Pharmacogenomics harnesses power of prediction, personalization

Branch of pharmacology stands at the precipice of the era of personalized medicine in cancer treatment

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When it comes to cancer research, the search for the "magic bullet" that could lead to a cure for one of the most insidious diseases facing humankind continues to be analogous to the proverbial search for a needle in a haystack. That leaves researchers looking for new and innovative ways to seek out potential drug candidates that can advance cancer treatment.
One of the most recent developments in cancer research is pharmacogenomics, the branch of pharmacology dealing with the influence of genetic variation on drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity. By doing so, pharmacogenomics aims to develop rational means to optimize drug therapy, with respect to the patients' genotype, to ensure maximum efficacy with minimal adverse effects.

In this, the second installment of our series exploring cancer research efforts, we will explore the growing trend of pharmacogenomics, which stands at the precipice of the era of personalized medicine in cancer treatment, in which drugs and drug combinations are optimized for each individual's unique genetic makeup.   
The power of prediction

According to James Peach, Cancer Research UK's director of stratified medicine, genetic analysis can give much more information on how likely the tumor is to grow or to react to certain treatments.

"For example, certain genetic types of prostate cancer grow more quickly, and certain types of lung cancer are more likely to respond well to targeted next-generation drugs like gefitinib and erlotinib," he says. "Importantly, tests could also predict whether certain drugs won't work—sparing patients potentially unnecessary treatment and making things more cost-effective. With some treatments, this is already happening."

According to Harry Glorikian, managing partner of Scientia Advisors, a management consulting firm specializing in growth strategies for major and emerging companies in healthcare and the life sciences worldwide, current cancer research relies heavily on newer molecular targets.

"Aberrations and mutations of those targets determine whether targeted therapies will be fully effective," he says. "In addition, pharmacogenomics allows researchers to fully understand how a drug will react in a tumor cell dependent on its current genotype."
This saves time and money, as the therapy chosen will be dependent on the readout of the pharmacogenomic result, thereby reducing the trial and error process of current disease management in oncology.

"A major contention will be the increased perceived value of the oncology product, since if efficacy is established in a finite number of patients, with a cost/benefit in reduction of using less efficacious drugs, then the value and therefore price of those 'more effective' products will increase," Glorikian adds.

According to Dr. Laxman Desai, president and CEO of Toxikon Corp., a preclinical contract research firm based in Bedford, Mass., while it is still in its infancy, knowledge of pharmacogenomics is increasing rapidly.

"Life science industries continue to delve into it and develop gene expression profiles for different classes of chemical carcinogens and possibly mutagens," Desai says.

"Pharmacogenomics is impacting in a good way because, at some point, we will be able to develop and direct new drugs in a more efficient and more personalized fashion when it comes to treating diseases, like cancer."

Moreover, Desai notes that major developments in pharmacogenomics will continue, but right now, improvements in drug efficacy and tolerability to ultimately determine the most advantageous dosage are best achieved when using in vivo mechanisms of drug action, pharmacokinetics.

Taking it personally

Glorikian points out that a key attraction to pharmacogenomics is the ability to practice personalized cancer treatment.

"In oncology, the disease manifests itself as a tumor. Unlike other disease states that have generalized root causes, tumors can arise from multiple mechanisms," he says. "Pharmacogenomics is another diagnostic to determine the cause of the tumor, and subsequently determine the type of therapy which will be most effective."

According to Desai, it is widely accepted that pharmacogenomics can identify biomarkers to aid drug development in the areas of exposure, efficacy, stratification and toxicity.

"These markers can determine whether the desired target tissues of a subject have been exposed to a drug at physiological concentrations," he says. "Efficacy markers give molecular evidence beyond traditional clinical findings. Stratification markers identify subsets of patients who could very well stand to benefit from a given therapy. Toxicity markers are the red flag, foretelling and hopefully preventing adverse events."

Desai says these markers are very useful information in the design and delivery of a drug to targeted areas of the body or disease.

"For example, treating a localized tumor through angiogenesis means using the vessels of the tumor to shrink it, and information from that procedure is useful to delineate the reactions due to toxicity," he says.  

While generating pharmacogenomic data is nothing new, as life science companies have been doing it for a long time, Desai explains that pharmacogenomics is still in its infancy, so it is cautiously used in a limited way because new information is always being accumulated.

"We have yet to get a complete picture of its capabilities, but someday, it will be developed and perhaps used widely," he says. "The information that is generated from it is not generally part of an IND or NDA. We did this same science 30 to 40 years ago at Dana Farber. We were targeting the same things to combat cancer, blood cancer being one of the most difficult. We were trying to make drugs less toxic. We modified the structure and improved the efficacy. We knew what the genome was there, but we didn't have a way to get there. Pharmacogenomics is that tool, but to use it, there will need to be a change in regulations. We can't use the same regulatory yardstick. It no longer applies."

The safety of pharmacogenomic drugs would need greater attention in order to properly evaluate safety and efficacy, Desai adds.

"Think about genetically modified grains and food. Do we know the long-term effects it has had or will have on us? Or how about the effect this science will have on a particular species, especially when we are crossing donkeys with zebras? There's really no difference."

Glorikian also notes that going forward, pharmacogenomics will be key to gaining a better understanding of the etiology of cancer.

"Since there are numerous molecular mechanisms which may go awry to cause tumor formation, there will be more work needed in cancer research to completely vet out the tumor and stage disease," he notes. "From state IV NSCLC will arise stage IV NSCLC with XYZ mutation. This will drive therapy decisions from a generalized population-based approach to a more targeted individual tumor class approach. We are likely to see continued changes in guidelines, creating detailed decision trees for more optimal cancer therapy. This work will result in our ability to not only treat cancer but in the long run beat cancer."

As pharmacogenomics continues to emerge, Desai says it may be one of the reasons companies like Toxikon are seeing demands for drug discovery services from their customer base.

"Along with safety studies, they also need assistance with synthesis of intermediates from milligrams to hundreds of grams," he says. "We are also poised to develop the small novel molecules for the treatment of cancer and viral diseases. We have these facilities and the expertise to synthesize metabolites for pharma studies from a few milligrams to 500 grams. We have upped our capabilities to undertake any and all safety evaluations of novel drugs because fields like pharmacogenomics are on the horizon."

Shining a light on gray areas

Looking to the future of pharmacogenomics and its role in cancer research, Desai says it is a tremendous tool that can shed light on many misunderstandings of biology, medicine and the development of novel drugs.

"These are not exact sciences like chemistry and physics," he adds. "There is a lot of gray area. While pharmacogenomics has the potential to revolutionize drug development and healthcare, it comes with inherent challenges."

Those challenges run the gamut, from significant changes to the regulatory landscape, to cracking the complexities of biological responses of diseases, to the development of rapid-detection methods that sequence the genome in its entirety.

"Aside from that, there are the social issues to contend with," says Desai. "Who would have access to this genetic information? How would you deal with the ethical and privacy issue since this information could have implications for employers and insurance companies? Then, there's the cost of genome sequencing, and the fact that insurance companies may not want to pay for it; never mind the task of educating healthcare providers and pharmacist on conducting or advising patients on diagnostic tests. That's why pharmacogenomics is still in its infancy, and like a child, it will have to experience the needed growing pains in order to realize its considerable promise for drug discovery and development."

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