A Roadmap for the Center for Cancer Genomics: An Interview with Dr. Louis Staudt

October 1, 2013, by Jessica Mazerik, Ph.D.

What are the lessons learned from The Cancer Genome Atlas (TCGA) and Therapeutically Applicable Research to Generate Effective Treatments (TARGET), two large-scale genome characterization projects that are near completion? How will CCG build on these insights for future studies?

We have to embrace the complexity of cancer. In order to make therapeutic progress, we need to fully understand the different molecular subtypes and the pathways that are activated in each one. Using a multi –ome approach to view mutations, copy number alterations, RNA and miRNA expression differences, and methylation pattern changes will help identify a constellation of molecular abnormalities that may reveal which biological pathways are affected.

We also must understand that the number of tumors analyzed is important. Statistical analysis shows that if we sequence 500 cases of a particular cancer type, as we have done at TCGA, we observe molecular events that occur in as low as 5-10% of patients. However, there are recurring mutations that affect only 1% of patients with a particular cancer type. Identifying and understanding these mutations and abnormalities may also lead to possible therapeutic interventions. Until we are able to describe rare lesions in common cancers, our analysis is not finished. To analyze enough tumor samples to accomplish this, we need to take advantage of more affordable advanced technologies and build on what we have learned already from TCGA and TARGET.

What are major challenges facing CCG and the cancer genomics community?
    
The genetic changes we have identified need to be integrated with functional insight. We know there are many recurrent mutations within a cancer subtype, but we do not understand the biological context of many of those mutations. Do they contribute to tumorigenesis? At what stage of tumor development do they occur? Do these alterations lead to aberrant signaling of particular pathways? One goal within CCG that will help address these questions is to develop new models for the functional study of human cancers. Cell lines, which are limited in number and do not always genetically reflect the primary tumor, are the workhorses for cancer biologists. In the spirit of the CTD² initiative, we want to develop more functionally relevant cell lines to study known genetic lesions. Newly available technologies, like organoid cultures, will allow for cell lines to be derived from stem-like progenitors within primary patient material. Because organoids are heterogeneous cell populations with both malignant and supporting stromal cells, they may recapitulate tumor biology more accurately. CCG would like to scale up this technology to provide cancer researchers with similar models of predefined and characterized genetic abnormalities. These tools will allow for functional testing using experimental techniques such as RNA interference.

How will CCG safeguard patient privacy, while simultaneously providing researchers access to clinical data that is critical to making scientific discoveries?

We will perpetuate all of the privacy regulations and permissions currently required to use TARGET and TCGA data. However, we need to improve the model of informed consent, because it creates barriers to research. The current procedure for consent limits the ability of cancer researchers to compare data across different studies. This is especially problematic in pediatric cancer research, where use of the data is restricted to the study of pediatric diseases and cannot include comparative analyses between pediatric and adult samples. To solve this problem, CCG and the cancer community should employ a new “library card” model for informed consent. This model would allow qualified and responsible cancer researchers broad access to genomic samples for many types of studies. Cancer patients typically respond positively when asked about their willingness to participate in this potential “library card” procedure. TCGA is a step in the right direction because a researcher is granted access to all TCGA samples at once without having to separately ask for access to unique tumor types.

What are your visions and future directions for CCG?

The plan going forward is to marry the different NCI divisions and centers that are doing genomics research into one functional unit. This genomic unit will pair closely with clinical trials in order to more rapidly and efficiently develop precision medicine. As part of this partnership, CCG will participate in two NCI clinical trial initiatives, the Exceptional Responders Initiative and the Adjunct Lung Cancer Enrichment Marker Identification and Sequencing Trial (ALChEMIST). The Exceptional Responders project aims to understand the genetic basis for why some patients have dramatic positive responses to therapies, while others do not. The ALChEMIST aims to identify patients with EGFR or ALK alterations and treat them with targeted inhibitors.

Additionally, the NCI genomics unit/clinical trials partnership will increase the scope of ongoing analyses at CCG by providing additional biopsies for study. It will build on the successes from TCGA and TARGET by providing opportunities to test new and investigational drugs on molecularly profiled cancers.

Can you talk briefly about how the human genome sequence has impacted your studies on diffuse large B-cell lymphoma (DLBCL)?

It has been a pretty exciting ride. When we started my lab, scientists were getting the first glimpses of the human genome. There was a big project at NCBI called UniGene that clustered human sequence data into individual gene models . We used those primitive sequences to make specialized microarrays that interrogated 5,000 – 6,000 genes involved in lymphocyte function, because we figured these genes would be significantly expressed in lymphoma. This “Lymphochip” was a great tool for identifying subtypes of lymphoma. More recent genomic analysis has determined these subtypes have unique genetic abnormalities and clinical outcomes. Identifying these subtypes would have been easier if we had waited 12 years for next generation sequencing technology, but we were too impatient.

Because we now understand the signaling pathways that are important for lymphomagenesis, we can test drugs that target those pathways. Ibrutinib is a drug that targets a component of the B-cell receptor (BCR) signaling pathway. We predicted the ABC subtype of DLBCL would respond to ibrutinib, because its growth depends on BCR signaling. This prediction was validated by recent clinical trials where 41% of ABC DLBCL cases responded to the drug. These results are promising and suggest we are on the right track in finding viable treatments for lymphoma.