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PDX models used in human surrogate trials are at the forefront of personalized medicine research

2015-09-02
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Clinical cancer research is a rapidly evolving industry, with personalized medicine now at the forefront of clinical trials. The promise of profiling a patient’s genetic makeup to guide the drugs or treatments to either choose a more successful result or to minimize unpleasant or harmful side effects has obvious benefits. Another key goal for personalized medicine is to tailor the dosage depending on each individual’s absorption rate. This will give the doctor and patient the opportunity to plan for monitoring and prevention, essentially resulting in the right drug for the right person for the first time.

PDX model cancer

Cancer research is a complex industry with human tumors being extremely diverse in histopathology types and heterogeneous pathogenic mechanisms. Personalized therapy based on each individual’s disease and genetic makeup is believed to be the future of cancer treatment. Before personalized medicine, patients with a specific type and stage of cancer received the same treatment. However, it became clear to doctors and patients that some treatments worked well for some patients and not as well for others.

Recent advances in the field of cancer genomics have shown that genetic differences in people and their tumors explained many of these divergent responses to treatment. Although a person with cancer now may receive a standard treatment plan (such as surgery to remove a tumor), the doctor may also recommend some type of personalized cancer treatment. Personalized cancer treatments may be offered as an active part of the treatment plan or as part of a clinical trial (research studies in patients).

Basket and umbrella trials

Because we now understand that two cancers from the same organ – which look the same under a microscope – can have different genetic causes, whereas cancer types from different organs can share the same genetic abnormalities, patients with different cancer types can be treated with same targeted therapy that is specifically tailored to the genetic makeup of their tumor. This has been the basis of “basket trials” that enroll patients across different cancer types with the same abnormality to all be tested with the same agent. This is in contrast to traditional clinical trials, which usually focus on only one cancer type and sometimes regardless of mutation status.

A different type of approach is undertaken in the so called “umbrella” trials; these take only one disease type but split patients by their mutations and genetic markers to trial a whole range of therapeutic options in parallel. In an umbrella trial patients with a given molecular makeup of their cancer are assigned to the specific treatment arm that should hopefully result in their maximum response. The trials are designed to be modular and fluid depending on patient results and when new drugs become available. This flexibility and the variety of drugs tested at the same time should mean that as many patient groups as possible have their optimum treatment options identified.

PDX models

Both approaches recognize the importance of precision profiling of patients to further personalize medicine that translates into finding “the right treatment for the right person at the right time.” The evolution of clinical trials towards study types that should find the correct targeted agent for the correct patient groups in the most efficient fashion possible is crucial as the oncology drug development process is currently highly inefficient and needs a rapid overhaul to reduce attrition rates. The key to reduce attrition rates and maximize the efficiency of drug discovery programs is the use of genomically characterized patient-derived xenograft (PDX) models that are truly reflective of the patient population which can be used in preclinical Phase 2-like, human surrogate trials to evaluate oncology agents.

PDX models used in human surrogate trials are at the forefront of personalized medicine research, offering a personalized diagnostic tool to identify the right compound for the appropriate patient population before new drugs are tested in the clinic.

Preclinical Phase 2-like trials, utilize a large cohort of PDX models 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. Human surrogate trials can help to screen lead drug candidates, discover or validate predictive biomarkers and genetic signatures, and to position or reposition agents through identification of responder populations.

A variation of this is to offer co-clinical mouse-human trials where the same treatment regimen is carried out on human tumors grown in mice avatars while the patient is enrolled in a clinical study. Not surprisingly this approach has more substantial cost implications and some time drawbacks for patients and it’s still not available for application on a large scale. PDX models give the most patient benefit by being used to improve the successes of translating novel drugs and therapies into the clinic rather than as a personalized diagnostic tool.

Medicilon’s PDX Model Services

Medicilon’s Pharmacology department functions in accordance with the needs of our customers for a variety of effective animal models used to detect drug effectiveness. We offer non-human primates, dogs, mice and rats, rabbits, guinea pigs and others in our services. At present, we have various proven effective animal models. Furthermore, our experienced staffs operate with strong theoretical basis. We offer the services which are flexible for custom development of various types of models to meet the requirements of our clients.

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