Genome and Metabolic Scans the new anti-Cancer Weapon

New cancer treatments are one of the most precipitous of all drugs to develop. But a renewed focus on the DNA mutations that make each cancer unique is about to expand our ability to find new treatments.

Cancer biomarkers may be detected using Mass Spectrmoetry

Traditionally, cancer drugs have been developed by identifying compounds, more recently antibodies, that have a highly toxic effect on cancer cells and animal models in the lab. They are then tested on small, then larger groups of patients to prove their efficacy. But this model is yielding less and less success. In the last 30 years, for example, there has been no real improvement in the drugs able to treat metastatic melanoma from which about 1000 Australians die every year.

The reason is that scientists have been slow to figure out ways to truly capitalize on our molecular knowledge of cancers. Our approach to disease is very linear – X mutation leads to Y disease – despite us knowing that most diseases are polygenetic in origin.We tend to work on particular molecular pathways in isolation. For example, individuals labs will often use one animal model for their own research.

In this article, the founders of Sage, a biomedical networking company, explain how our approach has to begin to use our knowledge of full molecular networks. They say that much of Merck’s metabolism pipeline was developed using such molecular knowledge.Another great example is the AstraZeneca/Biowisdom Safety Intelligence Program (SIP), described as the “largest forever-expanding collection of known chemical effects occurring in different tissues, drug effects on clinical biomarkers of tissue injury, and drug molecular mechanisms.” Currently, SIP contains almost 100,000 individual facts, or “assertions,” related to the liver’s response to more than 5,500 different compounds in over 20 species.

Fundamentally, this new style of research relies on powerful new approaches to sequencing and decoding genomes – something that DNA arrays initially promised, but never really delivered. I’ve previously written on this topic, but every month new astounding results come out of cutting edge labs that herald a new era in molecular science and particularly cancer treatment.

Helicos Biosciences, a company founded in 2004 to commercialize single DNA sequencing technology has just become the fourth next-gen sequencing platform to complete a genome. At the same time, a second leukemia genome has been fully sequenced leading to discoveries of previously unknown mutations and new potential drug targets.

The next step is to capitalize on these discoveries by testing the association between these markers and the various drugs on offer. As an example, these researchers at MIT have found that when both p53 and ATM (common tumor markers) are abnormal, tumors are highly susceptible to DNA-damaging chemotherapy. Tumors in which ATM is mutated but p53 is not, are highly resistant to chemotherapy. Tumors in which p53 is mutated but ATM is not seem to be less responsive to chemotherapy.

This is a solution that is applicable immediately. “You could use this today,” the author says. “You do immunohistochemistry for the tumor, for p53 and ATM, and based on [the results] you can choose anthrocyclines [if appropriate], or taxol as an alternative based on this data.”

Drug companies are beginning to use bio-markers more and more in their studies, but I would contend still not enough. If you do a medical literature search of recent cancer clinical trials, how many trials report collecting bio-markers such as p53 and ATM?

In a closely related field – metabolic profiling–an analysis of chemical reactions in the body- there has been a positive recent advancement. Metabolic profiling may help optimize drug use in patients.

Today, most doctors rely on broad measures like weight, sex and age to determine which drug and dose is most likely to be effective. It’s a notoriously hit-or-miss approach that commonly requires follow-up doctor visits and changes in drugs and dosing. Now are groups of UK scientists have determined that the chemicals created during the process of metabolism and then excreted in the urine could be a more effective tool for personalizing therapies.

To test their theory, scientists at Imperial College London and Pfizer took a urine test of 99 men who were given paracetamol, a common painkiller. What they found was that ascertaining the level of a compound in the urine–para-cresol sulphate–gave the scientists a clear picture of how the men would metabolize the drug. Higher levels of the compound, which is produced in the gut, indicated that men would metabolize the drug less effectively. They theorized that higher levels of the compound indicated that their bodies were depleted of sulphur, which many drugs rely on to work safely. Sulphur helps to detoxify the body. Engineering the bacteria in the gut could fine tune how a body metabolizes a drug.

The advantage of this pre-dose metabolite profiling is that it related to both genetic and environmental factors influencing drug treatment outcomes. Again, this is another step that will soon put an end to centuries old hit-and-miss medicine.