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MD Anderson’s CRC Moon Shot Team Designed to Fundamentally Change Detection, Treatment
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The University of Texas MD Anderson Cancer Center’s Colorectal Cancer Moon Shot team is making significant strides in its effort to increase early detection, advance treatment and improve patient outcomes.
The team is striving to identify new biomarkers, finalizing the certification process for a clinical assay that classifies patients into one of four colorectal cancer subtypes, and identifying new immunotherapy strategies to apply to these specific subtypes.
Healio Gastroenterology and Liver Disease spoke with Jeffrey S. Morris, PhD, professor in the department of biostatistics at MD Anderson, about the team’s short- and long-term goals, as well as what additional efforts are on the horizon.
Question: Can you provide some background on the Colorectal Cancer Moon Shot team?
Answer: The components of Colorectal Cancer Moon Shot involve three flagship project teams and focus areas. The first flagship team is focusing on finding blood-based biomarkers for early noninvasive diagnosis and/or treatment of colon cancer. Flagship two focuses on characterizing colorectal cancer subtypes and clinically applying this knowledge to finding new strategies for treating colon cancer. Flagship three is specifically working on personalized vaccine development and immunotherapy.
The overall leader and director of the Colorectal Cancer Moon Shot team is Scott Kopetz, MD; coleaders include Stan Hamilton, MD, in pathology, and Ernest Hawk, MD, on the prevention side. David Menter, PhD, is a key scientific and administrative leader of the project. Key leaders in flagship one are Robert Bresalier, MD, Arvind Dasari, MD, and Samir Hanash, MD, PhD, who have advanced the discovery of novel blood-based markers in colon cancer. My personal biggest involvement is in flagship two, along with other key members, including Dipen Maru, MD, and Raja Luthra, PhD, from pathology; Bradley Broom, PhD, in bioinformatics; Jennifer Davis, PhD, in epidemiology; and Christopher Bristow, PhD, Timothy Heffernan, PhD, and Giulio Draetta, MD, PhD, in our applied cancer institute. Key leaders in flagship three include Michael Overman, MD, Greg Lizee, PhD, and Chantale Bernatchez, PhD, who are leading the personalized peptide vaccine field.
Q: What are the top short-term priorities of the Colorectal Cancer Moon Shot program?
A: Priorities for flagship one include finding biomarkers to improve the early detection of colorectal cancer. Colonoscopy screening is the primary early detection and prevention approach. However, there are a lot of efforts underway to improve upon this with blood-based biomarkers that may be able to detect cancer earlier or indicate when people should be screened with colonoscopy. Another short-term goal is to figure out how to use circulating DNA adaptively in terms of treating patients.
Short-term priorities for flagship two include trying to get our clinical assay to classify patients into one of the four consensus molecular subtypes (CMS) pinned down and Clinical Laboratory Improvement Amendments-certified so that it can be used in clinical trials. Additional priorities include the deep molecular characterization of these subtypes, the use of this information to identify potentially novel subtype-specific therapeutic targets, and the development of pre-clinical patient-derived xenograft models to represent each of the subtypes to investigate these targets. The goal is to develop novel CMS-driven precision therapy strategies for colorectal cancer.
The focus for flagship three is on the various immunotherapy strategies applied to colorectal cancer. One of the key projects is a personalized peptide vaccine where experts survey the patient’s tumor to try to identify a targeted list of peptides to create a tumor vaccine, which is then delivered with an optimal combination of adjuvants and immunotherapy to patients with metastatic disease.
Q: What are the long-term priorities?
A: One of the goals of the overall Moon Shot program is being as ambitious as possible and thinking big to change the way colorectal cancer is defined, detected and treated. Our long-term goal is to ambitiously make fundamental changes, not just incremental improvements, in our understanding of colorectal cancer and making dramatic improvements in early detection, treatment and patient outcomes for cancer. The Moon Shot program consists of multi-disciplinary teams to directly attack these big problems.
Q: Can you talk more about efforts in profiling consensus molecular subtypes in colorectal cancer?
A: The big picture idea here is there are four molecular subtypes of colorectal cancer that have been established within the past few years that have very fundamentally different molecular characteristics, which suggest they may be different diseases. This is exciting. One of the key problems in any cancer, including colorectal cancer, is the heterogeneity of the cancer across patients. We know that the molecular characteristics of each patient’s tumor are different, and these differences may be the primary reason why patients do not respond equally to a particular treatment or why some cancers are more aggressive than others. These molecular subtypes explain a large degree of this heterogeneity, and by establishing the biological characteristics of each subtype, there is promise of identifying subtype-specific treatment strategies that will greatly improve upon the outcomes experienced by an approach that treats all patients with colorectal cancer identically. This has the potential to radically change the way we categorize and treat colorectal cancer.
Q: Can you describe the process that you and colleagues dubbed "integromics" and how it is being used in your ongoing research?
A: The idea of ‘integromics’ is basically that we want to combine information across multiple different genomic platforms in order to integrate information to gain a more holistic picture of the underlying biology. Modern biomedical research generates a vast array of molecular data on different resolution levels, ranging from DNA to RNA to protein, as well as epigenetic data including methylation, histone modifications and microRNA. These types of data each provide different snapshots of the whole biology that is going on within these subtypes of colorectal cancer, and each gives only a partial picture. We use the term ‘integromics’ to represent analytical tools designed to combine information across all of these different resolution levels to derive a more complete picture of the underlying biology. We fully expect that this deep molecular characterization will enable the discovery and development of CMS-specific therapeutic strategies.
Q: What exactly is the clinical assay that your team developed?
A: Our assay will identify which of the four consensus molecular subtypes we are subtyping for will categorize any given patient’s primary colon tumor sample. The original Nature Medicine paper introducing the consensus molecular subtypes presented research classifiers, but these are not suitable for clinical use because they involve impractically large number of genes and are designed for fresh-frozen tumor samples, not formalin-fixed, paraffin-embedded (FFPE) samples as commonly encountered in practice. Within the last few years, we have undertaken an effort to build an improved clinical classifier, and have found that we can build a reliable classifier for FFPE samples with a relatively small numbers of genes. This assay is now being used to select patients for clinical trials and we hope will eventually be used in clinical practice.
Q: Is there anything else that you would like to mention?
A: First, the complexity of cancer necessitates a multidisciplinary approach, and research engaging large, diverse, multidisciplinary research teams like the Moon Shot have the potential to make significant progress in cancer research. Second, we are in the era of ‘big data’ in biomedical research, and the increasing availability of large data sets with various types of molecular information in cancer opens incredible opportunities for discovery. Embedded in these big data are fundamental knowledge and insights regarding the underlying cancer, and armed with well-constructed analytical tools and guided by sound biomedical insight, it is possible to extract this knowledge and put it to use in devising more effective diagnosis, prevention and treatment strategies. – by Jennifer Southall
For more information:
Jeffrey S. Morris, PhD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 77030; email: jefmorris@mdanderson.org.
Disclosure: Morris reports no relevant financial disclosures.