Gaps into bridges
A diagnosis of cancer will certainly throw an individual into a state of fear, panic and uncertainty with concern and anticipation for their future. Many will seek out information on the latest research developments in the hope that scientists have found a cure for their particular cancer. Even the briefest inquiries will reveal a plethora of research institutes, universities, non-profit organizations, government research units, and pharmaceutical and biotechnology companies involved in cancer research. While this may be somewhat reassuring, what may not initially be so comforting is that the majority of the research is being performed in test-tubes or in animals. With a diagnosis of cancer you want to know that the investigational treatment will be effective in humans and most importantly that it will work for you and for your type of cancer. Scientists too are eager to envisage that their basic research will rapidly become diagnostic or therapeutic interventions that can be applied to the treatment or prevention of cancer. For investors, it also makes sense to be able to direct funds to the research that has the highest chance of success and hence return on investment. The reduction of scientific risk results in the eventual reduction in financial risk.
This pressing need to translate basic research into effective diagnostic tools and treatment options has led to the latest buzz word in the pharmaceutical and biotechnology industry – translational research. Translational research (TR) is essentially the bridge between late preclinical development and early clinical development and back again. It focuses on implementing bi-directional plans to enable better decision making at the pre- clinical/clinical interface through more informed lead selection and the earlier termination of high- risk projects.
Biomarkers into activity
In oncology, one approach has been to identify biomarkers of activity which will monitor or predict the activity of a compound in man. These biomarkers may be anatomic, physiologic, biochemical, and/or molecular parameters that have been associated with the presence and severity of a cancer. They are detectable and quantifiable by a variety of methods including physical examination, laboratory assays and most recently by medical imaging techniques. The most obvious biomarker is the presence and size of a tumor but there are a large number of other biomarkers that can be evaluated with modern imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET). MRI examples include tumor microenvironment (pH, cellular apoptosis, necrosis, hypoxia, etc.), and tumor vasculature (vessel size and number, permeability, blood oxygenation and flow, etc.). The tumor vasculature biomarkers have proven themselves particularly useful for testing anti-angiogenic compounds. MRI can also be used to look at response to treatment in terms of changes in cellular density and water motility. PET has been successfully applied to looking at tumor metabolism (again, an indicator of response to therapy), identifying and locating tumor metastases, and investigating the pharmacokinetic properties and biodistribution of drugs. An additional benefit of looking at biomarkers is that in addition to their application to investigate how tumors respond to individual therapeutics, they may also be applied in determining how to sequence and establish appropriate doses for drug combination therapy.
Animals into man
While it is useful to have data that shows drugs regress or inhibit tumor growth in animals, unfortunately this doesn’t necessarily predict activity in man. Patients and their clinicians want reassurance that the treatment is effective in humans. In addition existing strategies don’t always show spectacular direct anti-tumor activity because the drugs are designed to be used in combination. One innovative approach to this problem and probably the most recent tool in the TR arsenal is the application of small animal imaging (MRI & PET) to develop rodent imaging biomarkers that clinicians can follow with the human-scale imaging machines. This pioneering approach gives clinicians an idea of whether or not a drug is acting as it has been designed and if the individual patient is responding successfully and appropriately to treatment. The clinician is then empowered to make a fairly early decision about keeping a patient on the drug, adjusting the dose or taking the patient off treatment because it is not working effectively or because of other safety issues. The necessity to commit a patient to one specific and often expensive treatment regimen and hope for the best has been eliminated. This strategy also provides information of when to schedule combinations – this includes anti-angiogenics with cytoxics or other targeted therapeutics, specifically for individual patients based on how they respond.
Theory into practice
The advantages of using this approach in clinical trials are manifold. As the methodology entails looking at individual responses, fewer statistics are required and therefore fewer patients need to be recruited to the trial. Patients can be pre-screened for expression of certain cell surface receptors, targets, secreted factors in order to select the best patient population for the drug being tested. Ultimately the clinical trial is conducted faster, more effectively and more ethically.
The benefits of TR are not just theoretical. Oncodesign, a company using this technology, are routinely applying the strategy to the compounds they research. In one example they have determined preclinical biomarkers of vascular permeability in response to therapy with anti-angiogenic compounds and vascular targeting agents that are in use in phase I trials to determine when the compounds begin to have an effect on tumor vascular permeability, tumor blood oxygenation and blood flow as well as tumor growth.
Ideas into action
Pharmaceutical companies are increasingly looking to invest in small-animal imaging capabilities and several American and European biotechnology companies and research institutions are forming Translational Research or Translational Oncology departments that use these tools. Serono, Genentech and Chiron all have Translational Oncology departments. The National Cancer Institute (NCI), the European Organisation for Research and Treatment of Cancer (EORTC), the Curie Institute, Cancer Research UK, Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center, Roswell Park Cancer Institute have all initiated internal TR groups.
Fear into hope
A phase I clinical specialist recently commented that he considers the current state of cancer treatment to be in a very poor condition. However, he said that he was hopeful that now thanks to years of biological research and through the application and intelligent use of TR that we are finally starting to establish better ways to treat patients. As a clinician he is working very closely with preclinical specialists looking for ways to improve how he treats his patients. This is a philosophy which is very different from even 7 to 10 years ago. Most scientists have accepted that there will not be a magic bullet for the treatment of cancer but by applying TR to the drug discovery process we should at least be able to develop diagnostic and therapeutic tools that are more effective and have less side-effects than the current options. For patients the developments should mean that the fear, panic and uncertainty that a diagnosis of the “Big C” brings will at least be accompanied with a little hope!
For further information on translation oncology at Oncodesign contact Jonathan Ewing at jewing@oncodesign.com