Innovative Research/Grants
In 2006, The Bonnie J. Addario Lung Cancer Foundation awarded $250,000 to
A Systems Genetic Approach Towards Individual Diagnosis and TreatmentThe third installment of $250,000 was awarded in December, 2008 after receiving the Progress Report.
Next steps and future plans:
1. Detailed analysis of the data obtained to identify specific genetic events (mutations or copy number changes) and gene expression alterations associated clinical parameters (tumor type/grade, patient response to treatment or survival time).
2. Network analysis tools to find relationships Between SNPs, CGH copy number changes, and gene expression alterations in lung cancers, as well as in normal lung from the same patients.
3. Detailed analysis of the issue of “normal cell contamination of tumor tissue, to determine whether micro-dissection will be needed before proceeding to the analysis of the next set of 100 matched tumor-normal pairs. Our analysis of mouse gene expression arrays has suggested that their is great value in having normal cells as a “contaminant,” as this provides additional information on the nature of the inflammatory or stromal cell components of the tumor.
This, in turn can reveal important information of diagnostic or prognostic value. Our progress in steps 1 and 2 will tell us if it is necessary to change procedures using for isolating nucleic acids from the samples presently in the tissue bank.
4. Identification of the next set of matched tumor normal pairs from the tissue bank. Depending on the results of steps 1-3, we will isolate DNA and RNA from these samples for molecular analysis by the company we are currently using (or by another company depending on technological advances in this rapidly moving field).
Allan Balmain, PhD, FRSE, Professor of Cancer Genetics, Barbara Bakar Distinguished Professor of Cancer,
Director, Cancer Center Genomics Core, Co-Director, Cancer Genetics Program and David M. Jablons, MD,
Professor of Surgery, Chief of Thoracic Surgery, Ada Endowed Chair in Thoracic Oncology, Program Leader, Thoracic Oncology ProgramLung cancer treatment has traditionally depended on classifying patients into broad categories and then matching them to an established treatment protocol. Clearly this cookie-cutter approach has not worked because overall survival for lung cancer stands today at an abysmal 15%.
Researchers have concluded that lung cancer is not one, but a multiplex of diseases. In 2006, 174,470 new cases of lung cancer were diagnosed, each unique in its own way at the molecular level. Individuals inherit a unique set of genes consisting of DNA, two long strands twisted around each other, each composed millions of varying repetitions of four molecules, abbreviated as A,C,T, and G, that serve as the blueprint for life. Some of these genes, most of them as yet unknown, are “lung cancer susceptibility genes”, that predispose people to developing lung cancer.
Each tumor is also unique. Different combinations of genetic events or “somatic mutations” accumulate over time, some playing a critical role in lung carcinogenesis. Eventually, a tipping point can be reached where normal cells turn into lung cancer cells and wreak havoc in the body.
Researchers have been refocusing their sights on investigating lung cancer at the cellular or molecular level, with the view of developing better diagnostic tests and molecular-targeted therapies. Some new tests are aimed at identifying the so-called “bad actors”, lung cancers that recur, are invasive or tend to metastasize. Other tests are predictive and tell physicians what drugs to use and in what amounts, a science called “pharmacogenomics”.
Genzyme’s EGFR Mutation Assay, for example, tests for the presence of the EGFR mutation to determine if a patient should take an EGFR inhibitor such as Tarceva. Another, the Lung Metagene Model, looks for the presence of an array or “signature” of gene products to determine if chemotherapy is appropriate after surgery.
These tests, however, only touch on a small subset of genetic and molecular data available to researchers. Neither includes an analysis of critical lung cancer susceptibility genes. Moreover, the tests have limited utility. For example, most EGFR positive tumors invariably become resistant to Tarceva. Such tumors can easily surmount an attack by utilizing the redundancies present in a vast network of signaling pathways within the cell.
A more ambitious strategy, one that can identify and simultaneously inactivate multiple signaling hubs, is the premise behind the collaboration of Drs. Allan Balmain and David Jablons. The foundation has awarded them a grant to develop molecular predictors of individual prognosis and response to therapy in lung cancer, supporting the eventual development of novel molecular-targeted therapies.
This collaboration brings together two of the outstanding leaders of academic medicine. Dr. Allan Balmain is one of world’s foremost molecular geneticists, an NIH funded lung cancer scientist with a prolific record of publications including articles in the journal Nature. Dr. Jablons is a world-renowned thoracic surgeon, a recognized thought leader, the chair of countless cancer symposiums, and selected to be the co-Chair of the World Lung Cancer Conference in 2009. The UCSF thoracic tissue bank, begun by Dr. Jablons in the mid-1990s, is one of the largest in the U.S., and houses specimens from nearly 1,000 patients, tissue of the highest quality.
The proposal of Dr. Balmain and Dr. Jablons is revolutionary in design and unprecedented in scope. Specimens will be analyzed to identify the genetic events that occurred within the tumor. The molecular detail will then be used to develop prognostic markers and predictors of response to treatment.
There have been, as yet, no attempts to link both germline and somatic approaches in a concerted systems-based approach in lung cancer. The Foundation has underwritten the first such effort, a bold initiative to realize the promise and potential of molecular biomarkers for diagnosis of lung cancer, with the ultimate objective of establishing the wiring diagram of the lung cancer cell – the network of genetic variants and their expression patterns that influence individual cancer susceptibility, risk of progression, and response to therapy.
