Nav: Home

New tool mines whole-exome sequencing data to match cancer with best drug

March 29, 2016

A University of Colorado Cancer study published today in the Journal of the American Medical Informatics Association (JAMIA) describes a new tool that interprets the raw data of whole exome tumor sequencing and then matches the cancer's unique genetics to FDA-approved targeted treatments.

"Whole exome sequencing is becoming more available to patients and this tool will help them distill the sequencing data to candidate genes and link them with therapies," says Aik Choon Tan, PhD, investigator at the CU Cancer Center, associate professor of Bioinformatics at the CU School of Medicine, and the paper's senior author.

The tool, called Integrating Molecular Profiles with Actionable Therapeutics, or IMPACT, starts with the data generated by whole-exome sequencing - a string of A, T, C and G hundreds of millions of letters long. IMPACT then maps this string onto the human genome to partition the raw data into segments that correspond to the body's approximately 20,000 genes. The tool then compares the code of these genes to "normal" gene patterns to discover which genes differ in ways that could guide the development of cancer. (In a second step, IMPACT also counts the number of gene repeats, which when adjusted higher or lower can also drive the growth of cancer.)

"Now we have a list of candidate genes," Tan says. "The next step is to link candidate genes with therapeutics."

IMPACT does this by mining publicly available data including that of the NCI-MATCH clinical trial and the database at MyCancerGenome.org to discover which FDA-approved therapies target these candidate genes.

The Tan lab tested the tool by inputting whole-exome sequencing data for patients known to have EGFR-mutated non-small cell lung cancer from The Cancer Genome Atlas. Sure enough, IMPACT successfully identified the gene EGFR as a driving mutation and recommended FDA-approved EGFR inhibitors.

In collaboration with the laboratory of CU Cancer Center investigator William A. Robinson, MD, PhD, Tan and colleagues then used the tool to retrospectively analyze a series of exome-sequences from patients diagnosed with melanoma, validating the tool's ability to discover a patient's activating mutation and pair it with useful treatment.

"For example, a patient was found to have a BRAF mutation and was put on a clinical trial of the drug vemurafenib, which targets BRAF alterations," Tan says.

The drug controlled the patient's tumor. However, two years later the tumor relapsed. At this point, the group resequenced the tumor and found that in addition to BRAF mutation, the patient had developed NRAS mutation.

"Taking tumor samples over time, we could see the cancer cell figuring out how to become resistant," Tan says.

However, drugs also exist to disrupt cells that depend on NRAS mutation. The combination of dabrafenib (for BRAF) and trametinib (for NRAS) controlled the patient's melanoma for another two years. When the cancer relapsed, it was again resequenced and evaluated using IMPACT. Analysis showed loss of the gene CDKN2a, a known tumor suppressor gene that keeps in check cells that have learned to speed through the process of replication. Currently there are no inhibitors of the CDK family of genes approved by the FDA to treat melanoma. However, the drug palbocicilib recently earned FDA approval to treat a subset of breast cancers.

"We are trying to see if we can treat this melanoma with a CDK inhibitor. Will this drug overcome the cancer's resistance to the previous combination?" Tan says.

The IMPACT tool works in four steps: 1) identify possible cancer-causing mutations; 2) identify possible cancer-causing gene copy number alterations; 3) match cancer's genetic causes with the most likely therapeutic controls; 4) evaluate the ongoing evolution of cancer to continue matching controls with emerging causes.

"We hope that IMPACT proves to be an important tool in empowering the shift toward precision medicine," Tan says.
-end-


University of Colorado Anschutz Medical Campus

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
New analytical technology to quantify anti-cancer drugs inside cancer cells
University of Oklahoma researchers will apply a new analytical technology that could ultimately provide a powerful tool for improved treatment of cancer patients in Oklahoma and beyond.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Cancer expert says public health and prevention measures are key to defeating cancer
Is investment in research to develop new treatments the best approach to controlling cancer?
UI Cancer Center, Governors State to address cancer disparities in south suburbs
The University of Illinois Cancer Center and Governors State University have received a joint four-year, $1.5 million grant from the National Cancer Institute to help both institutions conduct community-based research to reduce cancer-related health disparities in Chicago's south suburbs.
Leading cancer research organizations to host international cancer immunotherapy conference
The Cancer Research Institute, the Association for Cancer Immunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research will join forces to sponsor the first International Cancer Immunotherapy Conference at the Sheraton New York Times Square Hotel in New York, Sept.

Related Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...