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.
Gastric cancer (GC) is commonly treated by chemotherapy using 5-fluorouracil (5-FU) derivatives and platinum combination, but predictive biomarker remains lacking. We develop patient-derived ...xenografts (PDXs) from 31 GC patients and treat with a combination of 5-FU and oxaliplatin, to determine biomarkers associated with responsiveness. When the PDXs are defined as either responders or non-responders according to tumor volume change after treatment, the responsiveness of PDXs is significantly consistent with the respective clinical outcomes of the patients. An integrative genomic and transcriptomic analysis of PDXs reveals that pathways associated with cell-to-cell and cell-to-extracellular matrix interactions enriched among the non-responders in both cancer cells and the tumor microenvironment (TME). We develop a 30-gene prediction model to determine the responsiveness to 5-FU and oxaliplatin-based chemotherapy and confirm the significant poor survival outcomes among cases classified as non-responder-like in three independent GC cohorts. Our study may inform clinical decision-making when designing treatment strategies.
Here, we discovered that targeting cell cycle processes or protein ubiquitination pathways are promising treatment strategies for overcoming resistance to EGFR inhibitors in lung cancer using a ...genome‐scale CRISPR‐Cas9 screening. Combination therapies targeting each of these two processes such as nutlin‐3 and carfilzomib increased cancer cell death when combined with erlotinib in both in vitro and in vivo experiments.
Erlotinib is highly effective in lung cancer patients with epidermal growth factor receptor (EGFR) mutations. However, despite initial favorable responses, most patients rapidly develop resistance to erlotinib soon after the initial treatment. This study aims to identify new genes and pathways associated with erlotinib resistance mechanisms in order to develop novel therapeutic strategies. Here, we induced knockout (KO) mutations in erlotinib‐resistant human lung cancer cells (NCI‐H820) using a genome‐scale CRISPR‐Cas9 sgRNA library to screen for genes involved in erlotinib susceptibility. The spectrum of sgRNAs incorporated among erlotinib‐treated cells was substantially different to that of the untreated cells. Gene set analyses showed a significant depletion of ‘cell cycle process’ and ‘protein ubiquitination pathway’ genes among erlotinib‐treated cells. Chemical inhibitors targeting genes in these two pathways, such as nutlin‐3 and carfilzomib, increased cancer cell death when combined with erlotinib in both in vitro cell line and in vivo patient‐derived xenograft experiments. Therefore, we propose that targeting cell cycle processes or protein ubiquitination pathways are promising treatment strategies for overcoming resistance to EGFR inhibitors in lung cancer.
Background: The typical treatment of the International Federation of Gynecology and Obstetrics 2018 stage IB2 cervical cancer is radical hysterectomy. With the trend of delayed childbearing, the ...importance of fertility sparing in the treatment of women with cervical cancer has drawn attention. Case: We report a case of stage IB2 cervical cancer treated by neoadjuvant chemotherapy with quick cisplatin-VP 16 followed by robotic radical trachelectomy. Conclusions: Neoadjuvant chemotherapy (NACT) using platinum-based therapy with cisplatin and trachelectomy performed through the vagina or abdominal approach was used in most previous cases. We successfully performed NACT with quick cisplatin-VP 16, followed by robotic radical trachelectomy in stage 1B2 cervical cancer. Further studies are needed to accumulate cases and outcomes of fertility-preserving treatment techniques.
The aim of this study was to verify the accuracy of echocardiography by dual-source computed tomography (DSCT). Seven normal beagles underwent DSCT and echocardiography. Echocardiographic ...measurements were obtained according to the American Society of Echocardiography guidelines. The DSCT images were reconstructed onto the same echocardiographic image plane by using a reconstruction program, and then anatomical measurements were obtained. Nonparametric analysis was used for verifying the significance of each of the measured parameters. The anatomical measurements obtained using echocardiography and DSCT were not significant (P>0.05), and the difference between the measurements obtained using both the methods were within 95% confidence intervals except those for interventricular septal thickness and left ventricular posterior wall thickness in end diastole. The reasons for these differences were considered to be the adjacent structures such as papillary muscles or chordae tendineae that may have influenced the echocardiographic findings, lower far-field image quality of echocardiography, low test-retest reproducibility of echocardiography, high-quality images of DSCT minimizing the motion artifact and the retrospective ECG gating technique of DSCT that offered an adequate timing decision for the systolic and diastolic phase during cardiac movement. Although there were differences in the measurements of interventricular septal thickness and left ventricular posterior wall thickness in end diastole obtained using echocardiography and DSCT, we could conclude that echocardiographic measurement is as accurate and reliable as DSCT for cardiac anatomical assessment.
The bronchoarterial (BA) ratio measured with computed tomography is widely used in human medicine to diagnose bronchial dilation or collapse. Although use of the BA ratio in veterinary medicine has ...been recently studied, this has not been evaluated in brachycephalic dogs predisposed to bronchial diseases including bronchial collapse. The purpose of this study was to establish BA ratios for brachycephalic dogs and compare the values with those of non-brachycephalic dogs. Twenty-three brachycephalic dogs and 15 non-brachycephalic dogs without clinical pulmonary disease were evaluated. The BA ratio of the lobar bronchi in the left and right cranial as well as the right middle, left, and right caudal lung lobes was measured. No significant difference in mean BA ratio was observed between lung lobes or the individual animals (p = 0.148). The mean BA ratio was 1.08 ± 0.10 (99%CI = 0.98~1.18) for brachycephalic dogs and 1.51 ± 0.05 (99% CI = 1.46~1.56) for the non-brachycephalic group. There was a significant difference between the mean BA ratios of the brachycephalic and non-brachycephalic groups (p = 0.00). Defining the normal limit of the BA ratio for brachycephalic breeds may be helpful for diagnosing bronchial disease in brachycephalic dogs.
Primary vaginal adenocarcinoma associated with human papillomavirus (HPV) infection is extremely rare. We report a case of primary adenocarcinoma of the vagina associated with human papilloma virus ...successfully treated with anterior pelvic exenteration and adjuvant concurrent chemoradiation therapy. A 51-year-old postmenopausal woman (gravida 1, para 1) presented with intermittent vaginal bleeding and pelvic pain. She was found to have a 5 × 5 cm necrotic tumor took up the vaginal. She had no previous history of antenatal exposure to diethylstilbestrol (DES). Pelvic magnetic resonance imaging (MRI) demonstrated a 4.8 × 6.0 cm mass in the vaginal canal, an 1.1 × 2.6 cm mass at the urinary bladder dome and a 1.1 cm irregular lymph node at the right external iliac chain with increased fluorodeoxyglucose (FDG) uptake from Fused whole-body positron emission tomography-computed tomography (PET-CT). Based on clinical investigations, the patient was diagnosed with a primary adenocarcinoma of vagina, staged International Fedestration of Gynecology and Obstetrics (FIGO) IVa. Anterior pelvic exenteration, simple vulvectomy, total vaginectomy, both pelvic lymph node dissection, and para-aortic lymph node dissection with ileal conduit urinary diversion (Bricker’s operation) was done. Histologically primary vaginal HPV type 16-associated adenocarcinoma was confirmed. Both obturator lymph node was positive for metastasis. Postoperatively, the patient received weekly cisplatin regimen administered with a dose of 40 mg/m2 on day 1 of external radiation therapy (RT), 1 to 4 hours before RT initiation. External beam pelvic RT dose prescription to the whole pelvis was 59.4 Gy in 33 fractions at the isocenter. But, after total dose of 43.2 Gy, patient complained severe bowel habit change and discontinued further treatment. The patient remains free from recurrence 8 months after initial surgery. In the lack of information and comparative analysis of management options for the more unusual and rare varieties of primary vaginal neoplasms in the literature, this suggests the possibility that surgical treatment may be preferentially selected on a case-by-case basis.
Colorectal cancer is the third most commonly diagnosed cancer in the world, and exhibits heterogeneous characteristics in terms of genomic alterations, expression signature, and drug responsiveness. ...Although there have been considerable efforts to classify this disease based on high-throughput sequencing techniques, targeted treatments for specific subgroups have been limited.
and
mutations are prevalent genetic alterations in colorectal cancers, and patients with mutations in either of these genes have a worse prognosis and are resistant to anti-EGFR treatments. In this study, we have found that a subgroup of colorectal cancers, defined by having either
or
(
) mutations and
(encoding BCL-X
) amplification, can be effectively targeted by simultaneous inhibition of BCL-X
(with ABT-263) and MCL1 (with YM-155). This combination treatment of ABT-263 and YM-155 was shown to have a synergistic effect
as well as in
patient-derived xenograft models. Our data suggest that combined inhibition of BCL-X
and MCL1 provides a promising treatment strategy for this genomically defined colorectal cancer subgroup.
.
Genomic and transcriptomic alterations during metastasis are considered to affect clinical outcome of colorectal cancers, but detailed clinical implications of metastatic alterations are not fully ...uncovered. We aimed to investigate the effect of metastatic evolution on
treatment outcome, and identify genomic and transcriptomic alterations associated with drug responsiveness.
We developed and analyzed patient-derived xenograft (PDX) models from 35 patients with colorectal cancer including 5 patients with multiple organ metastases (MOMs). We performed whole-exome, DNA methylation, and RNA sequencing for patient and PDX tumors. With samples from patients with MOMs, we conducted phylogenetic and subclonal analysis and
drug efficacy test on the corresponding PDX models.
Phylogenetic analysis using mutation, expression, and DNA methylation data in patients with MOMs showed that mutational alterations were closely connected with transcriptomic and epigenomic changes during the tumor evolution. Subclonal analysis revealed that initial primary tumors with larger number of subclones exhibited more dynamic changes in subclonal architecture according to metastasis, and loco-regional and distant metastases occurred in a parallel or independent fashion. The PDX models from MOMs demonstrated therapeutic heterogeneity for targeted treatment, due to subclonal acquisition of additional mutations or transcriptomic activation of bypass signaling pathway during tumor evolution.
This study demonstrated
therapeutic heterogeneity of colorectal cancers using PDX models, and suggests that acquired subclonal alterations in mutations or gene expression profiles during tumor metastatic processes can be associated with the development of drug resistance and therapeutic heterogeneity of colorectal cancers.
PDF
