Landon Foundation-AACR INNOVATOR Award for International Collaboration in Cancer Research
International research collaboration can successfully address the global health program of cancer through access to unique populations and environments, shared resources, specialized expertise, new concepts and perspectives, innovative methodologies, and/or emerging technologies. However, barriers to sustaining these collaborations exist such as the lack of funding and the sharing of knowledge about these important research partnerships. These Grants provide support of highly meritorious research that is being conducted collaboratively by investigators in different countries around the world. The goals of the program are to: promote international cancer research collaboration as an effective means to accelerate progress against cancer; provide the support necessary to sustain and enhance highly meritorious international cancer research collaborations; foster interactions between and among cancer scientists and disseminate the scientific knowledge gained from international collaboration; and contribute to a global impact against cancer.
2009-2011 Landon Foundation-AACR INNOVATOR Award for International Collaboration in Cancer Research
Josep M. Llovet, M.D.
Institut D'Investigacions Biomèdiques August Pi i Sunyer
Project: Oncogenic Addiction and Gatekeeper Genes in Hepatocellular Carcinoma
"Hepatocellular carcinoma (HCC) represents the third-leading cause of cancer-related deaths worldwide, but only one molecular therapy - sorafenib - is effective so far. In order to accelerate the knowledge of the pathogenesis of this cancer and the development of targeted therapies, we assembled an international multidisciplinary consortium of basic and translational researchers, the HCC Genomic Consortium, led by Dr. Josep M. Llovet and collaborators from Mount Sinai (New York), Dana-Farber-MIT (Boston), Hospital Clinic (Barcelona) and National Cancer Institute (Milan). As a result of the research conducted by the Consortium, we recently identified VEGFA high-level amplifications in HCC, demonstrated that inhibition of mTOR signaling ameliorates tumor progression in experimental models and generated a gene signature from the adjacent tumoral tissue that predicts patient outcome after surgical resection. The 2009 Landon Foundation-AACR INNOVATOR Award for International Collaboration in Cancer Research will further support a novel project of the Consortium aimed to assess novel mutations in oncogenes or tumor suppressor genes (TSG) that can provide markers of early detection and identify the driving molecular events that may represent targets for molecular therapies. For that purpose, we will survey the mutation status of 141 commonly mutated genes in a large cohort of preneoplastic nodules and human HCC samples and will integrate the molecular information (i.e. mutation data, gene expression dysregulation, signaling pathway activation and progenitor cell markers) with clinical outcome to define the potential drivers in each molecular subclass. This study might identify unknown gatekeeper genes and oncogenic addiction loops in HCC patients, which will lead towards better preventive and therapeutic strategies. "
2008-2010 Landon Foundation-AACR INNOVATOR Award for International Collaboration in Cancer Research
Michele Carbone, M.D., Ph.D.
University of Hawaii, Cancer Research Center of Hawaii and John A. Burns School of Medicine
Project: Gene Environment Interaction and Early Detection of Mesothelioma in Cappadocia, Turkey
"Malignant mesothelioma is the cancer of the membranes that surround the lungs and the abdomen. It is incurable unless detected in its earlier stages: current therapies have little or no effect and survival is one year from diagnosis. The incidence of mesothelioma has increased more than that of any other cancer in the past 50 years. This increase is related mostly to the use of asbestos in the shipping and construction industries. About 25 million Americans have been exposed to asbestos and are at risk of developing mesothelioma. In addition, erionite, a type of mineral fiber that shares some physical characteristics with crocidolite asbestos, and that is naturally present in the US and in other countries causes mesothelioma. To develop effective strategies for early detection and prevention, we must identify among the many millions of exposed individuals those at higher risk. In three villages in Cappadocia, Turkey, there is a unique epidemic of mesothelioma: 50 percent of all deaths are caused by mesothelioma. We discovered that this epidemic occurs in some families but not in others and that when members of high-risk families marry into low-risk families mesothelioma occurs in the descendents. When high-risk family members are born and raised outside these three villages, mesothelioma does not occur. We discovered that this epidemic is caused by the interaction of erionite with genetics. We also found that mesothelioma is very frequent in some US families. My hypothesis is that these families are very susceptible to mineral fiber carcinogenesis, and that erionite plays a major role in Turkey, while asbestos plays a role in the US families. We have also discovered novel serological markers for early detection of mesothelioma. I have now organized an international team of scientists to: 1) identify the gene or genes that predispose certain families in the US and in Turkey to mineral fiber (asbestos and erionite) carcinogenesis; and 2) to validate the specificity and sensitivity of the serological markers we discovered for early detection. The funding from the AACR Landon Foundation will be devoted to support these projects. The isolation of the mesothelioma gene will allow us to design specific preventive/therapeutic approaches for mesothelioma. The validation of the sensitivity and specificity of the serological markers for early detection in the high-risk population in Turkey will allow us to offer this screening to the workers at risk of developing mesothelioma because of asbestos exposure. By detecting mesothelioma in its early stage we should be able to cure these patients before the tumor invades other organs and becomes incurable. Therefore, the results of these studies will benefit many million people exposed to asbestos and to other carcinogenic mineral fibers in the US and worldwide. "
Landon Foundation-AACR INNOVATOR Award for Cancer Prevention Research
The Landon Foundation-AACR INNOVATOR Award for Cancer Prevention Research was established to recognize the outstanding achievement of an early career Assistant Professor in the field of cancer prevention, and to provide support for cancer prevention research of significant scientific merit in any discipline across the continuum of research. The goals of the program are to: encourage younger investigators to pursue cancer prevention research of significant scientific merit; provide the support necessary to sustain and enhance highly meritorious cancer prevention research; foster interactions between and among cancer scientists and disseminate the scientific knowledge about cancer prevention research; and contribute to a global impact against cancer.
2009-2011 Landon Foundation-AACR INNOVATOR Award for Cancer Prevention Research
Gregory P. Tochtrop, Ph.D.
Case Western Reserve University
Project: Novel Triterpenoid Chemopreventatives from the Natural Product Bryonolic Acid
"Although cancer and cancer research have been held of paramount importance for a number of decades, its prevention through the use of small molecules (drugs) has not garnered significant attention. This stands in stark contrast to cardiovascular disease, where chemoprevention is rich with examples such as antihypertensives to reduce cardiovascular stress, statins to control serum cholesterol, and NSAIDs (such as aspirin) being used to prevent initial or subsequent heart attack. The research funded by this award represents our ambitions to develop novel classes of small molecules to control the onset and progression of colon cancer in a mouse model predisposed to tumor formation. More specifically, we aim to explore a small molecule we have identified and purified from the sprouts of common zucchini (chemically similar to a class of chemopreventives derived from Chinese herbs) and test its potential to modulate key inflammatory enzymes we have hypothesized to be important for carcinogenesis and cancer progression. We will use a chemical discipline known as diversity oriented synthesis (DOS) to alter the chemical makeup of this molecule and identify which parts of the molecule are important for activity. To evaluate whether these molecules can control tumor formation and progression, we will use a two-stage evaluation procedure initially using cell culture to study the effects on key inflammatory enzymes. Subsequently, we will use a genetically altered mouse, predisposed to forming colon cancer, to test how well our molecules can prevent these animals from developing tumors. The Landon Foundation Award will be critical in providing resources helping our laboratory take our promising preliminary data and begin to complete the critical experiments that will, hopefully, uncover a new class of small molecules showing promise for cancer prevention. "
2008-2010 Landon Foundation-AACR INNOVATOR Award for Cancer Prevention Research
Carlo Maley, Ph.D.
The Wistar Institute
Project: Genetic Diversity within Intra-epithelial Neoplasms and Cancer Prevention
"My research focuses on the evolution of cells in tumors. This evolution accounts for both how we get cancer and why it has been so hard to cure. There are billions of cells in a tumor, carrying tens of thousands of mutations between them. These cells compete for space and resources, forming a microcosm of evolution. Therapies impose new selective pressures on the cancer cell population and tend to select for resistant mutants. This leads to relapse of the patient with a tumor that is no longer responsive to the therapy. The problem of therapeutic resistance has led to interest in preventing cancer, before tumors become difficult to cure. My lab is focused on measuring the evolutionary dynamics in tumors and developing new ways to intervene in those dynamics. We found that the amount of genetic diversity between biopsies of Barrett's esophagus, a pre-malignant tumor, predicted the risk that the patient would develop esophageal adenocarcinoma, the fastest increasing form of cancer in the western world. Because they appear to help prevent esophageal adenocarcinomas, we study the effects of non-steroidal anti-inflammatory drugs, like aspirin, on the evolution of cells in Barrett's esophagus. The Landon-AACR INNOVATOR Award in Cancer Prevention Research is helping us to develop methods to measure the amount of genetic diversity between cells within tumors and we plan to use those measures to predict progression to cancer, response to interventions, and to investigate the changes in tumors during progression. This will allow us to study the evolution of cancer cells in a wide variety of tumor types. Our work highlights the importance of evolutionary biology in cancer research as well as the need to further integrate the two fields. Our esophageal cancer research is only possible because of the dedication of the participants in the Seattle Barrett's Esophagus Research Program. "