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14
Mar
2014

The open-minded art and science of drug repurposing

 repurposing drugs

 

 

Beyond the headline stories of drugs for one condition, being applied successfully for another (think of Thalidomide being repurposed for leukaemia or good old Viagra that started off as a treatment for angina or hypertension) there is a significant body of work that is on the increase in repurposing, with huge potential for brain cancer.
 
Repurposed drugs are not only those that were unsuccessful for their intended target, like those above, but may be existing standard of care for other diseases. A project coming out of the Dana-Farber Cancer Institute and Boston Childrenís Hospital recently found a 50-year-old antipsychotic medication could work for a rare type of cancer called T-cell acute lymphoblastic leukemia (T-ALL). 


"The most fruitful basis for the discovery of a new drug is to start with an old drug."

Sir James Black, Nobel Laureate.


Antipsychotic drugs being used to combat glioblastoma

 

In the same vein, researchers at the University of California, San Diego School of Medicine have just discovered that anti-psychotic drugs possess tumour-killing activity against the most aggressive form of brain cancer, glioblastoma, also known as GBM.


The surprising finding was made when the UC San Diego team tested each gene in the human genome using a technique called shRNA (short for 'hairpin Ribonucleic Acids') to study its role in glioblastoma growth.

 

Serendipity occasionally happens in science, and the researchers discovered something unexpected. It turned out that many of the same genes required for glioblastoma growth are also required for dopamine receptor function.

 

Dopamine is a neurotransmitter that is released by neurons and binds to the dopamine receptor in nearby neurons, enabling neuron-to-neuron communication. Abnormal dopamine regulation is associated with a number of neurological and psychiatric disorders including schizophrenia, attention deficit hyperactivity disorder (ADHD) and Parkinson's disease. Patients with these disorders are often prescribed dopamine antagonists that block (ëantagoniseí) dopamine receptors.  One particular dopamine antagonist, called haloperidol, has been in use for many decades as an antipsychotic treatment for the symptoms of schizophrenia.

 

Following the clues, the researchers tested the effects of dopamine antagonists against glioblastoma and found that the anti-psychotic drugs exerted significant anti-tumour effects both in cultured cells and mice with brain tumours.  And, when the drugs were tested in combination with other anti-glioblastoma drugs, the effects on tumour growth were synergistic.

 

The concept of using anti-psychotics to treat brain cancer is not new. Itís been known for some time that patients with schizophrenia have a lower incidence of cancer in comparison with the overall population, and this has been attributed to the drugs that these patients use to manage their disease. 

 

"On the clinical front, this new finding is important for two reasons. First, these drugs are already FDA-cleared for human use in the treatment of other diseases, so it is possible these drugs may be re-purposed for glioblastoma treatment, thereby bypassing years of pre-clinical testing. Second, these drugs have been shown to cross the blood-brain barrier, a barrier that prevents more than 90 percent of drugs from entry into the brain."

 - Bob Carter, MD, PhD, chairman of UC San Diego, School of Medicine,division of neurosurgery. 

 

The team of scientists published their discovery in the journal Oncotarget in March and are now working with the UC San Diego Moores Cancer Center Neuro-Oncology team to translate these findings into a clinical trial.

 

Leapfrogging the traditional research pathway

 

Cure Brain Cancer's research strategy is all about getting therapeutics to patients as quickly as possible and we are encouraged to see research like this moving so rapidly to clinical trial. The development of novel uses for existing drugs bypasses the existing bottlenecks in the brand-new drug development process. Delays and barriers can mean that translation of a promising molecule into an approved drug often takes enormous amount of time, money and effort.

 

Drug repurposing offers the key advantage of harnessing previous research and development efforts. Approved drugs have already been tested on patients, and so detailed information is available on their pharmacology, formulation, dosing, and potential toxicity. Getting useful therapeutics to the market more quickly because of the already-established efficacy and safety data forms part Cure Brain Cancer's research strategy.

 

Other examples

 

Perhaps most famous example of drug-repurposing goes to Viagra. The drug was meant to help patients with angina, a painful heart condition in which the circulatory system constricts and does not get enough oxygenated blood to the heart. Although the medication failed to treat the disease, it had a side effect of increasing blood flow elsewhere. The test patients mentioned this (in fact, most of them asked for an on-going supply) and a new use made the pill famous.. 

Repurposing Avastin for brain cancer

 

An example of a repurposed drug for brain cancer is Avastin (Bevacizumab), a tumour-starving therapy that acts by blocking the growth of new blood vessels. Avastin was originally developed as a treatment for metastatic breast cancer, but it has not been shown to delay in the growth of tumour nor help women with breast cancer live longer or improve their quality of life, whilst it has had some success for patients with glioblastoma multiforme.

 

Increased investment


The strategy of repurposing already approved drugs leapfrogs the traditional research pathway and accelerates treatments to patients. The potential is becoming a greater focus as, for example, the NIH awarded $12.7 million last year for the exploration by nine academic research groups of a selection of existing compounds with a potential in eight new disease areas.

 

Current repurposing projects

 

Several of the projects Cure Brain Cancer Foundation is currently helping to fund through its support of the Brain Cancer Discovery Collaboarative (BCDC) focus on translating treatments for other diseases to those suitable for brain cancer, and at the moment we are evaluating a further potential project for applying a melanoma treatment to brain cancer.. 

 

Dr Sarah McKay, Medical Writer and Neuroscientist

 

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