Patient-derived Xenograft (PDX) Model - An evolution in Oncology Drug Study

Patient-derived Xenograft (PDX)

1. Introduction:
Cancer is considered to one of the greatest health burden impacting people globally. In fact, one in eight deaths worldwide occurs due to cancer. Cure for cancer gains higher priority as the number of patients suffering from the disease is expected to cross 21 million by 2030 which today stands at around 15million globally. Difficulty in replicating the disease and lack of appropriate model and technology in cancer study at early discovery stage creates an uphill task for pharma and academia alike.

2. Main:
In order to address shortcomings at the discovery stage in Oncology study, PDX has lately emerged as the upcoming technique. Through PDX model, original tumor characteristics of humans are simulated in the immunodeficient rodents which eventually offer better predictive insights in to the clinical outcome when evaluating the efficacy of novel cancer therapies.
This white paper further explores the adoption of this methods across industry participants across different geography.

3. Recommendation:
PDX holds a lot of promise for improvement in cancer treatment as it offers time reduction in model generation, higher predictive model, and an avenue for personalized medication. The adoption of these models is spearheaded by not just the large pharma but academia and CROs as well. The research model breeders as well as CRO are entering into partnerships with leading hospitals and universities, wherein the latter provide access to significant pool of patient tissues.

Why is Cancer drug development difficult?

The challenges in developing drugs targeting cancer are the sheer number of genes involved within a particular type of cancer and among different types of cancer. Furthermore, diversity of cancer genes leads to resistance to treatment, resulting in remission. Therefore, heterogeneity in tumors makes it discovery and development of new drugs complex.

This complexity at early stage of cancer drug development has brought forth a novel method in patient-derived xenograft (PDX) model through Xenotransplantation of human cancers into immunodeficient mice.

Introduction to PDX

Advancement in oncology drug development has been increasingly stalled by a lack of apt preclinical models that reliably predict clinical activity of novel compounds during oncology study in cancer patients. In order to attend these limitations, there has been a recent preference for the adoption of heterotransplantation of human cancer cell lines into immune-compromised rodents. Hence, several tumor specific PDX models have been generated which is biologically stable in terms of gene expression & mutation, drug sensitivity etc. This in vivo model has emerged as the latest approach for oncology related study by suppliers and research fraternity.

What is PDX?

Patient derived xenograft (PDX), also known as tumor graft models are based on the transmission of primary tumors directly from the cancer patient into an immunodeficient mice like BALB/C nude, SWISS nude and SCID mice. PDX help transform clinical samples into Mouse Models to further oncology study. Since, PDX are derived from human tumors, it act as a tool for designing anticancer therapies and personalized medicine for patients with cancer. Furthermore, these models help study metastasis and tumor genetic development.

Why do we need PDX?

The lack of appropriate animal models at the early discovery stage for oncology study forms a big hurdle as ~5% of cancer treatments entering clinical trials get approved. Major reasons of attrition are efficacy (~30%) and safety (30%). Hence, an appropriate predictive model at preclinical stage contributes to the likeliness of a promising oncology drug development program.

Patient derived xenograft (PDX) aims at replicating the human situation better, thus being more predictive than through the use of conventional cell-based models.

Process Flow: Existing Vs. PDX

The tumors derived from patients are grafted into animal models (immune suppressed), and the tumor is allow to proliferate for about 1-2 months. Once the tumor grows, the research model is bred to generate multiple offspring that carry the grafts. The research model populations, thus obtained are quite similar to humans in clinical trials. The cells of the initial graft can be also be propagated as PDX cell lines, which can be cryopreserved and used for generating multiple hosts.

Qualitative Analysis (Traditional versus PDX)

PDX model not only refines the testing method but also significantly help reduce the valuable timelines. PDX methods stands way ahead from its traditional method counterpart on account of below parameters: 

Traditional versus PDX Methods:

Traditional method of preclinical trials utilizes conventional research models including genetically modified species for predicting the efficacy of the investigational drug. However, the efficacy prediction for oncology drugs is relatively low when translated into clinical trials on humans, as these models fail to account for the heterogeneity observed in humans. Therefore, only after phase II clinical trials, the efficacy of drug can be judiciously determined. Overall the determination of efficacy of a drug through above mentioned conventional methods ranges from 7-9 years.

The virtual method, on the other hand uses PDX research models, which mimics the heterogeneity encountered in humans within preclinical trials. Therefore, the resultant efficacy data from studies on PDX models is equivalent to the Phase II clinical trial data. This in turn reduces considerable time, capital and manpower associated with development of drug in comparison to the conventional methods.

Geographic Outlook (Western market & China)

The PDX model development originated in developed markets due to availability of technical sophistication and infrastructure. However, this technology is seeing a rapid shift to emerging nations, mainly China, as witnessed in the recent past.

A leading Chinese CRO WuXi AppTec, entered into a strategic partnership with Mayo Clinic to generate PDX models for oncology using tissue samples from >500 patients. This partnership enables WuXi AppTec to access the extensive tumor collection of Mayo Clinic.

On similar lines, Crown Bioscience acquired PRECOS, a preclinical CRO specializing in Oncology drug development and a pioneer in PDX model development. This acquisition brings Crown Bioscience as one of the prominent providers in China, USA and Europe for Oncology PDX models.

Others venturing into this lucrative market are leading research biology service provider GenScript and genomics giant BGI.

Furthermore, the suppliers in western market are adopting applying imaging techniques on PDX models to enhance the sensitivity of pharmacology studies. For example: Molecular Imaging, Inc. and Oncotest GmbH has recently collaborated to co-promote their individual expertise i.e. apply experience of the former in in-vivo pre-clinical imaging to the pioneering Patient Derived Xenograft (PDX) capability of Oncotest.

These developments indicate a highly competitive market in China in next 3-5 years for PDX model generation as well as testing services.