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3D ex vivo Microfluidics Platform

Beyond Limitations: New Microfluidics Platform for Cancer Drug Screening and Profiling

| Author / Editor: Sumeer dhar*,Theresa Mullholand** et al. / Dr. Ilka Ottleben

Fig. 1 3D illustration of a cancer cell in the process of mitosis
Fig. 1 3D illustration of a cancer cell in the process of mitosis (Source: ©Christoph Burgstedt - stock.adobe.com)

High-attrition rates during clinical development of new cancer therapies still persist. A new 3D ex vivo microfluidics platform shall now enhance cancer drug screening and early development process by creating cancer models which predict clinical outcomes with significantly increased reliability.

Cancer is one of the leading causes of mortality. Specific cancer types, such as glioma and pancreatic, remain intractable to new therapies and advanced cancers represent critical areas of unmet therapeutic need. The challenges in developing successful cancer therapeutics is not just limited to the discovery of new drug therapies, but also to the availability of robust preclinical ex vivo models. Recent technological advances in high-throughput and content phenotypic screening, as well as 3D multicellular assay methods, have opened doors for reshaping several key processes during drug discovery and development.

Challenges in cancer therapeutics

Despite increased research investments and ongoing efforts toward finding novel modalities for the treatment of the most challenging cancers, translation into patient benefit has been slow. Progress from preclinical drug discovery to positive clinical outcomes is limited by the fact that translational cancer research from early drug discovery to late stage drug development and assessment in clinical trials is a long process. Moreover, traditional drug discovery and discovery medicine activities have relied upon rudimentary 2D cell monolayer models , 3D clonogenic assay platforms and small animal models, mostly utilizing established cancer cell lines.

It is now apparent that such preclinical models do not accurately recapitulate the complex pathophysiology of cancers found in patients and poorly predict clinical response. Therefore, development of more predictive, patient-specific models of human cancer are pivotal in the quest for profiling of novel anticancer drugs, either as single entities or as drug combinations. Oncologists have recognized the biological similarities of cells grown ex vivo in 3D culture systems with avascular tumors in vivo several decades ago [1, 2). The better the in-vitro models reflect the function and structure of their in-vivo counter parts, the more predictive the cell-based assays becomes. In this regard, several advances have been made in developing robust ex vivo 3D cell culture platforms using microtiter plate formats, 3D perfusion systems and 3D microfluidics formats with special focus on multicellular tumor spheroids (MCTS) systems. The emergence of these technologies have made it possible to conduct drug screening and early development programs in cost effective and efficient ways using clinically relevant cell types derived from multiple cancers.

Currently, the use of ex vivo 3D assay platforms is being pursued by researchers as a tool for drug activity response and monitoring potential changes at subcellular levels to identify downstream targets post drug treatment. Additionally, these platforms are extensively being used as a drug development tool as it has been shown to closely simulate the tumour microenvironment within the in vitro milieu [3-6]. It has previously been reported that the drug response of cancer cells is not just determined by the inherent characteristics of the epithelial tumor cells, but, are also controlled by signals derived from other cells (stromal/fibroblasts/distinct immune cell compartments) within the tumor microenvironment [7-10].

Harris AL (2002) [11] and Mellor & Callaghan (2008) [12] have reported that the abnormal vascularization of solid tumors leads to the generation of tumor microenvironments that are chronically starved of oxygen and nutrients. As a result, cells residing in such environment demonstrate altered phenotypic characteristics when compared to the cells located in more vascularized regions around the outer core [13-15]. Therefore, there has been immense drive towards developing methods which can exploit the altered phenotype of tumors.

Additional Information
 
Final aim: clinical success

One of the earliest 3D-related effects, which were correlated to in-vivo observations, included multicellular drug resistance (MDR). Cancer cells grown as 3D spheroids generally display reduced drug sensitivity compared to 2D monolayer cultures [16]. These observations indicate that the use of 3D spherical microtissues may enable improved discrimination of the most active anti-cancer drugs with improved therapeutic index.

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