Nowadays, poor ability of the animal models to resemble human biology represents one of the major medical research drawbacks. According to a Tufts University study, the overall cost to develop a new pharmaceutical drug exceeds 2.5 billion dollars1. This jaw-dropping amount of money, takes also into account all the failures encountered during the tortuous way from bench to the bedside. Increasing the drug development success rate would, in first place, already dramatically reduce the costs.
But let’s give some numbers. Also when passing preclinical stages, about 85% of therapies fail in early clinical trials. Moreover, those that make it to Phase III, the last step before regulatory approval, only about half are approved2. In order to avoid this huge waste of money and time, companies and academic institutions are striving to find new and better drug screening methods.
Organotypic 3D cultures have been the first advance in the field. Whole organs, slices of organs, stem cell organoids and primary cells, can be cultured in a manner aimed at preserving the original 3D structure present in the human body3. This system is extremely suitable for developmental research purposes or for generating patients-derived tissue to test toxicity and efficacy of candidate drugs. However, scalability is low, it is not always possible to create large-scale automated systems and standard protocols are used regardless of the specific tumor of interest.
3D cultures have been tremendously improved by two approaches:organ-on-chip technology developed by the Wyss Institute and the Reconstructed Organ (r-Organ™) technology developed by zPredicta biotech company.
The organ-on-chip technology, developed by the Wyss Institute director Donald E. Ingber, consists of flexible polymer microchips, which accurately resemble target tissue structures, functions and mechanical motions. Chips that mimic the kidney, brain, liver, and gut, as well as bone marrow and the airways in the lungs, have already been realized. Some of them are currently being tested to find new drugs for several indications. What makes this technology so appealing is that differently from organoid cell cultures, it is possible to supply the chip with blood and immune cells resembling what really happens in the human organs during exposure to a pharmaceutical. Moreover, personalized chips can be made to test directly the drugs on patient biopsies. The ultimate aim of this technology is to create an entire human-body-on-a-chip and finally replacing animal testing: 10 different organs coupled in a single “machine” re-capitulating pharmacodynamic and pharmacokinetic properties of a given drug candidate. Still, many challenges have to be overcome before rendering this technology of widespread use in research laboratories (reviewed here 4). Among the others:
- Identify suitable materials to produce low-cost organs-on chip
- Improve technical robustness
- Generate and automated instrumentation that provides constant monitoring and experimental data collection for basic research purposes
Lastly, this technology may serve to test and prioritize leading compounds rather than high-throughput screenings.
An extremely valuable, and already commercially available, approach is represented by the r-Organ technology by zPredicta. 3-dimensional microenvironment of human organs is reproduced in suitable formats for both basic research and high-throughput drug screening. In a classical workflow, patient-derived tumor cells are cultured in matrix scaffolds, which recapitulate the comprehensive 3D microenvironment of a specific tumor type, making possible to test specific drugs in a personalized-medicine fashion.
Take it Science reached out for the founder and CEO of the company, Dr. Julia Kirshner, to ask some questions regarding this technology that can dramatically improve drug testing and, hopefully, drastically cut related costs.
Can you illustrate more specifically how zPredicta 3D reproduces tumor microenvironment? Which publications did you base your product on?
Our Reconstructed Organ (r-Organ) technology is focused on reconstructing both cellular and extracellular features of tumor microenvironment in an organ-specific and disease-specific manner. For example, in our Reconstructed Lung (r-Lung) platform cells from a patient with lung cancer, will be placed into extracellular matrix that mimics the physical environment of the lung. To reproduce the pathology of lung cancer, factors present in patients with lung cancer are added to the system along with stromal and immune-components. Over the years various aspects of our technology have been published in peer-reviewed journals such as Blood, Leukemia and Lymphoma, Biotechnology Journal, and others (http://zpredicta.com/).
Your platform is amazingly suitable for studying haematological neoplasm. Do you also plan to reconstruct other tumor micro-milieu such as for lung or liver?
Yes, outside of blood cancers we have developed formulations for multiple solid tumors: lung, stomach, liver, breast, and a number of others. In addition, our technology has the capacity to identify cells with metastatic and cancer stem cell properties, which allows our partners to identify therapeutic agents targeting metastatic cell populations and cells with the capacity to support the long-term tumorigenicity. For blood cancers, especially multiple myeloma, our Reconstructed Bone (r-Bone) platform is the only system that can support proliferation and survival of primary patient-derived cells, which is critical to accurately access the true efficacy of therapeutic agents, a capability currently lacking in pharmaceutical industry.
Do you think it is possible in the future to recapitulate the 3D micro-environment present at the interface between blood brain barrier and primary brain tumors to study drug penetrance and efficacy?
Absolutely. We are currently working on the Reconstructed Brain (r-Brain) system to reconstruct the brain microenvironment that supports glioblastoma. The elements of the blood-brain barrier (endothelium, etc.) would then be added to the platform, with the complete system ideally suited to study drug delivery mechanisms.
Do you have direct examples of translational cancer research discoveries using your technology that demonstrated success in human patients?
We are working with a number of pharmaceutical partners who utilize our products to guide pipeline prioritization and drug development strategies. We are constantly expanding our partnerships into new areas, for example immuno-oncology, and engaging with new groups in both industry and academia.
How do zPredicta products differ from tissue culture organoids currently used? Which similarities to they share?
While standard organoid models utilize generic extracellular matrix, we reconstruct tumor microenvironment in an organ-specific and disease-specific manner. This means that when, for example, patient-derived lung tumor tissue is grown in our system, the cells will be exposed to the microenvironment mimicking the physiological environment of the lung and will be exposed to factors present in patients with lung cancer. Thus, drugs tested using our Reconstructed Organ (r-Organ) technology exhibit the same behavior seen in patients.
zPredicta has been founded with the mission to eliminate the guesswork from drug development, starting from the principle that cures for human diseases require human-specific discovery and testing environment. Besides partially solving the ethical problems intrinsically related to the animal testing, this kind of technology might help to increase drug approval success rate and reduce medical costs. One day not too far away, entire drug development workflow will be run on chips resembling the entire human body. The future of drug testing is bright and we just cannot wait for the next breakthrough!