Jantzen Sperry, PhD, Director of Scientific Operations at Certis Oncology looks at how the adoption of orthotopic PDX models can elevate the impact of cancer research and improve translation in oncology drug development.
The recent passage of the FDA Modernization Act, which removed the requirement for animal testing when suitable alternatives are available, has highlighted the inadequacy of animal models most often used for in vivo research. The methods hailed as new alternatives (cell-based assays, tissue modelling, organoids, organ-on- a-chip technology, computer modelling, etc.) can improve decision-making leading up to in vivo studies; however, they are not suitable replacements for functional testing in a living system. Cancer is far more complex than the sum of its parts.
Despite considerable progress in cancer drug development over the past few decades, there remains a chasm between the number of investigational new drug (IND) approvals and commercialised oncology drugs. Fewer than 5% of oncology drugs that enter clinical trials in the US receive US FDA approval.
This abysmal success rate significantly trails the overall approval rate for compounds entering human trials (about 10% of which reach commercialisation). One well-understood cause for this ‘translation gap’ in oncology is the types of models typically used in preclinical studies.
Rethinking patient-derived xenograft mouse models
Mice have long been heroes of preclinical cancer research. They are the most-used species because they are small, reproduce quickly, have been studied for decades, and can model the same diseases humans experience, including cancer. Mice and humans share the same set of organs and over 85% of their genetic makeup, which enables researchers to study interdependent biological consequences of genetic variation and clinical responses to anti-cancer compounds before advancing to human clinical trials.
Patient-derived xenograft (PDX) models, which are developed by transplanting human cancer cells or pieces of live tumour tissue in immuno-deficient mice, are the workhorses of cancer research. Often overlooked by those who point out the shortcomings of mouse models is that not all PDX models are developed equally. The most common approach is to implant cancer cells under the skin of the animal, typically the flank. These are known as subcutaneous PDX models, often incorrectly generalised to simply ‘PDX’ models. Although the process for subcutaneous model development is less complex and makes tumours easily accessible for measurement by manual calipers, it is well known that subcutaneous PDX models have significant shortcomings. Perhaps most significant is that they do a poor job of recapitulating the human tumour microenvironment, known for decades to play a critical role in immune response and the complex biological activities collectively described as the hallmarks of cancer. Today’s emphasis on immuno-therapy and other targeted therapies amplifies the limitations of subcutaneous PDX models.
The case for the transition to orthotopic implantation methods
An alternative to subcutaneous implantation is orthotopic engraftment, whereby human tissue is surgically inserted in the site of origin in the animal (e.g., a liver cancer tumour in the liver, a brain cancer tumour in the brain, a lung cancer tumour in the lung, etc.). A significant body of research shows orthotopic PDX models more reliably recapitulate tumour micro- environment, which is materially important to tumour initiation, growth, invasion, metastasis, and drug response.
In a July 2022 letter titled “The local microenvironment matters in preclinical basic and translational studies of cancer immunology and immunotherapy,” published in Cancer Cell, an international group of cancer researchers emphasised the cruciality of avoiding unnaturally, influencing the biology of the disease and increasing the clinical relevance of models. Specifically, they pointedly state “modelling tumours in their natural orthotopic microenvironment improves the relevance of preclinical animal studies of cancer progression and treatment.”
Importantly, the study of in situ tumours also compels the use of advanced imaging technology to accurately quantify tumour volume measurements, replacing error-prone, caliper-based methods.
Beyond preclinical development
In addition to their role in preclinical investigations, O-PDX models can be employed during clinical testing as a functional precision medicine complement to real-world evidence. This ‘co-clinical trial’ approach involves testing in humans and personalised mouse avatars in parallel, enabling iteration in the clinical trial itself. These types of studies facilitate more accurate patient stratification based on biomarkers, providing insight into drug resistance mechanisms, and even enabling the identification of an appropriate next-line therapy for each patient at the conclusion of the trial.
This approach was described in a study recently published in British Journal of Cancer, in which PDX models were subjected to combinations of drugs being tested in parallel in patients with head and neck cancers. Results from the mouse models helped optimise patient treatment using the drug combinations shown to have the highest likelihood of safety and effectiveness.
A case for fewer, but more impactful animal studies
The FDA Modernization Act will likely increase the number of cancer drugs entering clinical trials. But unless we simultaneously embrace the use of more advanced mouse models, it also will likely increase the number of clinical failures. Minimising the use of animals in medical research is a noble, right- minded endeavour. However, cancer is a complex disease and today’s sophisticated anticancer therapeutics still require functional testing in whole-body, living systems. Rather than asking cancer patients to function as those test subjects, we can employ more clinically relevant O-PDX models to improve the translation to the clinic— and in doing so, elevate the impact of fewer animal studies.
DDW Volume 24 – Issue 2, Spring 2023
About the author:
Dr Jantzen Sperry, PhD is a translational research scientist with over 10 years of experience working with various models of disease, including inflammation of the central nervous system which contributes to neurodevelopmental disorders, neuro- oncology, and preclinical animal models of various cancer subtypes. Currently serving as the Director of Scientific Operations at Certis Oncology Solutions, he manages a highly skilled and diverse scientific team with research projects spanning in vitro, ex vivo, and in vivo preclinical platforms.