To Establish a Reproducible Organoid Culture Model With Human Kidney Cancer

Kidney cancer is one of the ten most common malignancies, and the incidence is increasing in recent year. From Hong Kong Cancer Registry, there was about 670 new cases diagnosed in 2016, and had been increased by 46% compared to 2007. The rapid increase in incidence is partly due to the greater prevalence of putative risk factors including smoking, obesity, and hypertension, as well as improvements in diagnostic imaging. Within the broad classification of kidney cancers, renal cell carcinoma (RCC) accounts for approximately 85% of all cases and greater than 90% of all renal malignancies.

Despite the improved understanding and also diagnosis for kidney cancer, still about one fourth of patients will presented at metastatic stage or developed recurrence after initial treatment and required further systemic therapy. Fortunately, with recent advances in the development of novel therapeutic agents, there are many potential effective treatments available for patients, including tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors, immune checkpoint blockers etc. Facing the wide range of available options for systemic therapy, the current challenge is how to select the most effective treatment for individual patients, in particular as the first line therapy.

Currently, there are some guidelines, basing on the clinical parameters and tumor subtype and grading, for selection of therapy for patients.Unfortunately, there is no good biomarkers available to aid treatment selection. As there is increasing recognition of inter-tumor variation, therefore, there is a need to develop more personalized approach to assess the treatment response of individual patient / cancer to the panel of available drugs, in order to select the best options for each patient.

Three-dimensional (3D) organoid culture model and its potential advantages Organoid technology has recently emerged to become an independent research tool and can provide opportunities for new drug development and drug screening. Organoids are cell-derived in vitro 3D organ constructs which allow the study of many biological processes. This specific model can be developed from embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), somatic SCs, and cancer cells in specific 3D culture systems. These groundbreaking 3D tissues were first created in the laboratory in small scale and closely resembled the parent organ in vivo in terms of its structure and function. The major benefits of the 3D organoid culture model include, firstly, it contains multiple cell types comparable with the in vivo counterpart; secondly, the cells inside the 3D structure can organize similarly to the primary tissue; and lastly, it functions specifically like the parent organ. With the scaffold supporting and the nascent phenotype needed, emerging 3D culture methods can improve our ability to model tumor behavior in vitro and provide a native environment for different research purposes, such as cell behavior, tissue repair, drugs screening and mutation monitoring. Development of kidney cancer organoid Different studies have demonstrated that gastrointestinal cancers organoid models provide better prediction to a patient's treatment responses. There is limited publication on successful 3D kidney cancer organoid recently, and the one published by Batchelder CA in 2015 had analyzed limited amount of genes. Besides, majority of the cases reported had been undergone 2D culture on plasticwares before implanting inside the 3D scaffold, which may offer the chance of cells selection.Lacking a widely acceptable 3D kidney cancer model, this pushes the need to develop a reproducible kidney cancer organoid system for better drug selection on significant heterogeneity cancers. In our study, total cells will be mixed with the Matrigel scaffold without any manipulation or culture selection, and more advance Next Generation Sequencing will be used to evaluate the genetic similarity of the culture organoids and the primary tissues. Starting as a major technological breakthrough, 3D organoids are now more firmly established as an essential tool in biological research and have important implications for clinical use. In the future, successful expansion of the model can provide a platform to identify the most effective personalized treatment option and improve the treatment outcome of kidney cancer patients.

Therefore, investigator proposed to establish a sustainable human kidney tumor 3D Matrigel culture system with a stable phenotype from local population. Investigators hypothesize that the successful of our project would produce reliable and effective method to cultivate kidney cancer cells from our local patients, and will provide personalized and targeted therapy on kidney cancer for local Hong Kong patients.