Tumor Tissue Xenograft Models Research Articles

Abstract 7229: In situ trans-differentiation therapy effectively terminates the growth and recurrence of glioblastoma

Abstract Background: Glioblastoma (GBM) is the most common and malignant brain tumor in adults, and remains almost invariably lethal due to its aggressive and invasive nature. The standard first-line treatment for GBM is surgical resection, postoperative radiotherapy and chemotherapy with temozolomide (TMZ), but it exhibits short-term effects due to a high recurrence rate of GBM is its (up to almost one hundred percent). This long-existing clinical challenge has demanded development of novel and effective therapeutic strategies. In situ cell trans-differentiation therapy which direct reprograms tumor cells into terminally differentiated benign cells represents a novel therapeutic strategy for tumors. We further explored the application of in situ trans-differentiation therapy for glioblastoma. Results: In the present study, we have conducted a large-scale screen for transcription factors which can reprogram glioblastoma cells into terminally differentiated postmitotic cells. Over-expression of a combo of selected trans-differentiation factors that possess the highest trans-differentiation rate effectively reprogramed human glioma cells into neuronal-like cells with characteristic neuronal morphology and expression of neuronal genes in culture, as a result substantially reducing glioblastoma cell proliferation and tumor development after orthotopic transplantation. With replicable recombinant oncolytic virus vectors, product candidate can specifically replicate in glioma cells, therefore transcription factors can be specifically delivered to all tumor cells rather than normal cells. In either cell line-derived or patient-derived tumor tissue xenograft models, intra-tumoral injection product candidate inhibited glioblastoma cells growth at an exceptionally high efficiency. Remarkably product candidate combination with TMZ resulted in a complete regression of tumor and no recurrence was observed in animal model cases. Conclusion: In summary, our findings have established a novel therapeutic approach for treating glioblastoma by terminating sustained proliferation of glioma cells via transcription factors-induced in situ cell trans-differentiation and supported further clinic investigations in patients. Citation Format: Huihui Zhao, Zhaozhong Li, Xiaohui Zhang, Congjian Zhao, Zhao Zhu, Yueguang Liu. In situ trans-differentiation therapy effectively terminates the growth and recurrence of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7229.

Advances in Patient Derived Tumor Xenograft (PDTX) Model from Lung Cancer

当前随着肿瘤分子生物学及基因组学的发展，人们已经认识到同一瘤种在不同个体间其生物学特征、分子分型以及对药物干预的反应性都存在巨大的异质性，这种个体化差异是导致肿瘤治疗过程中同病同治而不同效的重要原因，因此为了实现真正的肿瘤个体化精准治疗，肿瘤研究领域提出了一个新的概念即人源肿瘤组织异种移植模型（patient derived tumor xenograft, PDTX）；该模型可以真实地反映患者肿瘤组织的生物学特性以及药物疗效，是研究个体化治疗、药物耐药以及新药研发的重要手段，已被运用包括肺癌在内多个瘤种的临床诊治过程中。本文就当前肺癌PDTX模型的研究进展进行综述。

The Non‐Coding Transcriptome as a Dynamic Regulator of Prostate Cancer Metastasis

While localized prostate cancer (PCa) is readily treated using surgery or radiotherapy, there are no curative therapeutic options available for metastatic PCa. Long non‐coding RNAs (lncRNAs) play critical roles in cancer, either as oncogenes or tumor suppressors, although the mechanisms by which they regulate tumor development and progression are still poorly understood. We utilized our unique collection of patient‐derived prostate tumor tissue xenograft models to identify lncRNAs differentially expressed in metastatic versus non‐metastatic xenografts. PCAT18 is a previously uncharacterized lncRNA specifically expressed in the prostate compared to 11 other normal tissues and up‐regulated in PCa compared to 15 other neoplasms. PCAT18 silencing significantly inhibited PCa cell proliferation, migration and invasion, and also triggered caspase 3/7 activation, with no effect on non‐neoplastic BPH1 cells. Among the lncRNAs down‐regulated in the metastatic xenograft, we focused on LOC153684, which is classified as an uncharacterized lncRNA. Higher expression of this transcript is associated with longer progression‐free survival after prostatectomy (p=0.03). In keeping with its putative onco‐suppressive role, LOC153684 is significantly down‐regulated in prostate cancer specimens, compared to normal prostatic tissue (p=0.04, average fold change ‐1.99). In addition, expression of this transcript is higher in BPH1 cells (non‐neoplastic) compared to all PCa cell lines tested. Understanding the molecular mechanisms by which these lncRNAs regulate PCa progression may facilitate the development of novel therapeutics.

Antitumor effect of FP3 in a breast cancer xenograft model

FP3 is a novel vascular endothelial growth factor (VEGF) blocker proposed to have antiangiogenic properties. Previous studies revealed that FP3 is a new promising agent for treating human choroidal neovascularization (CNV)-associated age-associated macular degeneration (AMD) and has an inhibitory effect on VEGF-mediated proliferation and migration of human umbilical vein endothelial cells and VEGF-mediated vessel sprouting of the rat aortic ring in vitro. Previous studies have also revealed that FP3 has antitumor effects and antiangiogenic effects in a non-small cell lung cancer cell line (A549), as well as in patient-derived tumor tissue xenograft models of gastric cancer and colon carcinoma with lymphatic and hepatic metastases in nude mice. In the present study, the antitumor effect of FP3 in an MDA-MB-231 breast cancer xenograft model was investigated. Treatment with FP3 for 3 weeks significantly suppressed xenograft growth and this inhibition was associated with a significant decrease in angiogenesis and direct inhibition of tumor cells. The results of the present study indicate that FP3 inhibits breast cancer tumor growth via the indirect inhibition of angiogenesis as well as a direct effect on tumor cells.

Differential response to EGFR- and VEGF-targeted therapies in patient-derived tumor tissue xenograft models of colon carcinoma and related metastases

Heterogeneity in primary tumors and related metastases may result in failure of antitumor therapies, particularly in targeted therapies for the treatment of cancer. In this study, patient-derived tumor tissue (PDTT) xenograft models of colon carcinoma with lymphatic and hepatic metastases were used to evaluate the response to EGFR- and VEGF-targeted therapies. Our results showed that primary colon carcinoma and its corresponding lymphatic and hepatic metastases have a different response rate to anti-EGFR (cetuximab) and anti-VEGF (bevacizumab) therapies. However, the underlying mechanism of these types of phenomenon is still unclear. To investigate whether such phenomena may result from the heterogeneity in primary colon carcinoma and related metastases, we compared the expression levels of cell signaling pathway proteins using immunohistochemical staining and western blotting, and the gene status of KRAS using pyrosequencing in the same primary colon carcinoma and its corresponding lymphatic and hepatic metastatic tissues which were used for establishing the PDTT xenograft models. Our results showed that the expression levels of EGFR, VEGF, Akt/pAkt, ERK/pERK, MAPK/pMAPK, and mTOR/pmTOR were different in primary colon carcinoma and matched lymphatic and hepatic metastases although the KRAS gene status in all cases was wild-type. Our results indicate that the heterogeneity in primary colon carcinoma and its corresponding lymphatic and hepatic metastases may result in differences in the response to dual-inhibition of EGFR and VEGF.

Antitumor effect of FP3 in combination with cetuximab on patient-derived tumor tissue xenograft models of primary colon carcinoma and related lymphatic and hepatic metastases

FP3 is an engineered protein which contains the extracellular domain 2 of vascular endothelial growth factor (VEGF) receptor 1 (Flt-1) and the extracellular domain 3 and 4 of VEGF receptor 2 (Flk-1, KDR) fused to the Fc portion of human immunoglobulin G1. Previous studies have demonstrated its antiangiogenic effects in vitro and in vivo, and its antitumor activity in vivo. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combined inhibition of VEGF and EGF signaling may act additively or synergistically. In this study, patient-derived tumor tissue (PDTT) xenograft models of primary colon carcinoma and lymphatic and hepatic metastases were established for assessment of the antitumor activity of FP3 in combination with cetuximab. Xenografts were treated with FP3 and cetuximab, alone or in combination. After tumor growth was confirmed, volume and microvessel density in tumors were evaluated. Levels of VEGF, EGFR and PCNA in the tumor were examined by immunohistochemical staining, and levels of related cell signaling pathway proteins were examined by western blotting. FP3 in combination with cetuximab showed significant antitumor activity in three xenograft models (primary colon carcinoma, lymphatic metastasis and hepatic metastasis). The microvessel density in tumor tissues treated with FP3 in combination with cetuximab was lower compared to that of the control. Antitumor activity of FP3 in combination with cetuximab was significantly higher than that of each agent alone in two xenograft models (colon carcinoma lymphatic metastasis and hepatic metastasis). This study indicated that addition of FP3 to cetuximab significantly improved tumor growth inhibition in the PDTT xenograft models of colon carcinoma lymphatic and hepatic metastases. Combination anti-VEGF (FP3) and anti-EGFR (cetuximab) therapies may represent a novel therapeutic strategy for the management of metastatic colon carcinoma.

Antitumor effect of FP3 in a patient-derived tumor tissue xenograft model of gastric carcinoma through an antiangiogenic mechanism

FP3 (KH902/KH903) is a novel vascular endothelial growth factor (VEGF) blocker with antiangiogenic properties. Previous studies revealed that FP3, a humanized fusion protein that combines ligand binding elements from the extracellular domains of VEGF receptors 1 and 2 and the Fc portion of IgG1, has an inhibitory effect on the VEGF-mediated proliferation and migration of human umbilical vein endothelial cells, and VEGF-mediated vessel sprouting of rat aortic rings in vitro. Thus, FP3 was considered as a new promising agent in treating human choroidal neovascularization (CNV) caused by age-related macular degeneration (AMD). FP3 also has an antitumor effect in a non-small cell lung cancer cell line (A549) xenograft model in nude mice. However, little is known of the direct effects of FP3 on tumor vessels. In this study, we investigated the effects of FP3 on blood vessels in a patient-derived tumor tissue (PDTT) xenograft model of gastric carcinoma, using large tumors with established vasculature. Treatment with FP3 caused robust and early changes in endothelial cells and pericytes of vessels in the PDTT xenograft model. Vascular density decreased and vascular sprouting was suppressed by treatment with FP3. Pericytes did not degenerate to the same extent as endothelial cells, and those on surviving tumor vessels achieved a more normal phenotype. Our results revealed that FP3 has a direct and rapid antiangiogenic effect on tumor vessels, which was achieved mainly via regression of tumor vasculature, inhibition of new and recurrent vessel growth, and normalization of existing tumor vasculature.

Assessment of a novel VEGF targeted agent using patient-derived tumor tissue xenograft models of colon carcinoma with lymphatic and hepatic metastases.

The lack of appropriate tumor models of primary tumors and corresponding metastases that can reliably predict for response to anticancer agents remains a major deficiency in the clinical practice of cancer therapy. It was the aim of our study to establish patient-derived tumor tissue (PDTT) xenograft models of colon carcinoma with lymphatic and hepatic metastases useful for testing of novel molecularly targeted agents. PDTT of primary colon carcinoma, lymphatic and hepatic metastases were used to create xenograft models. Hematoxylin and eosin staining, immunohistochemical staining, genome-wide gene expression analysis, pyrosequencing, qRT-PCR, and western blotting were used to determine the biological stability of the xenografts during serial transplantation compared with the original tumor tissues. Early passages of the PDTT xenograft models of primary colon carcinoma, lymphatic and hepatic metastases revealed a high degree of similarity with the original clinical tumor samples with regard to histology, immunohistochemistry, genes expression, and mutation status as well as mRNA expression. After we have ascertained that these xenografts models retained similar histopathological features and molecular signatures as the original tumors, drug sensitivities of the xenografts to a novel VEGF targeted agent, FP3 was evaluated. In this study, PDTT xenograft models of colon carcinoma with lymphatic and hepatic metastasis have been successfully established. They provide appropriate models for testing of novel molecularly targeted agents.

Heterogeneity in primary tumors and corresponding metastases: could it provide us with any hints to personalize cancer therapy?

Interpatient variability in response to anticancer drugs is associated with different clinical outcomes, which is partially owing to the individual differences among patients. Many investigators have hoped that tumor heterogeneity would help to reveal the underlying mechanism of interpatient variability in response to anticancer therapy. Numerous studies have demonstrated the presence of intratumor heterogeneity and the heterogeneity in primary tumors and corresponding metastases in a wide range of tumors at different levels and have indicated that the heterogeneity might make sense as a potential determinant of anticancer therapy response. This article discusses tumor heterogeneity, focusing on the heterogeneity in primary tumors and corresponding metastases as well as the effect on anticancer therapy response. Furthermore, an idea of tumor-site-based personalized cancer therapy for patients with metastatic malignancies was hypothesized, and a strategy using a patient-derived tumor tissue xenograft model to realize this idea is also proposed in this article.

Personalized cancer therapy using a patient-derived tumor tissue xenograft model: a translational field worthy of exploring further?

It has long been observed that interpatient variability in response to anticancer drugs is associated with different outcomes. Oncologists continually hold the desire of matching the right therapeutic regimen with the right cancer patient, which is termed 'personalized cancer therapy'. Rapid advances in genetics, genomics and related technologies are promising a new era of personalized cancer therapy based on individual molecular biomarkers. However, these molecular predictors of tumor response are far from perfect. Because of the inherent limitations in the current approaches for anticancer drugs response prediction, the need for new techniques to predict tumor response to therapy is urgent. Using a patient-derived human tumor tissue (PDTT) xenograft model to predict tumor response to therapy might be an ideal candidate method to choose. This article provides an overview of the achievements and limitations of genetic, genomic and proteomic molecular markers for personalized cancer therapy, and further discusses the potentials of using a PDTT xenograft model as a candidate strategy for personalized cancer therapy.