June 2, 2014 in Blog by tahera

By Tahera Zabuawala, PhD

Just a few years ago, sequencing the first human genome cost about $1 billion and took 13 years to complete. Today the same task typically costs $1,000 to $4,000 and takes as little as a few hours. With sub-$1,000 genome sequencing soon becoming a reality, it will enable large-scale sequencing studies that could lead to revolutionary advances in personalized medicine.

Diagram Blog Post 060214Next Generation Sequencing-based strategy to develop targeted therapeutics in oncology

Next Generation DNA sequencing technology will be the engine that powers targeted cancer therapeutics to navigate the clinical trials road map. Not only the ‘engine’ has achieved an exponential increase in horsepower, we have also gained an insight about the fuel (tumor DNA). There is strong evidence that a tumor from a given primary site or histology type is genomically heterogeneous which has a dramatic influence on responsiveness to a drug. Several kinase inhibitors developed along with companion diagnostic tests have achieved success by selecting patients that are mostly likely to benefit or by excluding patients that are least likely to benefit from the regimen. Companion tests evaluate whether the patient harbors a mutation in the ‘druggable’ target; patients are selected based on the test results. For example, a companion test for erlotinib analyzes mutations in the EGFR gene.

A downside of using only companion tests is that it does not aid in tailoring alternate therapies for patients that develop resistance for the ‘druggable’ target. For example, even if the patient did not harbor EGFR mutations, the patient may be resilient to erlotinib treatment due to the impact of an alteration in another gene in the molecular pathway. Whole genome/exome sequencing provides an ‘actionable genome’ that highlights functional aspects of the druggable target and its associated molecular pathways.

Another important application of whole genome sequencing lies in pharmacogenomics or pharmacogenetics. Pharmacogenetics is the study of an individual’s genotype and the ability of the individual to metabolize a drug. Gene sequencing technology helps in identifying the network of genes that determine responsiveness to a drug. Consequently, in the preclinical setting, one may start screening compounds with the least variation across individuals and the compound that works best overall against all its subtypes may be chosen.

Continuing with the car analogy, engineering a car based on the type of fuel – gas, diesel, ethanol or electricity, will increase the performance and reduce its carbon emission. Similarly, whole genome or exome sequencing enables stratification of patient’s genotype (fuel) that will increase the success rates of drug development. This information can also be used to rescue failed or failing drugs by redefining the patient population. An informed and rational-based strategy of genetic subtyping of patient response, whether due to different molecular subtypes or differential drug effects, will expedite drug development and entry of more targeted cancer drugs in the market with potential increases in efficacy and an improved side effect profile.

Life Science Strategy Group, LLC is experienced in helping companies define a commercialization pathway for targeted oncology therapeutics. Dr. Wade Sunada, Ph.D., LSSG’s oncology practice leader, explains: “Developing a commercialization pathway in oncology for targeted therapeutics requires more than knowledge of the oncology market, but also an understanding of the science. LSSG can help identify potential hurdles and streamline the commercialization pathway to help companies bring their targeted therapeutics to market.