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MedImmune Turns to NGS in Collaboration with Shanghai Chest Hospital to Study Lung Cancer


By Monica Heger

Over the next
two to three years, AstraZeneca's biologics arm MedImmune plans to use whole-genome sequencing in combination with either targeted sequencing or arrays to study 500 non-small cell lung cancer tumors from patients at China's Shanghai Chest Hospital.

One of the project's goals is to identify novel drug targets as well as targets for which the company either already has available drugs or has compounds in development. The collaborators also aim to eventually identify markers to stratify patients in clinical trials.

Koustubh Ranade, a fellow in translational sciences at MedImmune, told Clinical Sequencing News that rather than examining the tumor samples at one time point, the researchers will track patients over time, evaluating the cancer at multiple stages. The collaboration with the hospital was key for this, he said, because it has patient samples with extensive clinical and phenotype data.

"The plan is to get tumor biopsies at baseline — that is, prior to any therapy — and assess their molecular profile," he said. The patient will then be put on standard-of-care therapy and if he or she relapses, the researchers will take another biopsy, assess again, and compare the tumors at baseline to the relapse tumors to identify new mutations in the relapse tumor, mutations that have expanded since the baseline, and also to see if any mutations have disappeared following treatment.

Ranade said that the information will then be used to determine whether there are any potential new drug targets and also whether there are mutations that could be used to guide treatment decisions with currently available drugs.

However, he said, the information would not be used to guide treatment for that particular patient. The results would have to be confirmed in an independent set of patients.

Ranade said that the team will take a "triaged approach" to evaluating the baseline tumors, first looking at a set of well-defined cancer genes, such as EGFR and KRAS. For this, he said they will either use a targeted sequencing approach, a commercially available array that is specific for cancer genes, or allele-specific PCR.

Then, in the samples that do not have mutations to one of the cancer genes, the company will do whole-genome sequencing. Additionally, the company will do whole-genome sequencing on all the relapse tumors.

While MedImmune is currently equipped with an Illumina HiSeq instrument, Ranade said that the sequencing would be outsourced to biotech companies in China because of regulations that prohibit samples from being transported out of the country.

Because the project is a research project and "exploratory analysis," results will not be returned to the patients, said Ranade.

Aside from non-small cell lung cancer, Ranade said MedImmune is looking to incorporate sequencing into other drug development pipelines.

"We're evaluating how we might use next-gen sequencing to understand disease heterogeneity in inflammatory areas as well — diseases like lupus and asthma," for which the company has a strong drug pipeline, he said.

Testable Hypotheses

MedImmune's projects are also indicative of pharmaceutical companies' increasing, although cautious, use of next-gen sequencing in their drug development pipelines.

Pharmaceutical companies are now "using next-gen sequencing approaches in a wide variety of settings," Tom Turi, vice president of science and technology at contract research organization Covance, told Clinical Sequencing News, including early on for target discovery, at later discovery stages to do expression or transcript profiles, and even in clinical development, "where they're asking specific, refined questions for patient stratification."

Ranade said that MedImmune's use of sequencing is primarily to "develop testable hypotheses that we can evaluate in clinical trials," both to "discover new targets," and also to "develop diagnostic hypotheses that we can test in clinical trials."

For instance, in the Shanghai Chest Hospital collaboration, in cases where mutations are found that are potentially druggable with a compound in MedImmune's pipeline, it would spur a clinical trial to test that compound in patients with a similar molecular profile.

Using the technology early in drug development to form testable hypotheses in clinical trials is quickly becoming a main application, Turi added, and sequencing has "been embraced as a technology platform for discovery applications." It is even "complementing many array-based platforms that have been used historically in discovery."

In some cases, sequencing is being used so early in development that drug companies are not worried about sharing proprietary drug formulas and are collaborating on the research. For instance, the Asia Cancer Research Consortium, which is a collaboration between Pfizer, Eli Lilly, and Merck, plans to use whole-genome sequencing to study the basic biology and genetics of liver, lung, and gastric cancer (CSN 2/22/2012).

In order for sequencing to move out of the early discovery stage and into later clinical development stages, said Turi, clinical interpretation will have to improve. For large-scale clinical trials, it is likely that sequencing would be outsourced, he said, and would have to be done in a CLIA laboratory.

So service providers would have to have the "logistical infrastructure to transport samples from a clinical site to a laboratory," he said. Additionally, sequencing, and in particular, the analysis will have to be done "in a timely fashion, a cost-efficient manner, and [be of] high quality."

Even still, said Ranade, it is still unlikely that sequencing will be used to stratify patients, but rather to discover the biomarkers that could be used for patient stratification. Once those one or two markers are identified, it will be "much easier to identify those mutations using another technology," such as a PCR-based approach, he said.

Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.