LICR’s Clinical Genomics Program - An Introduction and the Future
The LICR Clinical Genomics Program is moving into its next phase, during which investigators will determine the scientific value of the tumor samples collected during the initial stage of the project. The program will compare the genetic expression of malignant cells to that of normal tissue, and correlate these findings with clinical parameters such as survival rate, treatment response, and time to metastasis. The main goal of the project is to identify new therapeutic agents for the treatment of cancer on the basis of these genetic abnormalities and their relevance to the clinical features of various malignancies. The Clinical Genomics Program is funded by LICR and the State of São Paulo Research Foundation (Fundacao de Amparo a Pesquisa do Estado de Sao Paulo), or FAPESP.
As Dr. Andy Simpson (LICR’s Executive Director for Programs and Operations) explains, “The Institute’s mission is to further the understanding of cancer, and to transform the discoveries of individual researchers into therapies that will benefit humankind. One of the advantages of LICR’s structure and model is that we can access the best research resources and people where-ever they may be found. The partnerships formed within Brazil to form the Clinical Genomics Program is a commendable example of this”.
The Start
The program’s threshold objective was to organize collaborative groups of clinicians, surgeons, pathologists, and clinical epidemiologists to collect data and biological samples from well-defined populations of patients with cancer. These collaborations were formed to allow the gathering of the strongest clinical and epidemiological data possible.
The first phase of the project lasted from September 2002 to September 2005. It involved 19 surgical and clinical groups, who gathered data and samples from approximately 2,000 cases representing nine different types of cancer: astrocytomas, carcinomas of the head and neck, adenocarcinoma of the stomach, carcinoma of the cardia, adenocarcinoma of the colon and rectum, esophageal squamous cell carcinoma, acute lymphocytic leukemia of childhood, multiple myeloma, and osteosarcoma. The investigators also gathered corresponding information from approximately 2,000 controls matched by age, sex, and ethnicity.
The best use of the samples collected must be determined by mutual agreement between LICR, FAPESP, and the Institutions involved. A Materials Transfer Agreement (MTA) document should be prepared. The tissue banks should be registered at the respective institutional and governmental review board and specific projects must be approved by a steering committee. In addition, eligibility criteria to apply for patents and the appropriate strategy for doing so must be established.
“The collaborative process is very complex and requires ethical review and institutional review board (IRB) approval,” Simpson says. “LICR’s Clinical Genomics Program is organized with the intention of nurturing the research of investigators who are collecting tissue samples and other clinical data in their labs.”
Structure and Function
Participants at the Clinical Genomics Program Meeting held in August 2006 in Sao Paulo, Brazil, agreed to a structure for the next phase of the program as described below.
- Functional projects will involve five different types of malignancy, samples of which were collected during the initial stage of the project: CNS tumors (coordinated by Dr. Suely Marie); digestive tract tumors (coordinated by Dr. Angelita Gama); head and neck tumors (coordinated by Dr. Eloiza Tajara); osteosarcoma (coordinated by Dr. Silvia Toledo); and multiple myeloma (coordinated by Dr. Gisele Colleoni).
- These five groups will investigate new targets for cancer therapy by focusing their investigation on the following areas and using the specified methods:
- Differential gene expression in tumors: Serial Analysis of Gene Expression, microarrays, and real-time PCR (RT-PCR). The sites involved are Faculdade de Medicina de Ribeirao Preto (FMRP, Drs. Zago and Rego), Hospital Albert Einstein (AE, Drs. Cacau and Keith), and Universidad de Sao Paulo (USP, Drs. Marie and Kreiger). All five cancer types (CNS, digestive, head and neck, osteosarcoma, and multiple myeloma) are involved.
- Protein studies: Immunohistochemistry (IHC) and tissue microarrays. The pathologists involved are Drs. Achim Jungbluth (LICR New York Branch), Venancio Alves (USP), Sergio Rosenberg (USP), Luciano Neder (FMRP), Patricia Curi (Faculdade de Medicina de San Jose do Rio Preto, FAMERP), Maria Tereza Alves (Universidade Federal de Sao Paulo, UNIFESP), and Marcelo Franco (UNIFESP). LICR’s New York Branch will provide these researchers with specific mouse monoclonal antibodies.
- DNA Mutation studies: Sequencing. These studies will be coordinated by Dr. Andy Simpson (LICR New York Branch), with the participation of Drs. Robert Strausberg (The J. Craig Venter Institute) and Gregory Riggins (Johns Hopkins University).
- All project participants will abide by the following rules:
- To work with the tumor samples that we have available in the Clinical Genomics Tumor Bank.
- To continue patient follow up and maintain the database.
- To support the quality assurance manager and project coordinators (Drs. Simpson and Zago), the project manager (Dr. Jucara Parra), and the central bioinformatics, epidemiology, and pathology groups that control patient follow up.
- To have an aggressive technology transfer strategy.
- To have an official exchange of reagents and biological material between LICR, TIGR, and the Sao Paulo Institutions, which require specific MTAs and ethics committee approval. The project manager will be responsible for all material and technology transfer activities.
Projects for 2007
The investigators propose to identify new markers and therapeutic targets through evaluation of antigen and gene expression. They can then compare the genetic profile of cancerous tissues to that of normal tissues. The priority for this particular project is the digestive system tumors, specifically the comparison of gene and protein expression between different polyps and tumors.
The researchers also propose to analyze the epidermal growth factor receptor gene (EGFR) gene in astrocytoma. The investigators have completed expression analysis and quantification by RT-PCR, detection of EGFRvIII by RT-PCR, protein distribution by IHC with commercial (Zymed) antibody, single-nucleotide polymorphism (SNP) analysis (promoter region and exon 16), and CA repeat analysis (at intron 1). The researchers will evaluate the correlation of their findings with clinical features of these cancers, particularly survival time.
The second project on the agenda is the evaluation of cancer testis (CT) antigen expression by IHC and tissue microarrays, and comparison of the gene expression profiles of CT antigen-positive with those of CT antigen-negative tumors using arrays and RT-PCR. The investigators will begin by evaluating the mRNA expression of CT antigens MAGE 1, MAGE 4, MAGE 10, MAGE 12, BAGE, LAGE, GAGE, and PRAME. They will correlate their findings to clinical data, treatment, and prognosis.
The final project is a search for somatic mutations in tumor DNA. This collaborative effort, by Drs. Robert Strausberg, Gregory Riggins and Otavia Caballero (LICR New York Branch), involves a survey of somatic mutations in specific genes that have been related to different types of tumors by sequencing. This research team has already been successful at detecting receptor tyrosine kinase mutations in glioblastoma (Rand et al. PNAS (2005) Oct 4;102(40):14344-9).
“Many times research is thwarted from being directly applied to cancer because of a lack of access to patients and tissue samples. We’ve created an initiative to make this access possible for LICR researchers in a systematic, organized way.”
Dr. Andy Simpson
LICR Executive Director for Programs & Operations