Monday, October 27, 2014

HuTrial - human surrogates for clinical trials becomes a reality

In early June, Crown Bioscience unveiled its new human surrogate trial platform, HuTrial, which functions as a low-cost substitute for a phase-II trial. Through conducting a HuTrial, researchers could be able to predict the efficacy of a prospective candidate early in the drug development process, helping to reduce the failure rate at the later stages of clinical trials. Abby Miller spoke to Jean-Pierre Wery, president of Crown Bioscience, to find out more. It's a regrettably common story: a drug candidate shows great potential, only to fall at the final hurdle. After investing millions of dollars into its development, a pharma company is left with nothing to show for their efforts. Nothing, that is, except the hefty price tag associated with late-stage drug attrition.
HuTrials are conducted using Crown's HuPrime patient-derived xenographs (PDX), which involve transplanting primary tumour cells directly from a patient into an immunodeficient mouse. As the new tumour develops, it retains all the key characteristics of the original. This means the surrogate truly represents the patient, and accurately determines how their cancer is likely to behave. While patient-derived xenographs in themselves are nothing new, this is the first time the technique has been used to simulate clinical trials.

FIGURE: HuPrime patient-derived xenographs (PDX) involve transplanting primary tumour cells directly from a patient into an immunodeficient mouse.

Targeting patients

Especially within oncology, phase-II clinical trials are notorious for their failure rate - an exciting preclinical candidate does not always translate into a successful drug. This is largely due to the fact that cancer is such a heterogeneous disease. Even if you take two lung cancer patients, nominally suffering the same 'type' of cancer, the underlying biology may be entirely different.
This means that any given drug candidate is unlikely to work well across the board. You need to pinpoint exactly which patient group will benefit, if the candidate is ever to make it past the preclinical stage.
HuTrials provides an intriguing potential solution. In essence, Crown enrols not patients but tumour models into a clinical trial. This gives a great deal of flexibility to test out treatments, discerning the different effects of each drug on any given tumour type.

Cutting time and costs

Technically, the requirements are similar to those in a human trial: you need an adequate number of 'patients', and sufficient diversity in your tumour models. Here, though, there is an additional important factor, which is keeping the tumours alive. Typically mouse tumours would be cryopreserved until needed, but when conducting HuTrials the timelines are too short to make that a viable option. Crown therefore keeps a ready stock of mice available for trial enrolment.
"If you want a HuTrial with 50 models, and you have go back and regenerate all these models from frozen tumours, that's very cumbersome," says Wery. "Most of your customers will say you're going to get clinical trial information too late. So unlike many companies, Crown keeps a lot of models alive whether or not the customer's going to use them."
If speed is one key advantage, the other is surely cost. While a typical phase-II or III trial costs millions of dollars, a pharma company can undertake a HuTrial at a fraction of the price. It's a worthwhile investment, ensuring that only the most effective candidates make it through to the next phase of testing.

Bridging the divide

The idea, of this technique, is to accelerate the passage of promising drugs to the clinic - ensuring that clients do not waste resources on ineffective treatments, while at the same time helping pinpoint drugs that could benefit a specific population. HuTrials can enable companies to go from an interesting pre-clinical drug candidate to clinical success."

Posted By:-
Biotechnology Department

Tuesday, October 21, 2014

'Designer' nanodevice could improve treatment options for cancer sufferers

Cancer diagnostics and treatment options could be drastically improved with the creation of a ‘designer’ nanodevice currently being developed by an international team of researchers. The diagnostic 'nanodecoder', which will consist of self-assembled DNA and protein nanostructures, will greatly advance biomarker detection and provide accurate molecular characterization enabling more detailed evaluation of how diseased tissues respond to therapies.
The diagnostic 'nanodecoder', which will consist of self-assembled DNA and protein nanostructures, will greatly advance biomarker detection and provide accurate molecular characterisation enabling more detailed evaluation of how diseased tissues respond to therapies. A biomarker, or biological marker, refers to a measurable indicator of some biological state or condition. One example of a commonly used biomarker in medicine is prostate-specific antigen (PSA). This marker can be measured as a proxy of prostate size with rapid changes potentially indicating cancer. The four-year 'Immuno-NanoDecoder' project involves lead partner University of Rome Tor Vergata, Italy; together with University of Lincoln, UK; Hospital of Udine, Italy; Temple University, Philadelphia, Pennsylvania; and University of Buenos Aires, Argentina.
The project's long-term goal is to develop a molecular nanodevice for imaging of biomarkers in tissue samples and cells. It will initially help to accurately characterize skin cancers and glycogenosis type II (where the body cannot get rid of glycogen from the muscles), being especially useful to assess in vitro the effectiveness of experimental therapies. It is funded with a 441,000 Euro grant from the Marie Skłodowska-Curie Research and Innovation Staff Exchange (RISE) programme. The University of Lincoln team will be responsible for engineering and synthesising a key component of the nanodevice: a two way molecular connector to bind the protein part to the DNA scaffold.

"Once a cancer has been diagnosed the next stage is to try various treatment methods, but it is often difficult to understand the specific effect of treatment. This nanodecoder is the perfect tool to be able to both diagnose cancer accurately and record therapeutic effects. Hybrid nanodevice is an artificial device made out of DNA and protein. Molecules arranged in a very specific way can perform a function -- this is what we are trying to achieve, in an artificial way. It's like DNA origami; it's possible to engineer different shaped molecules but we want to engineer molecules that also have a function. After this project, we will be in a position to claim we have a very well defined expertise to make hybrid molecular devices. Using a high-resolution method called Atomic Force Microscopy the team will be able to look closely at the assembled nanodevice.
"Each nanodevice will be coupled to a specific molecular probe, such as an antibody, peptide, or protein that uniquely recognise disease biomarkers. The coupling will allow the nanodecoder to detect biomarker presence and distribution in cells and tissues using optical fluorescence microscopy -- in other words making them shine. Different biomarkers can indicate whether the disease is in remission or where it may have spread. From this set of markers doctors can understand what the next step in the treatment process should be. The number of biomarkers that can be detected will be essentially unlimited and therefore the nanodecoder could serve as a platform to diagnose other cancers and diseases. This project is an excellent vehicle to test our molecular tools and understand the potential of our first hybrid device."
The nanodecoder, once created, will be trialled at the University of Buenos Aires, Argentina and at the Hospital of Udine, Italy. Complementary research programs, ranging from nanotechnology to molecular medicine and pathology, will support the project.

Posted By:-
Biotechnology Department
BII Noida