0.632), respectively. The Kep and Ktrans/ADC had the best positive (0.811) and negative (0.769) predictive values, respectively. The OR was highest for Ktrans/ADC (17.38; p=0.0013). CONCLUSION The Ktrans, Kep, ADC, and Ktrans/ADC could help to detect malignant lesions from bone tumours and Ktrans/ADC appears to be the superior variable among them.

Clinical relevance of the apparent diffusion coefficient value of metastatic bone tumours on diffusion-weighted MRI images: differences according to the types of primary tumour, the affected bones, and clinical factors

AIM To evaluate whether the apparent diffusion coefficient (ADC) of metastatic bone tumours on diffusion-weighted magnetic resonance imaging (MRI) images differs according to the type of primary cancer, the affected bone, and clinical factors. MATERIALS AND METHODS For this retrospective study, two radiologists reviewed MRI images, including ADC maps, of 67 patients (M:F=38:29; median age, 48 years) who were diagnosed with bone metastasis by means of histological or clinical confirmation. The primary tumours included 29 lung adenocarcinomas, 15 invasive ductal adenocarcinomas of the breast, 13 hepatocellular carcinomas, six prostatic carcinomas, and four renal cell carcinomas. ADC values of the metastatic tumour were compared according to the type of primary malignancy, the affected bone, and the age and sex of the patient using Kruskal-Wallis and Mann-Whitney U-tests with Bonferroni correction. In addition, pre-contrast CT images were available in 38 of 67 patients; a subanalysis of the CT radiodensity and ADC values were performed with Spearman correlation. RESULTS The mean, standard deviation, and minimum and maximum values of the ADC of metastatic bone tumours did not differ significantly according to type of primary malignancy, the affected bone, or clinical variables (p>0.1). The ADC value was not significantly correlated with CT radiodensity (p=0.24). Intra- and interobserver agreements for the mean ADC values were excellent (intra-observer: p=0.98; interobserver: p=0.98). CONCLUSIONS Assessment of the ADC value of metastatic bone tumours is not reliable for differentiation of the type of primary cancer.