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Large-Scale Screening Using Patient Avatars Aid Clinical Trial Design

by Federica Parisi PhD, May 19, 2016 at 12:05 PM | Tags

As scientists are learning about the heterogeneity between patients that supposedly have the same tumor, they are growing increasingly interested in understanding whether a given compound can be broadly efficacious or only applicable to a subset of patients with the same disease. Patient-derived xenografts (PDXs) are the model of choice to address these questions as they conserve the original features of a patient’s tumor. CrownBio is now launching HuScreen™ a new platform that allows the use of PDXs in large-scale screenings to evaluate the efficacy of multiple treatments at the same time.

It is estimated that about 95% of new anticancer agents entering clinical trials eventually fail to reach the market because of lack of efficacy, with only small subsets of patients responding to a novel agent.

However drugs that are only effective for a subpopulation of patients, can still be of interest, particularly if patients can be properly stratified prior to treatment. Selecting the correct patient population has become possible thanks to our greater understanding of the molecular makeup of tumors, which has allowed us to identify biomarkers and genetic signature that correlate with a good response, reducing attrition rates.

How Can PDX Trials Help Drive Forward Precision Medicine in Oncology?

Scientists are actively searching for methods and models that better reflect the patient disease. PDX models are highly relevant because they conserve the original features of the patient tumor and have been shown to be predictive of patient response.

PDX models can be utilized to run preclinical Phase II-like mouse clinical trials (MCT) that closely reflect the human trial design, with each PDX subject reflecting the pathology of its original patient (behaving as a patient avatar), and the cohort of patient avatars representing the diversity of the human patient population.

Using this population of models approach, Gao and collaborators recently reported on the establishment of 1,075 PDX models from a range of human solid tumors and carried out a MCT with 62 treatments. Their findings demonstrated a correlation between specific genomic alterations and PDX responses to therapy, which is strikingly similar to what had been observed in the clinic, thus validating this preclinical approach for screening the in vivo efficacy of anticancer drugs before the transition to the human trials.

CrownBio has a long-standing track record of research on MCT. CrownBio’s preclinical Phase II-like MCT, or HuTrials, utilize PDX models from our HuPrime® collection of approximately 3,000 validated PDX models, which have been extensively characterized by expression profiling (U219) and gene copy number (SNP6) data, as well as microRNA, exome sequencing, RNAseq, and hotspot mutational analysis. The extensive characterization of HuPrime models allows quick and easy selection of the avatars that most closely represent the patient tumor molecular features.

All HuPrime model data are annotated within HuBase, CrownBio’s free-to-access, online database.

To improve the predictive power and cost effectiveness of HuTrials, CrownBio has now developed HuScreen a high-throughput screening platform to assess the antitumor efficacy of candidate compounds using large cohorts of PDX models.

In a HuScreen tens of compounds can be tested as single agents or combination therapies on hundreds of PDX models at the same time to rapidly assess population responses across more than 70 indications. HuScreen can replicate the multitude of clinical trial designs in a preclinical setting, which will enable clients to make informed decisions on lead candidates and patient selection while reducing costs and accelerating the drug discovery process.

HuScreen has just started recruiting compounds. To register your interest, email us today at busdev@crownbio.com.


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