• Molecules and Cells
• /
• v.39 no.2
• /
• pp.77-86
• /
• 2016

Cancer is a heterogeneous disease caused by diverse genomic alterations in oncogenes and tumor suppressor genes. Despite recent advances in high-throughput sequencing technologies and development of targeted therapies, novel cancer drug development is limited due to the high attrition rate from clinical studies. Patient-derived xenografts (PDX), which are established by the transfer of patient tumors into immunodeficient mice, serve as a platform for co-clinical trials by enabling the integration of clinical data, genomic profiles, and drug responsiveness data to determine precisely targeted therapies. PDX models retain many of the key characteristics of patients' tumors including histology, genomic signature, cellular heterogeneity, and drug responsiveness. These models can also be applied to the development of biomarkers for drug responsiveness and personalized drug selection. This review summarizes our current knowledge of this field, including methodologic aspects, applications in drug development, challenges and limitations, and utilization for precision cancer medicine.

• Oncology Letters
• /
• v.42 no.5
• /
• pp.2029-20238
• /
• 2019

In vitro culture of patient-derived tumor cells offers many advantages in the development of novel therapies for colorectal cancer. Although various culture systems have been developed, the long-term expansion of patient-derived tumor cells remains challenging. The present results suggested that tumor cells isolated from colorectal cancer patient-derived xenografts can be efficiently immortalized in conditioned medium from irradiated feeder cells containing Y-27632, a rho-associated coiled-coil containing protein kinase (ROCK) inhibitor. Patient-derived tumor cells proliferated rapidly, reaching 90-95% confluence in ~6 days. Short tandem repeat analysis suggested that these tumor tissues and cultured cells presented 13 identical short tandem repeat loci, including Amelogenin, Penta E, Penta D, D2S1338 and D19S433. Their epithelial phenotype was confirmed by staining for epithelial cell adhesion molecule and cytokeratin 20, whereas vimentin was used as a mesenchymal marker. When cells were transferred to 3D cultures, they continued to proliferate, forming well-defined tumor spheroids. Expression levels of human telomerase reverse transcriptase and C-Myc mRNA were increased in cultured cells. Finally, immortalized cells were used for the screening of 65 anticancer drugs approved by the Food and Drug Administration, allowing the identification of gene-drug associations. In the present study, primary culture models of colorectal cancer were efficiently established using a ROCK inhibitor and feeder cells, and this approach could be used for personalized treatment strategies for patients with colorectal cancer.

• Journal of Gastric Cancer
• /
• v.19 no.3
• /
• pp.235-253
• /
• 2019

Gastric cancer (GC) is one of the deadliest malignancies in the world. Currently, clinical treatment decisions are mostly made based on the extent of the tumor and its anatomy, such as tumor-node-metastasis staging. Recent advances in genome-wide molecular technology have enabled delineation of the molecular characteristics of GC. Based on this, efforts have been made to classify GC into molecular subtypes with distinct prognosis and therapeutic response. Simplified algorithms based on protein and RNA expressions have been proposed to reproduce the GC classification in the clinical field. Furthermore, a recent study established a single patient classifier (SPC) predicting the prognosis and chemotherapy response of resectable GC patients based on a 4-gene real-time polymerase chain reaction assay. GC patient stratification according to SPC will enable personalized therapeutic strategies in adjuvant settings. At the same time, patient-derived xenografts and patient-derived organoids are now emerging as novel preclinical models for the treatment of GC. These models recapitulate the complex features of the primary tumor, which is expected to facilitate both drug development and clinical therapeutic decision making. An integrated approach applying molecular patient stratification and patient-derived models in the clinical realm is considered a turning point in precision medicine in GC.

• Experimental and Molecular Medicine
• /
• v.50 no.11
• /
• pp.12.1-12.12
• /
• 2018

Drugs targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, have been prescribed for metastatic colorectal cancer (CRC), but patients harboring KRAS mutations are insensitive to them and do not have an alternative drug to overcome the problem. The levels of ${\beta}$-catenin, EGFR, and RAS, especially mutant KRAS, are increased in CRC patient tissues due to mutations of adenomatous polyposis coli (APC), which occur in 90% of human CRCs. The increases in these proteins by APC loss synergistically promote tumorigenesis. Therefore, we tested KYA1797K, a recently identified small molecule that degrades both ${\beta}$-catenin and Ras via $GSK3{\beta}$ activation, and its capability to suppress the cetuximab resistance of KRAS-mutated CRC cells. KYA1797K suppressed the growth of tumor xenografts induced by CRC cells as well as tumor organoids derived from CRC patients having both APC and KRAS mutations. Lowering the levels of both ${\beta}$-catenin and RAS as well as EGFR via targeting the $Wnt/{\beta}$-catenin pathway is a therapeutic strategy for controlling CRC and other types of cancer with aberrantly activated the $Wnt/{\beta}$-catenin and EGFR-RAS pathways, including those with resistance to EGFR-targeting drugs attributed to KRAS mutations.

• Journal of Periodontal and Implant Science
• /
• v.32 no.3
• /
• pp.565-576
• /
• 2002

The ultimate goal of periodontal therapy is the regeneration of periodontal tissue which has been lost due to destructive periodontal disease. To achieve periodontal regeneration, various kinds of methods have been investigated and developed, including guided tissue regeneration and bone graft. Bone graft can be catagorized into autografts, allografts, xenografts, bone substitutes. And materials of all types have different biological activity and the capacity for periodontal regeneration, but ideal graft material has not been developed that fits all the requirement of ideal bone graft material. Intensive research is underway to identity, purify, synthesize a variety biologic modulators that may enhance wound healing and regeneration of lost tissues in periodontal therapy. The present study evaluates the effects of ABM/P-15 on the periodontal regeneration in intrabony defects of human. We used thirty four 2-wall or 3-wall osseous defects in premolars and molars of chronic peridontitis patient that have more than 5mm pockets and more than 3mm in intrabony defect. 12 negative control group underwent flap procedure only, 11 positive control group received DFDBA graft with flap procedure, and 11 experimental group received ABM/P-15 graft with flap procedure. The changes of probing pocket depth, loss of attachment and bone probing depth following 6months after treatment revealed the following results: 1. The changes of probing pocket depth showed a statistically significant decrease between after scaling and 6months after treatment in negative control(2.0${\pm}$0.9mm), positive control(3.0${\pm}$0.9mm), and experimental group (3.4${\pm}$1.5mm) (P<0.01). Significantly more reduction was seen in experimental group compared to negative control group (P<0.05). 2. The changes of loss of attachment showed a statistically significant decrease between after scaling and 6months after treatment in positive control(2.0${\pm}$0.6mm), and experimental group (2.2${\pm}$l.0mm) except negative control group(0.1${\pm}$0.7mm) (P<0.01). Significantly more reduction was seen in both experimental and positive control group compared to negative control group(P<0.05). 3. The changes of bone probing depth showed a statistically significant decrease between after scaling and 6months after treatment in positive control(2.7${\pm}$l.0mm), and experimental group (3.4${\pm}$1.3mm) except negative control(0.l${\pm}$0.9mm) (9<0.01). Significantly more reduction was seen in both experimental and positive control group compared to negative control group (P<0.05). The results suggest that the use of ABM/P-15 in the treatment of periodontal intrabony defects can reduce loss of attachment and bone probing depth more than flap operation only. It suggests that ABM/P-15 may be an effective bone graft material for the regeneration of periodontal tissue in intrabony defects.