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SUMMARY Full waveform inversion (FWI) is a highly non-linear optimization problem that aims to reconstruct high-resolution subsurface structures. The success of FWI in reflection seismology relies on appropriate updates of low-wavenumber background velocity structures, which are generally driven by the diving waves in conventional FWI. On the other hand, the reflected waves mainly contribute to updating high-wavenumber components rather than low-wavenumber components. To extract low-wavenumber information from the reflected waves in addition to the diving waves, we propose a two-step FWI strategy that separates a given model into the reflectivity and background velocity models and then alternately update them using the scale-separation technique based on diffraction-angle filtering (DAF; which was proposed to effectively control wavenumber components of the FWI gradient). Our strategy first inverts the high-wavenumber reflectivity model by suppressing energy at large diffraction angles, which are necessary to compute the reflection wave paths (i.e. the rabbit-ears-shaped kernels) for low-wavenumber updates in the subsequent stage. Then, we extract low-wavenumber components due to the diving (banana-shaped kernels) and reflected waves (rabbit-ears-shaped kernels) from the gradient by suppressing energy at small diffraction angles. Our strategy is similar to reflection waveform inversion (RWI) in that it separates a given model into high- and low-wavenumber components and uses the rabbit-ears-shaped kernels for low-wavenumber updates. The main difference between our strategy and RWI is that our strategy adopts the DAF-based scale-separation technique in the space domain, which makes our algorithm of using both the banana-shaped and rabbit-ears-shaped kernels computationally attractive. By applying our two-step inversion strategy to the synthetic data for the Marmousi-II model and the real ocean-bottom cable data from the North sea, we demonstrate that our method properly reconstructs low-wavenumber structures even if initial models deviate from the true models.

Full-waveform inversion (FWI), which is among the most powerful seismic data processing techniques for imaging subsurface geological structures, has a huge computational cost in proportion to the n...

Prostaglandin E2 (PGE2) is widely recognized as one of the major bioactive lipids that, with the striking regenerative potential, promote drug-resistance in cancer cells as well as immune evasion in the tumor microenvironment (TME). Primarily driven by apoptotic cell death, PGE2 is thought to elicit wound-healing responses to help provide an immunosuppressive and proliferative niche that supports cancer stem cell repopulation and thereby therapy-resistance. While COX1/2 inhibitors that attenuate PGE2 production have shown promising anti-cancer effects in various (pre-)clinical settings, the gastrointestinal- and cardiotoxicities precluded their development as anti-cancer agents. It is anticipated that specific targeting of PGE2 signaling via its cognate receptors constitutes a safer and potentially more effective approach. Of the receptor subtypes EP1-4, Gα,s-coupled EP2 and EP4 are believed to be directly involved in immunosuppressive effects of PGE2.OCT-598 is a novel, highly potent and selective EP2/EP4 dual antagonist with Ki values of 23 nM and 0.2 nM vs EP2 and EP4, respectively. PGE2 inhibited normal differentiation of human monocytes into CD1a+CD16- dendritic cells under the presence of GM-CSF and IL-4 and promoted differentiation towards CD1a-CD16+ macrophages in vitro. However, EP2/EP4 dual inhibition by OCT-598 reversed this phenomenon to a greater extent than either EP2- or EP4-specific inhibitor alone. In vivo, OCT-598 effected tumor growth inhibition in multiple syngeneic mouse models as a single agent as well as in combination with an immune checkpoint blocker (ICB). Furthermore, the addition of OCT-598 to the lung cancer standard-of-care regimen (anti-PD-1 plus chemotherapy) in TC-1 mouse lung adenocarcinoma model gave rise to complete tumor regression. In conclusion, dual blockade of EP2 and EP4 by OCT-598 is shown to be a compelling strategy to reinforce antitumor effects by thwarting PGE2-mediated therapy resistance and immune evasion.Findings from this study provide a rationale for clinical development of OCT-598 as a therapeutic option for human malignant cancers. Citation Format: Youngrae Lee, Sujeong Baek, Dong Kwon Kim, Yeri Lee, Donggeon Kim, Seongin Jo, Sang Kyun Lim, Young Sook Shin, Soonsang Kwon, Seung Min Yang, Young Taek Kim, Seong-San Kang, Chun-Bong Synn, Kwangmin Na, Mi Hyun Kim, Heekyung Han, Yu Jin Han, Sungwoo Lee, Jae Hwan Kim, Mi Ran Yun, Youngseon Byeon, Young Seob Kim, Ji Yun Lee, Jii Bum Lee, Chang Gon Kim, Min Hee Hong, Sun Min Lim, Kyoung-Ho Pyo, Byoung Chul Cho, Taeyoung Yoon. OCT-598, a novel EP2/EP4 dual antagonist, promotes anti-tumor immune responses in syngeneic mouse tumor models in combination with standard-of-care chemo- and immunotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3234.

Abnormal activating mutation of KRAS is frequently found in many human cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and non-small cell lung cancer (NSCLC). KRAS activating mutations lead to hyperactivation of the MAPK/ERK signaling pathway, resulting in promotion of cell proliferation and growth. SOS1 is one of the major guanine nucleotide exchange factors (GEFs) that regulates RAS proteins including KRAS. Since SOS1 plays a critical role in converting the GDP-bound inactive KRAS “off” state to the GTP-bound active KRAS “on” state, disruption of SOS1 and KRAS protein-protein interaction would be effective to block KRAS-driven oncogenic signaling regardless of its mutation status. Importantly, SOS1 activity is crucial during the reactivation of the KRAS/MAPK signaling upon the treatment of RAS/MEK/ERK inhibitors, thus a SOS1 inhibitor would be an effective therapeutic option to treat KRAS-driven tumors in combination with RAS pathway inhibitors. We developed potent, selective, and orally available small molecules that effectively disrupt the interaction between SOS1 and KRAS. Current lead compounds originated from a virtual screening displayed excellent ADME and PK profiles. In cellular assays, a robust reduction of phospho-ERK level and cancer cell growth were shown. We also observed excellent in vivo antitumor activity in the mouse xenograft models. Moreover, combination with Sotorasib synergistically inhibited tumor cell growth both in vitro and in vivo. Overall, our SOS1 inhibitors demonstrate great therapeutic potential for cancer patients with KRAS mutations. Citation Format: Ha Na Yu, Dong Hyuk Ki, Joonwoo Nam, Eun-Jung Kim, Sungeun Kim, Hunmi Choi, Jieun Kim, Jihyun Yu, Donggeon Kim, Dohyun Park, Kyeong Jin Yoon, Seongin Jo, So-Hyeon Hwang, Sang Kyun Lim, Young Sook Shin, Wooseok Han. Discovery of potent and orally available small molecule inhibitors of the SOS1-KRAS interaction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 515.

EGFR is one of receptor tyrosine kinases (RTKs) and, upon ligand binding, turns on the downstream signals that include oncogenic RAS/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways. EGFR gene mutations, such as Exon 19 deletion (Del19) and L858R mutations, induce abnormal activation of the EGFR protein even in the absence of the ligand leading to various cancers. EGFR mutations are found in non-small cell lung cancer (NSCLC) patients with 10-15% frequency (approximately 50% in Asian patients). Starting from Del19 and L8585R mutations, additional mutations in the EGFR gene occur during the treatment with 1st/2nd/3rd generation EGFR inhibitors, resulting in Del19/T790M, L858R/T790M, Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, and L858R/C797S mutations. While double mutations that include the T790M mutation have been efficaciously treated with Osimertinib, there are currently no approved therapies that can effectively target the C797S-containing mutants. Here we present preclinical data showing a small-molecule inhibitor that effectively disables EGFR mutants, including Del19/T790M/C797S, L858R/T790M/C797S, Del19/C797S, and L858R/C797S mutants. High potency and selectivity were confirmed by in vitro kinase assays and cellular assays. Outstanding anti-cancer activity was observed in mouse xenograft models with various EGFR mutations and, importantly, it was inactive in the EGFR wild-type model. With confirmed brain penetrance through in vivo studies, our potent EGFR inhibitor may provide a great therapeutic potential for patients with EGFR mutation-driven NSCLC. Citation Format: Yeejin Jeon, Kiram Lee, Anna Jang, Miyeon Kim, Kyeong Jin Yoon, Yeri Lee, Dongsu Kim, Donggeon Kim, Dohyun Park, Sang Kyun Lim, Sung Pil Choi. Discovery of a small-molecule EGFR inhibitor that can potently target various EGFR mutants, including C797S mutant, in vitro and in vivo. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4016.

High-intensity focused ultrasound (HIFU) therapy has emerged as an option for skin rejuvenation. However, the application against photo-damaged skin remains obscure. This study evaluates the effect of HIFU against photoaged skin using a mouse model.A total of 60 mice were used and divided into 3 groups; group 1: natural aging control group (n = 20), group 2: UVB irradiation group (n = 20), and group 3: UVB irradiation followed by HIFU treatment (n = 20). The evaluation was made grossly by analyzing wrinkles and histologically by performing HE, Toluidine Blue, Masson's Trichrome, and immunohistochemistry for TGF-β and MMP3. Imaging software was used to quantify the findings.Gross findings showed HIFU treated group 3 with similar findings with the control group supporting the rejuvenation effect for photo-aged skin. Histology findings with HE show a significant reduction in skin thickness after HIFU treatment (60.115 units (group 2) vs. 40.853 units (group 3), p0.05). Toluidine Blue and Masson's Trichrome showed improved collagen array and significantly increased distribution for group 3 over group 2 (272,879.88 units (group 2) vs. 533,805.78 units (group 3), p0.05). Immunohistochemistry for TGF-β showed a significantly higher value for group 3 (2.45450 units) over group 2 (0.58880 units) and MMP3 with a significantly lower value for group 3 (99,180 units) over group 2 (559,830 units) (p0.05).The treatment of HIFU supports the rejuvenation effect for photoaged skin. Findings show that HIFU provides benefits of collagen formation and rearrangement by enhancing TGF-β and inhibiting MMP3 activity. This study is the first animal study to show the direct effect of HIFU on photo-aged skin further supporting the use of HIFU in aging skin aiming to reverse the morphological effects of aging.

Background Glioblastoma (GBM) is a complex disease with extensive molecular and transcriptional heterogeneity. GBM can be subcategorized into four distinct subtypes; tumors that shift towards the mesenchymal phenotype upon recurrence are generally associated with treatment resistance, unfavorable prognosis, and the infiltration of pro-tumorigenic macrophages. Results We explore the transcriptional regulatory networks of mesenchymal-associated tumor-associated macrophages (MA-TAMs), which drive the malignant phenotypic state of GBM, and identify macrophage receptor with collagenous structure (MARCO) as the most highly differentially expressed gene. MARCOhigh TAMs induce a phenotypic shift towards mesenchymal cellular state of glioma stem cells, promoting both invasive and proliferative activities, as well as therapeutic resistance to irradiation. MARCOhigh TAMs also significantly accelerate tumor engraftment and growth in vivo. Moreover, both MA-TAM master regulators and their target genes are significantly correlated with poor clinical outcomes and are often associated with genomic aberrations in neurofibromin 1 (NF1) and phosphoinositide 3-kinases/mammalian target of rapamycin/Akt pathway (PI3K-mTOR-AKT)-related genes. We further demonstrate the origination of MA-TAMs from peripheral blood, as well as their potential association with tumor-induced polarization states and immunosuppressive environments. Conclusions Collectively, our study characterizes the global transcriptional profile of TAMs driving mesenchymal GBM pathogenesis, providing potential therapeutic targets for improving the effectiveness of GBM immunotherapy.

Glioblastoma (GBM) is the most lethal primary brain tumor with few treatment options. The survival of glioma-initiating cells (GICs) is one of the major factors contributing to treatment failure. GICs frequently produce and respond to their own growth factors that support cell proliferation and survival. In this study, we aimed to identify critical autocrine factors mediating GIC survival and to evaluate the anti-GBM effect of antagonizing these factors. Proteomic analysis was performed using conditioned media from two different patient-derived GBM tumor spheres under a growth factor-depleted status. Then, the antitumor effects of inhibiting an identified autocrine factor were evaluated by bioinformatic analysis and molecular validation. Proteins secreted by sphere-forming GICs promote cell proliferation/survival and detoxify reactive oxygen species (ROS). Among these proteins, we focused on midkine (MDK) as a clinically significant and pathologically relevant autocrine factor. Antagonizing MDK reduced the survival of GBM tumor spheres through the promotion of cell cycle arrest and the consequent apoptotic cell death caused by oxidative stress-induced DNA damage. We also identified PCBP4, a novel molecular predictor of resistance to anti-MDK treatment. Collectively, our results indicate that MDK inhibition is an important therapeutic option by suppressing GIC survival through the induction of ROS-mediated cell cycle arrest and apoptosis., Brain cancer: a key growth factor Targeting the growth factor midkine (MDK) may offer improved treatment for glioblastoma, the most lethal brain cancer. In glioblastoma, the tumor-initiating cells produce their own growth factors, encouraging themselves to keep multiplying, and making glioblastoma very difficult to treat. Do-Hyun Nam and Hyun Ju Kang at the Samsung Medical Center, Seoul, South Korea and coworkers screened the growth factors produced by two glioblastoma samples, then focused on a single cancer-associated factor, MDK. Antagonizing MDK slowed tumor cell growth, and further investigation showed that suppressing MDK restored the susceptibility of tumor cells to DNA damage and the mechanisms that weed out damaged cells. Noting that treatment efficacy varied between tumor samples, the researchers identified a biomarker for sensitivity to MDK treatment. These results point the way to new treatments for this particularly deadly cancer.

Ground penetrating radar (GPR) is one of the most widely used geophysical survey methods to locate cavities under roads due to its speedy exploration and high-resolution imaging. To locate underground cavities using GPR, we need to distinguish between cavity-induced reflections and other reflections, which can be achieved by examining the polarity change in reflections compared to the polarity of the transmitted signal. The polarity change can be measured from the phase shift between the target and first reflections. To estimate the phase shift in reflections, the method of computing the power spectrum difference between the original trace and background signal was proposed, but the method has a limitation for shallow reflectors. As an alternative method to avoid this limitation, we propose using only one component of the power spectrum difference, the cross-correlation between the target reflection and background signal. The cross-correlation has its maximum peak at a time lag between the target and first reflection (from the air-ground interface). Additionally, the phase at that time lag represents a phase shift between the two reflections. We compare our cross-correlation-based method with the conventional method of computing the whole power spectrum difference and investigate the feasibility of our method for distinguishing cavity-induced reflections using a 2D field data set acquired in a testbed in Sudeoksa, Korea.

Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.

EGFR is a transmembrane protein that functions as a receptor tyrosine kinase (RTK). Upon ligand binding or by activating mutations (Exon19 deletion, L858R mutation, and others), EGFR turns on the downstream signals that include oncogenic RAS/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways. EGFR gene mutations and amplifications are frequently found in various human cancers and, in non-small cell lung cancer (NSCLC), the EGFR gene is mutated with 10-15% frequency (about 50% in Asian patients). While the 1st and 2nd generation EGFR inhibitors are effective in targeting EGFR mutants with Exon19 deletion and L858R mutation, additional T790M mutation in the EGFR gene causes resistance. The 3rd generation EGFR inhibitor (Osimertinib) works against EGFR mutants with T790M mutation; however, another EGFR mutation occurs at the amino acid 797 position (C797S), which makes Osimertinib ineffective. This is one of the major resistance mechanisms in Osimertinib-treated patients, and the 4th generation EGFR inhibitor that can target the C797S mutant is needed. We developed a compound that effectively disables various EGFR mutations, including Del19/T790M/C797S, L858R/T790/C797S, Del19/C797S, and L858R/C797S. In vitro kinase assay and cellular assays showed high potency and selectivity. In vivo PK/PD and efficacy tests confirmed the great therapeutic potential of this inhibitor for patients with EGFR mutations. Citation Format: Dongsu Kim, Woo Seung Son, Anna Jang, Yeri Lee, Donggeon Kim, Changyu Choi, Kyung Hoon Min, Sung Pil Choi, Sang Kyun Lim. Discovery of a small-molecule inhibitor that can target EGFR with C797S mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3323.

PTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.

Background Prostaglandin E2 (PGE2) is one of the most abundant prostaglandins, with crucial roles in normal and pathologic physiology. Especially, PGE2 levels are abnormally elevated in many cancers, and high levels of PGE2 are known to be pro-tumorigenic, likely due to the immune suppressive effect in the tumor microenvironment.1–4 There are four types of PGE2 receptors; EP1, EP2, EP3 and EP4. Among them, EP2 and EP4 activate adenylate cyclase and increase cAMP levels, which induce the cAMP-dependent protein kinase (PKA) signaling pathway. EP2 and EP4 are expressed in various immune cells (e.g. macrophages, dendritic cells, NK cells and CTLs), and genetic and pharmacological inhibition of EP2 and EP4 increases immune activity and suppresses tumor growth. Methods To evaluate the binding affinity against EP2 and EP4, a radioligand binding assay was conducted using EP2 or EP4 transfected HEK293 cells. Cell membrane homogenates were incubated with [3H]PGE2 in the absence or presence of the test compounds. Following incubation, the samples were filtered rapidly under vacuum through glass fiber filters and rinsed several times with cold Tris-HCl. The filters were dried then counted for radioactivity in a scintillation counter using a scintillation cocktail. The results were expressed as a percent inhibition of the control radioligand specific binding.The antagonistic activity against EP2 and EP4 was assessed via LANCE Ultra cAMP assay (PerkinElmer). HEK293 cells overexpressing EP2 or EP4 were seeded into the plate and treated by PGE2 and compounds. After 30 minutes of incubation, cAMP levels were measured by FRET signal using Varioskan plate reader, following the manufacturer’s protocol.Anti-tumor activity of KT-00113 was evaluated using LLC1 syngeneic model. When tumor volume reached approximatively 100 mm3, mice were treated PO, QD. Tumor size was measured twice every week. Results Systematic structure-activity relationship (SAR) investigation identified novel EP2 and EP4 dual antagonists. The most promising compound KT-00113 possesses high potency against both EP2 and EP4, while maintaining high selectivity over other prostanoid receptors. In vitro and in vivo ADMET studies show that KT-00113 has a favorable profile, apt for further examination in in vivo cancer models and immune cell function in tumors. Conclusions KT-00113, a highly potent and selective EP2/4 dual antagonist has strong potential to become the best-in-class immune suppression lifting cancer immunotherapy and may be suitable for further development in a clinical setting. References Cordes T, Hoellen F, Dittmer C, Salehin D, Kummel S, Friedrich M, Koster F, Becker S, Diedrich K, Thill M. Correlation of prostaglandin metabolizing enzymes and serum PGE2 levels with vitamin D receptor and serum 25(OH)2D3 levels in breast and ovarian cancer. Anticancer Res;32 ( 2012):351–357. Diakowska D, Markocka-Maczka K, Nienartowicz M, Lewandowski A, Grabowski K. Increased level of serum prostaglandin-2 in early stage of esophageal squamous cell carcinoma, Arch Med Sci ( 2014);10:956–961. Akbari N, Ghorbani M, Salimi V, Alimohammadi A, Khamseh ME, Akbari H, Nourbakhsh M, Sheikhi A, Taghavi SF, Tavakoli-Yaraki M. Cyclooxygenase enzyme and PGE2 expression in patients with functional and non-functional pituitary adenomas. BMC Endocr Disord 2020;20:39. Gomes RN, Felipe da Costa S, Colquhoun A. Eicosanoids and cancer, Clinics (Sao Paulo), 73 ( 2018) e530s.

Background Although cancer immunotherapy showed promising results in hematological malignancies, it has come up with relatively low tumor response for many solid tumors partly due to immune-suppressive tumor microenvironment (TME). Because of the immune-suppressive nature of TME, TME has been an active area of research and therapeutic target for restoring immune system and subsequent tumor growth inhibition. Among the many components in TME, cancer-associated fibroblasts (CAFs) are one of the key cell components of TME where one of the promising solid-tumor TME marker, fibroblast-activating protein (FAP) is highly expressed. Here we have developed an antibody-cytokine fusion protein from our TMEkine™ platform containing anti-FAP and IL-12. Our TMEkine™ (anti-FAP-IL-12) molecule induced strong anti-cancer effects in preclinical solid tumor models by immune-modulation. Methods IL-12 cytokine was mutated in TMEkine™ (anti-FAP-IL-12) to reduce systemic toxicity and its binding affinity was tested to FAP and IL-12 receptor. The anti-tumor activity of anti-FAP-IL-12 was investigated on CT26 (murine colorectal cancer) syngeneic mouse models with/without NIH-3T3 (murine fibroblast). Additionally, mice showing complete response after anti-FAP-IL-12 administration were re-injected CT26 with/without 4T1 cells for re-challenge study to monitor long-term durable response generated from the initial immune activation. Results We showed that TMEkine™ (anti-FAP-IL-12) interacts with FAP and IL-12 receptor. IL-12 activity was attenuated by our IL-12 mutants. We also showed that TMEkine™ (anti-FAP-IL-12) induced IFN-γ from primary human T cells and NK cells. TMEkine™ (anti-FAP-IL-12) administration resulted in significant reduction of the tumor burden in both CT26+NIH-3T3/FAP+ and CT26/FAP+ models. In the re-challenge experiments, CT26 tumor growth was inhibited significantly compared to 4T1 tumor suggesting memory immune response was generated in TMEkine™ (anti-FAP-IL-12) treated mice. Conclusions These findings provide evidences that the treatment of anti-FAP/IL-12 TMEkine™ induced anti-cancer effects without serious adverse effects. Anti-FAP/IL-12 has a strong potential to provide a therapeutic option for cancer-specific immunomodulator and cancer cell eradication.

Background We developed tumor microenvironment-targeting immunocytokine or TMEkine™ utilizing strong anti-tumoral effect of interleukin 12 (IL-12). In this effort, we created a bi-specific 1+1 antibody fusion with conventional knob-in-hole technology where anti-CD20 was paired with IL-12 fc fusion arm. A couple of IL-12 muteins were used in our therapeutic molecules to reduce systemic toxicity. IL-12 has been known for a key orchestrator in immune response. The main actions of IL-12 include the induction of CD4+ Th0 cells toward Th1 type and enhancement of IFN-γ production, stimulation of cytotoxicity and growth of natural killer (NK) cells and CD8+ T cells. For these reasons, IL-12 has long been considered as a potential therapeutic molecule for treating cancers by enhancing immune activity toward tumor cells. However, systemic administration of IL-12 showed poor efficacy and severe adverse effects. With our therapeutic approach of tumor targeting and attenuated IL-12 mutein, we expect that our IL12-based TMEkine™ holds great promise for the future of cancer immunotherapy.In this study, we targeted CD-20 expressing cancers such as B-cell lymphoma with our anti-CD20/IL-12 mutein TMEkine. We evaluated the biological activity of our molecules with in vitro and in vivo efficacy and safety. Methods The target specific binding to CD20 and IL-12 receptor was analyzed by FACS and ELISA. Biological activities as signaling transduction and T cell activation were confirmed in vitro using HEKblue IL12 cell line, primary human T cells and NK cells. The anti-tumor efficacy of TMEkine (CD20-IL-12) was assessed in A20 lymphoma syngeneic mouse model. To demonstrate long term protection to A20, the cured five mice after TMEkine administration were re-challenged with A20 and 4T1 cells. Results First, we analyzed the specific binding of our TMEkine molecules to CD20 expressing B-cell lymphoma cell lines (such as Raji). We showed that TMEkine (CD20-IL-12) binds to Raji and Ramos, which express CD20, but not to Jurkat, which does not express CD20. We also showed that TMEkine molecules bind to IL-12 receptor in a dose-dependent manner. pSTAT4 alphaLISA assay revealed that TMEkine (CD20-IL-12) transduces STAT4 signaling. In our IL-12 mutein, key residues for heparin binding were mutated. The biological activity of our mutein molecule was attenuated due to this change in human PBMC. In addition, our TMEkine molecules significantly induced IFN-γ secretion from primary human T cells and NK cells. An A20 B-cell lymphoma syngeneic mouse model was utilized to investigate the anti-tumor activity of TMEkine (CD20-IL-12). TMEkine molecules were injected three times with Q3D intraperitoneally. Tumor growth was substantially reduced and no cytotoxicity was observed. To further investigate the underlying mechanism, we analyzed tumor infiltrating lymphocytes (TIL) and as expected, we observed the increase in the number of CD8+ T cells in TIL, compared to control group. Interestingly, our tumor re-challenge result demonstrates that TMEkine (CD20-IL-12) protected animals from tumor recurrence implying that immunologic memory response was generated upon our TMEkine (CD20-IL-12) treatment. Conclusions Altogether, our data suggest that TMEkine (CD20-IL-12) as an efficacious tumor targeting cytokine opening up a new avenue for the treatment of B-cell lymphoma.

We aimed to evaluate the preclinical efficacy of GC1118, a novel anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), against glioblastoma (GBM) tumors using patient-derived xenograft (PDX) models. A total of 15 distinct GBM PDX models were used to evaluate the therapeutic efficacy of GC1118. Genomic data derived from PDX models were analyzed to identify potential biomarkers associated with the anti-tumor efficacy of GC1118. A patient-derived cell-based high-throughput drug screening assay was performed to further validate the efficacy of GC1118. Compared to cetuximab, GC1118 exerted comparable growth inhibitory effects on the GBM tumors in the PDX models. We confirmed that GC1118 accumulated within the tumor by crossing the blood&ndash, brain barrier in in vivo specimens and observed the survival benefit in GC1118-treated intracranial models. Genomic analysis revealed high EGFR amplification as a potent biomarker for predicting the therapeutic efficacy of GC1118 in GBM tumors. In summary, GC1118 exerted a potent anti-tumor effect on GBM tumors in PDX models, and its therapeutic efficacy was especially pronounced in the tumors with high EGFR amplification. Our study supports the importance of patient stratification based on EGFR copy number variation in clinical trials for GBM. The superiority of GC1118 over other EGFR mAbs in GBM tumors should be assessed in future studies.

Additional file 2. Review History.

Background Despite extensive efforts on the genomic characterization of gliomas, very few studies have reported the genetic alterations of cerebellar glioblastoma (C-GBM), a rare and lethal disease. Here, we provide a systematic study of C-GBM to better understand its specific genomic features. Methods We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies with supratentorial glioblastoma (S-GBM). To uncover the molecular characteristics, we performed DNA and mRNA sequencing and DNA methylation arrays on 19, 6, and 4 C-GBM cases, respectively. Moreover, chemical drug screening was conducted to identify potential therapeutic options for C-GBMs. Results Despite differing anatomical origins of C-GBM and S-GBM, neither histological, cytological, nor patient demographics appeared significantly different between the 2 types. However, we observed striking differences in mutational patterns, including frequent alterations of ATRX, PDGFRA, NF1, and RAS and absence of EGFR alterations in C-GBM. These results show a distinct evolutionary path in C-GBM, suggesting specific therapeutic targeted options. Targeted-drug screening revealed that C-GBMs were more responsive to mitogen-activated protein kinase kinase (MEK) inhibitor and resistant to epidermal growth factor receptor inhibitors than S-GBMs. Also, differential expression analysis indicated that C-GBMs may have originated from oligodendrocyte progenitor cells, suggesting that different types of cells can undergo malignant transformation according to their location in brain. Master regulator analysis with differentially expressed genes between C-GBM and proneural S-GBM revealed NR4A1 as a potential therapeutic target. Conclusions Our results imply that unique gliomagenesis mechanisms occur in adult cerebellum and new treatment strategies are needed to provide greater therapeutic benefits for C-GBM patients. Key points 1. Distinct genomic profiles of 19 adult cerebellar GBMs were characterized. 2. MEK inhibitor was highly sensitive to cerebellar GBM compared with supratentorial GBM. 3. Master regulator analysis revealed NR4A1 as a potential therapeutic target in cerebellar GBM.

Background Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. Methods To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. Results We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Conclusions Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.

During tumor development, stromal cells are co-opted to the tumor milieu and provide favorable conditions for the tumor. Hypoxia stimulates cancer cells to acquire a more malignant phenotype via activation of hypoxia-inducible factor 1 (HIF-1). Given that cancer cells and astrocytes in glioblastomas coexist in a hypoxic microenvironment, we examined whether astrocytes affect the adaptation of glioblastoma cells to hypoxia. Immunoblotting, reporter assays, quantitative RT-PCR, and chromatin immunoprecipitation were performed to evaluate HIF-1 signaling in glioblastoma cells. Astrocyte-derived chemokine C-C motif ligand 20 (CCL20) was identified using cytokine arrays, and its role in glioblastoma development was evaluated in orthotopic xenografts. Astrocytes augmented HIF-1α expression in glioblastoma cells under hypoxia. The expression of HIF-1 downstream genes, cancer colony formation, and Matrigel invasion of glioblastoma cells were stimulated by conditioned medium from astrocytes pre-exposed to hypoxia. CCL20 was secreted in a hypoxia-dependent manner from astrocytes and busted the hypoxic induction of HIF-1α in glioblastoma cells. Mechanistically, the CCL20/CCR6 signaling pathway upregulates HIF-1α by stimulating nuclear factor kappa B-driven transactivation of the HIF1A gene. Compared with the control tumors, CCR6-deficient glioblastoma xenografts grew more slowly, with poor vascularization, and expressed lower levels of HIF-1α and its downstream proteins. Furthermore, CCR6 expression was correlated with HIF-1α expression in GEO and TCGA datasets from human glioblastoma tissues. These results suggest that glioblastoma cells adapt well to hypoxic stress by virtue of CCL20 derived from neighboring astrocytes.

The receptor tyrosine kinase c-Met plays critical roles in promoting tumor growth, invasion, metastasis, and angiogenesis in various types of cancer and is a promising therapeutic target. The development of a species cross-reactive therapeutic antibody could provide useful to comprehensive preclinical assessment in animal models. Towards this goal, we developed human/mouse cross-reactive c-Met antibodies using an antibody phage library. IRCR201, a c-Met antibody with species cross-reactivity, successfully inhibited the HGF/c-Met signaling pathway via degradation of c-Met and disruption of the binding with its partners, and demonstrated strong in vivo antitumor activity. In pharmacokinetic analysis, IRCR201 exhibited a nonlinear pharmacokinetic profile and showed rapid serum clearance at low dosage. Ex vivo fluorescence imaging and immunohistochemistry demonstrated strong tumor accumulation of IRCR201. Hepatotoxicity analysis revealed that IRCR201 does not significantly affect primary human and mouse hepatocytes. Serum chemistry analysis demonstrated that the alanine aminotransferase serum level was elevated in mice treated with 30 mg/kg IRCR201 than in PBS-treated mice, whereas the levels of aspartate aminotransferase and blood urea nitrogen did not significantly differ. Thus, IRCR201 is a potent therapeutic antibody that can disrupt the HGF/c-Met signaling axis and its species cross-reactivity would enable to evaluate precise biological activity in animal models.

Epidermal growth factor receptor (EGFR)-targeted monoclonal antibodies, including cetuximab and panitumumab, are used to treat metastatic colorectal cancer (mCRC). However, this treatment is only effective for a small subset of mCRC patients positive for the wild-type KRAS GTPase. GC1118 is a novel, fully humanized anti-EGFR IgG1 antibody that displays potent inhibitory effects on high-affinity EGFR ligand-induced signaling and enhanced antibody-mediated cytotoxicity. In this study, using 51 CRC patient-derived xenografts (PDXs), we showed that KRAS mutants expressed remarkably elevated autocrine levels of high-affinity EGFR ligands compared with wild-type KRAS. In three KRAS-mutant CRCPDXs, GC1118 was more effective than cetuximab, whereas the two agents demonstrated comparable efficacy against three wild-type KRAS PDXs. Persistent phosphatidylinositol-3-kinase (PI3K)/AKT signaling was thought to underlie resistance to GC1118. In support of these findings, a preliminary improved anti-cancer response was observed in a CRC PDX harboring mutated KRAS with intrinsically high AKT activity using GC1118 combined with the dual PI3K/mammalian target of rapamycin (mTOR)/AKT inhibitor BEZ-235, without observed toxicity. Taken together, the superior antitumor efficacy of GC1118 alone or in combination with PI3K/mTOR/AKT inhibitors shows great therapeutic potential for the treatment of KRAS-mutant mCRC with elevated ratios of high- to low-affinity EGFR ligands and PI3K-AKT pathway activation.

// Dong Geon Kim 1, 2 , Kang Ho Kim 2 , Yun Jee Seo 2 , Heekyoung Yang 2, 3 , Eric G. Marcusson 6 , Eunju Son 2, 4 , Kyoungmin Lee 1, 2 , Jason K. Sa 1, 2 , Hye Won Lee 1, 2, 5 , Do-Hyun Nam 1, 2, 3 1 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea 2 Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea 3 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Anatomy and Cell Biology, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Urology, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea 6 Providence Therapeutics, Calgary, Canada Correspondence to: Do-Hyun Nam, email: nsnam@skku.edu Keywords: anti-miR, glioblastoma, intratumoral injection, intraventricular injection, delivery efficiency Received: December 03, 2015 Accepted: March 28, 2016 Published: April 19, 2016 ABSTRACT Small non-coding RNAs called miRNAs are key regulators in various biological processes, including tumor initiation, propagation, and metastasis in glioblastoma as well as other cancers. Recent studies have shown the potential for oncogenic miRNAs as therapeutic targets in glioblastoma. However, the application of antisense oligomers, or anti-miRs, to the brain is limited due to the blood-brain barrier (BBB), when administered in the traditional systemic manner. To induce a therapeutic effect in glioblastoma, anti-miR therapy requires a robust and effective delivery system to overcome this obstacle. To bypass the BBB, different delivery administration methods for anti-miRs were evaluated. Stereotaxic surgery was performed to administer anti-Let-7 through intratumoral (ITu), intrathecal (ITh), and intraventricular (ICV) routes, and each method’s efficacy was determined by changes in the expression of anti-Let-7 target genes as well as by immunohistochemical analysis. ITu administration of anti-miRs led to a high rate of anti-miR delivery to tumors in the brain by both bolus and continuous administration. In addition, ICV administration, compared with ITu administration, showed a greater distribution of the miR across entire brain tissues. This study suggests that local administration methods are a promising strategy for anti-miR treatment and may overcome current limitations in the treatment of glioblastoma in preclinical animal models.

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.

In this paper, using the globular structure designed and implemented for the transmitter and the receiver resonant wireless power transfer(WPT). The coil of the transmitter was proposed to emit a magnetic energy in three-dimensional space by winding a ball shape. Each side of the transmitter has been designed to obtain a high Q value by a spiral structure. This solves the problem that the transfer efficiency decreases rapidly depending on the location in the conventional WPT. The resonance frequency is used 6.78 MHz and the distance between the trasnitter and the receiver is 200 mm. The transfer efficiency of the proposed WPT system is higher than 40% at all direction.

온라인 소셜 네트워크 서비스 중 하나인 트위터는 가장 보편적으로 사용되는 마이크로 블로그인데, 트위터의 개방적 구조로 인해 자동화 프로그램인 트윗 봇이 많이 생성되고 있다. 이 트윗 봇은 적법한 봇과 악성 봇으로 분류되는데, 이 중 악성 봇은 일반 사용자들에게 많은 양의 스팸 정보나 유해한 컨텐츠를 배포하기 때문에 트윗 봇을 검출하는 작업은 반드시 필요하다. 기존 연구에서는 시간적 정보를 활용하여 사람과 트윗 봇을 분류하였다. 본 논문에서는 사용자들의 고 정밀 위치 정보를 알려주는 공간 태그된 트윗 정보를 활용하여 트위터 사용자들의 정확한 위치와 트윗 전송시각을 알아낸 후, 각 사용자의 시공간 엔트로피를 계산하여 트윗 봇을 검출하는 개선된 두 단계 알고리즘을 제안한다. 주요 결과로써, 시간 정보만을 이용한 기존 연구결과보다 각 신뢰도별 봇 검출 확률 및 거짓 경보 확률이 모두 우수하게 나타난다.

Twitter, one of online social network services, is one of the most popular micro-blogs, which generates a large number of automated programs, known as tweet bots because of the open structure of Twitter. While these tweet bots are categorized to legitimate bots and malicious bots, it is important to detect tweet bots since malicious bots spread spam and malicious contents to human users. In the conventional work, temporal information was utilized for the classficiation of human and bot. In this paper, by utilizing geo-tagged tweets that provide high-precision location information of users, we first identify both Twitter users' exact location. Then, we propose a new tweet bot detection algorithm by using both an entropy based on geographic variable of each user and device information of each user. As a main result, the proposed algorithm shows superior bot detection and false alarm probabilities over the conventional result which only uses temporal information.

The dominant-negative effect of PTEN mutation has been described previously, suggesting that aberrant gain of function attributed to mutation might be more disastrous than deletion in respect to malignant potential. In present study, we explored the functional implications of hot spot mutations of PTEN in GBM tumors. Subcellular location of PTEN is important for its distinct function and spatial distribution within the cytoplasm is known to be associated with cellular locomotion. We evaluated the subcellular compartmentalization of different PTEN mutants and found that some PTEN mutants located at cellular edges of chemotaxing cells. Moreover, these PTEN mutations exhibited invasive phenotype, which was not disrupted by PI3K inhibitor, but microtubule inhibitors. This finding suggests that cytoskeletal assembly as a novel non-canonical pathway of PTEN, thus unraveling a novel therapeutic vulnerability of PTEN. Mutation-specific therapeutic options should be considered in treating GBM patients with PTEN mutations.

Diffusely infiltrating gliomas (DIGs) are difficult to completely resect and are associated with a high rate of tumor relapse and progression from low- to high-grade glioma. In particular, optimized short-term culture-enriching patient-derived glioma stem cells (GSCs) are essential for customizing the therapeutic strategy based on clinically feasible in vitro drug screening for a wide range of DIGs, owing to the high inter-tumoral heterogeneity. Herein, we constructed a novel high-throughput culture condition screening platform called &lsquo, GFSCAN&rsquo, which evaluated the cellular growth rates of GSCs for each DIG sample in 132 serum-free combinations, using 13 previously reported growth factors closely associated with glioma aggressiveness. In total, 72 patient-derived GSCs with available genomic profiles were tested in GFSCAN to explore the association between cellular growth rates in specific growth factor combinations and genomic/molecular backgrounds, including isocitrate dehydrogenase 1 (IDH1) mutation, chromosome arm 1p and 19q co-deletion, ATRX chromatin remodeler alteration, and transcriptional subtype. GSCs were clustered according to the dependency on epidermal growth factor and basic fibroblast growth factor (E&amp, F), and isocitrate dehydrogenase 1 (IDH1) wild-type GSCs showed higher E&amp, F dependencies than IDH1 mutant GSCs. More importantly, we elucidated optimal combinations for IDH1 mutant glioblastoma and lower grade glioma GSCs with low dependencies on E&amp, F, which could be an aid in clinical decision-making for these DIGs. Thus, we demonstrated the utility of GFSCAN in personalizing in vitro cultivation to nominate personalized therapeutic options, in a clinically relevant time frame, for individual DIG patients, where standard clinical options have been exhausted.

Outcomes of anticancer therapy vary dramatically among patients due to diverse genetic and molecular backgrounds, highlighting extensive inter-tumoral 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 landscape of 462 patient-derived tumor cells (PDCs) across 14 cancer types, together with genomic and transcriptomic profiling in 385 of these tumors. Compared to the traditional long-term cultured cancer cell-line models, PDCs recapitulate the molecular properties and biology of the diseases more precisely. In present study, we provide unprecedented insights into dynamic pharmacogenomic associations, including molecular determinants that elicit therapeutic resistance to EGFR inhibitors and potential repurposing of ibrutinib (currently being used in hematological malignancies) for EGFR-specific therapy in gliomas. Lastly, we present potential implementation of PDC-derived drug sensitivities for prediction of clinical response to targeted therapeutics using retrospective clinical studies.

Background/aim The aim of our study was to investigate the pharmacokinetics (PK), tissue distribution and toxicity of F11 antibody to semaphorin 3A in mouse models and explore its anti-angiogenic and tumor-inhibitory effect. Materials and methods Patient-derived xenograft (PDX) models were established via subcutaneous implantation of glioblastoma multiforme (GBM) cells and treated with F11. Results F11 significantly attenuated tumor growth and angiogenesis in the GBM PDX model. Within the range of administered doses, the PK of F11 in serum demonstrated a linear fashion, consistent with general PK profiles of soluble antigen-targeting antibodies. Additionally, the clearance level was detected at between 4.63 and 7.12 ml/d/kg, while the biological half-life was measured at 6.9 and 9.4 days. Tissue distribution of F11 in kidney, liver and heart was consistent with previously reported antibody patterns. However, the presence of F11 in the brain was an interesting finding. Conclusion Collectively, our results revealed angiogenic and tumor-inhibitory effect of F11 antibody and its potential therapeutic use within a clinical framework based on PK, biodistribution and toxicity evaluation in mouse models.

The aim of our study was to investigate the pharmacokinetics (PK), tissue distribution and toxicity of F11 antibody to semaphorin 3A in mouse models and explore its anti-angiogenic and tumor-inhibitory effect.Patient-derived xenograft (PDX) models were established via subcutaneous implantation of glioblastoma multiforme (GBM) cells and treated with F11.F11 significantly attenuated tumor growth and angiogenesis in the GBM PDX model. Within the range of administered doses, the PK of F11 in serum demonstrated a linear fashion, consistent with general PK profiles of soluble antigen-targeting antibodies. Additionally, the clearance level was detected at between 4.63 and 7.12 ml/d/kg, while the biological half-life was measured at 6.9 and 9.4 days. Tissue distribution of F11 in kidney, liver and heart was consistent with previously reported antibody patterns. However, the presence of F11 in the brain was an interesting finding.Collectively, our results revealed angiogenic and tumor-inhibitory effect of F11 antibody and its potential therapeutic use within a clinical framework based on PK, biodistribution and toxicity evaluation in mouse models.

Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of tumor-induced angiogenesis. Specifically, VEGFR-2/kinase insert domain receptor (KDR) is part of the major signaling pathway that plays a significant role in tumor angiogenesis, which is associated with the development of various types of tumor and metastasis. In particular, KDR is involved in tumor angiogenesis as well as cancer cell growth and survival. In this study, we evaluated the therapeutic potential of TTAC-0001, a fully human antibody against VEGFR-2/KDR. To assess the efficacy of the antibody and pharmacokinetic (PK) relationship in vivo, we tested the potency of TTAC-0001 in glioblastoma and colorectal cancer xenograft models. Antitumor activity of TTAC-0001 in preclinical models correlated with tumor growth arrest, induction of tumor cell apoptosis, and inhibition of angiogenesis. We also evaluated the combination effect of TTAC-0001 with a chemotherapeutic agent in xenograft models. We were able to determine the relationship between PK and the efficacy of TTAC-0001 through in vivo single-dose PK study. Taken together, our data suggest that targeting VEGFR-2 with TTAC-0001 could be a promising approach for cancer treatment.