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 interaction between and among cancer scientists and disseminate the scientific knowledge about cancer prevention research; and contribute to a global impact against cancer.
2015 Grantee Rong Xu, PhD
Assistant Professor of Medical Informatics
Case Western Reserve University
Uncovering links between microbiome metabolites and colorectal cancer
Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. CRC susceptibility and progression are primarily driven by gene–environment interactions. Human gut microbiota (>1014 microbial cells comprising about 500-1000 different species) are important modifiable environmental factors that we are exposed to continuously. These microbiota exist in a symbiotic relationship with a human host by metabolizing compounds that humans are unable to utilize and by controlling the immune balance of the human body. Gut microbiota and its metabolites are increasingly recognized as important environmental factors influencing colon carcinogenesis not only via the pro-carcinogenic inflammatory activities of specific pathogens but also via the cumulative effects of microbial metabolites of the resident gut microbiota. Although the link between human gut microbial metabolism and colon carcinogenesis has been recognized, systematic evaluation of gut microbial metabolites and the interacting genetic pathways in relation to CRC is lacking. Dr. Xu proposes to develop innovative computational approaches to integrate and analyze vast amounts of heterogeneious and complex biomedical data towards deciphering the interplay between host genetics, microbes, and CRC carcinogenesis. The identification of microbial metabolites and the understanding of their role as key mediators through which these bacteria promote/protect against CRC will greatly facilitate our understanding of the complex host genome-microbiome interaction in colon carcinogenesis and enable/activate new possibilities for its diagnosis, prevention, and treatment.
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Tamas Gonda, MD
Assistant Professor, Department of Medicine
Columbia University Medical Center
New York, New York
Epigenetic Targeting of the Microenvironment in Gastric Chemoprevention
Dr. Gonda’s main research interest is in the field of gastrointestinal chemoprevention. In prior works he has focused on epigenetic changes, mainly DNA methylation, as a modifiable target of chemoprevention. In animal models he has studied the effect of both methyl donor supplementation and demethylating agents and their effect on gastric and pancreatic carcinogenesis. The current proposal expands on these observations to evaluate the role and epigenetic mechanisms of folate based methyl donor supplementation in transgenic and chemical models of gastric carcinogenesis. As epigenetic alterations are particularly significant in the tumor microenvironment a secondary aim of this proposal is to investigate the role of targeting DNA methylation in these cells as a way to prevent development of carcinoma. Two cell populations are examined closely: cancer associated fibroblasts and tumor infiltrating immune cells. An important goal will be to evaluate the way these populations of cells may be targeted to synergize with methyl donor supplementation. The results of these studies may have direct effect on clinical studies. The animal models used recapitulate most features of gastric carcinogenesis and many of the intervention strategies tested can be adopted in human trials.
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Kenneth Y. Tsai, MD, PhD
University of Texas MD Anderson Cancer Center
Genomic Analysis of Cutaneous Squamous Cell Carcinoma Progression
Skin cancer is the most common class of malignancy in humans. Cutaneous squamous cell carcinoma (cSCC) comprises 15-20 percent of the over 3.5 million cases of skin cancer in the U.S. annually. There is no effective therapy for metastatic cSCC and recent estimates show that cSCCs result in over 12,000 nodal metastases and 8,000 deaths per year, with mortality rates that approach those of melanoma in the southern U.S. Of all the skin cancers, cSCC has the best-defined progression sequence from a distinct precancerous lesion, the actinic keratosis (AK), to invasive cSCC, which has appreciable metastatic potential. AKs are likely to be the most common precancerous lesion in humans. Although they can be treated, the morbidity of repetitive applications of destructive modalities is high. Because large areas are often involved, the degree of inflammation and pain makes these therapies inconvenient, difficult to tolerate, and, therefore, ineffective. For high-risk patients (high UV exposure/immunosuppression) with dozens of such lesions, knowing which ones are most likely to progress would enable targeted treatment. Because metastatic cSCC is incurable, preventing progression at earlier stages is an important goal. We have used a novel approach combining matched human tissues, a UV-driven mouse skin cancer model, and next-generation sequencing to identify the genomic drivers of cSCC progression. By using paired functional analysis of microRNA and mRNA expression, we identified several microRNA-driven pathways that impinge upon apoptosis, DNA damage responses, and the epithelial-mesenchymal transition. We plan to validate these targets in cells and in vivo, and we expect that our findings will lead to the identification of specific genetic targets to enable molecularly targeted therapy and chemoprevention. The implications of success include improved prognostication of risk of progression and molecular targets for chemoprevention for an extremely common, yet poorly understood cancer that affects millions. This project is possible not only because of the hard work of the individuals in our laboratory, but because of our close collaboration with dermatologists, dermatopathologists, trainees, bioinformaticians, and scientists at MD Anderson, University of Houston, and the greater Houston area. The Duncan Family Institute at MD Anderson deserves special thanks for supporting the initial work for this project. Funding from the Landon Foundation-AACR Innovator Award is critically important for validating and extending our initial findings in a way that will enable their translation into chemoprevention strategies.
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Guang Peng, MD, PhD
University of Texas MD Anderson Cancer Center
Targeting the DNA Repair Network as a Novel Approach for Cancer Prevention
An important way to reduce cancer deaths in the future is to improve cancer prevention. However, a big challenge for effective cancer prevention is to identify chemopreventive agents with demonstrable efficacy and safety. To overcome this challenge, the most promising approach is to develop targeted chemopreventive agents that are based on the genetic alterations in premalignant cells. DNA repair pathways play a critical role in the cellular response to replication stress, a common feature of premalignant cells across multiple types of cancer. Early in the process of tumorigenesis, genetic alterations such as activation of oncogenes and loss of tumor suppressor genes are implicated in inducing replication stress by providing premalignant cells with excessive growth signals. Replication stress results in the higher level of replication-associated lesions, predominantly double-strand DNA breaks (DSBs). An essential mechanism utilized by cells to repair and survive from replication-associated DSBs is homologous recombination (HR). This key link between HR repair and cellular survival responses to replication stress provides us with a mechanistic rationale for exploiting synthetic lethality between HR repair inhibition and replication stress in premalignant cells.
Our research goal is to identify novel inhibitors of the HR repair pathway that selectively kill premalignant cells by targeting cellular survival responses to replication stress. With the support from this award, we aim to use an innovative, imaging-based, high-throughput HR repair assay to conduct screenings with chemical libraries containing FDA-approved drugs and natural products. We will also use both an in vitro cell culture system and an in vivo xenograft animal model to test the chemopreventive effects of the newly identified chemical inhibitors. The funding support from The Landon Foundation-AACR INNOVATOR Award for Cancer Prevention Research is essential for the success of our research in this very promising direction. We anticipate identifying agents that can convert existing replication lesions into fatal lesions that selectively kill premalignant cells. This preventive strategy has a great potential to be applied to a broad spectrum of cancers with the same characteristic feature, i.e., elevated replication stress.
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