Newswise — Five innovative young investigators have been selected to present their work at the Future Leaders in Translational Cancer Research Special Symposium during the AACR 101st Annual Meeting 2010 in Washington, D.C., April 17-21. Their work spans the fields of carcinogenesis, cellular biology, radiation biology, experimental therapeutics, molecular biology, immunology, bioengineering, and clinical investigations. Senior scientists will share the stage, providing context for the talks and elucidating the continuum of achievement within these research areas.

“These five investigators were selected through a highly competitive process based on scientific merit, research design, innovation and independent contributions,” said Kimberly Brown Dahlman, Ph.D., chair of the AACR Associate Member Council. “These early-career scientists are at the cutting edge of cancer science and I expect that their findings will influence the treatment of cancer in the coming years.”

The Future Leaders in Translational Cancer Research Special Symposium was first developed and presented in 2007 by the AACR Associate Member Council — an advisory body of young investigators — in conjunction with the AACR leaders in an effort to highlight outstanding early-career scientists in cancer research whose work reflects innovation, independent thought and creativity.

The symposium will be held at 1 p.m. ET on April 18, in room 102 of the Walter E. Washington Convention Center.

Selected speakers:

Emma Ito, a doctoral student at the Ontario Cancer Institute, has discovered a key mediator of heme biosynthesis as a novel radio-sensitizer. Inhibition selectively radio-sensitizes human cancers via the sudden perturbation of iron homeostasis in cancer cells, which in turn induces reactive oxygen species production, the major mechanism by which ionizing radiation causes lethal DNA double-strand breaks. The translational impact of this discovery could be profound clinically by potentially improving patient outcomes once a drug targeting the enzyme is synthesized. It could also be profound scientifically, in demonstrating cancer cells' vulnerabilities in the context of iron perturbation. Based on the scientific strengths of her data and the anticipated minimal toxicity, the Ontario Cancer Institute has filed a U.S. Provisional Patent.

Ito earned a Bachelor of Science degree in life sciences and a Master of Science degree in microbiology and immunology from Queen's University, Kingston, ON. She is in the process of earning her Doctor of Philosophy in the Department of Medical Biophysics at the University of Toronto, Toronto, ON.

Florian A. Karreth, Ph.D., who is conducting research at Cambridge Research Institute in the UK, is working on research that could lead to a deeper mechanistic understanding of the failure of the Raf kinase inhibitor sorafenib in melanoma patients. Karreth successfully generated germline conditional B-Raf V619E mice (V600E in humans) and is using these animals to probe the biology of melanoma in vivo. During the cloning of the murine BRAF genomic region, he discovered an alternatively spliced form of murine exon 3 due to intra-exonic splicing. While searching for any functional relevance of the splice form, Karreth realized that this shorter form of the BRAF oncogene activated the MAPK cascade to a higher degree. By analyzing the known binding partners of BRAF, he made the observation that CRAF was less well bound to BRAF in the setting of this shorter form. In fact, Karreth found that CRAF potently inhibited the kinase activity of BRAF-V600E in vitro, and knock-down of CRAF led to increased MAPK activation and proliferation of melanoma cells expressing BRAF-V600E. This antagonistic function of CRAF on BRAF-V600E offers a potential explanation for the poor activity of sorafenib in melanoma patients, because sorafenib preferentially inhibits CRAF and, thereby, “activates” BRAF-V600E at low doses (which is likely relevant as Sorafenib only achieves low blood levels). Also, Karreth showed that oncogenic Ras promoted this inhibitory activity of CRAF on BRAF-V600E, and, thereby, provided a more compelling reason for the mutual exclusivity of Ras and BRAF mutations in tumors than the redundancy hypothesis published by Bert Vogelstein et al. in 2002 in Nature.

Karreth conducted his undergraduate work and earned a Master of Science degree in genetics at the University of Vienna, Vienna, Austria. He earned a doctorate in cancer biology, also at the University of Vienna.

Peter H. O’Donnell, M.D., a fellow in clinical pharmacology and pharmacogenomics and clinical instructor at the University of Chicago, is developing genome-wide approaches to identify genetic variants that are associated with chemotherapeutic susceptibility, with a focus on capecitabine and platinating agents, using International HapMap cell lines. To validate his findings from this preclinical model, he conceptualized three clinical trials centered around testing pharmacogenetic variants for their effects on toxicity and/or response in patients receiving these chemotherapies.

O’Donnell earned a Bachelor of Science degree in biochemistry from the University of Notre Dame and received a medical degree from the University of Chicago. He completed an internal medicine internship at the University of North Carolina and an internal medicine residency and hematology/oncology fellowship at the University of Chicago.

Matthias Stephan, M.D., Ph.D., a postdoctoral research fellow at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, is developing a strategy to enhance cell therapies. In his approach, drug-loaded synthetic nanoparticles are chemically linked to the surface of live tumor-specific T-cells in a simple two-step process that is performed just before adoptive transfer of the cells into recipients. The particles remain localized on the surface of T-cells for at least a week and allow the engineering of pseudo-autocrine signaling, as protein or small-molecule drugs released from the particles are recaptured with high efficiency by the donor T-cell. Stephan demonstrated that this elicits anti-cancer effects in murine animal models for T-cell based cancer therapy, dramatically enhancing the proliferation, persistence and anti-tumor activity of transferred T-cells, while using minimal doses of adjuvant drug molecules that appear to have no side effects when delivered in this cell-localized manner. In addition, he has shown that drug delivery particle conjugation to donor cells is a general concept that can be used for other types of cell therapy currently used clinically, such as making bone marrow transplants that reconstitute recipients up to fivefold more quickly. The technology is complementary to gene therapy and other approaches being explored to enhance adoptive T-cell therapy.

Stephan earned a medical degree from the University of Lubeck, Germany, and a doctorate in immunology from Cornell University.

Jialiang Wang, Ph.D., a postdoctoral fellow at the Duke Translational Research Institute, initiated a project aimed at elucidating the importance of Notch signaling in radiation resistance of glioma cancer stem cells. His findings lay the groundwork for a novel therapeutic application of Notch inhibitors to improve radiotherapy for treatment of gliomas. In this regard, Wang has demonstrated that Notch inhibition augment radiotherapy in murine models of brain cancer. Thus, this study provides an example of Wang’s ability to translate a basic observation on Notch signaling in brain tumor stem cells into a potential new therapy for treating cancer.

Wang earned a Bachelor of Science degree in life science and technology at Zhejiang University, China; a Master of Science degree in biochemistry at the Institute of Microbiology, Chinese Academy of Sciences; and received a doctorate in biochemistry at the University of North Carolina, Chapel Hill. He was a postdoctoral fellow at the Ingram Cancer Center at Vanderbilt before joining Duke University.

Download interviews with cancer researchers and recordings of the teleconferences by subscribing to the AACR Scientific Podcasts via iTunes (http://www.aacr.org/itunes) or an RSS Reader (http://www.aacr.org/rss).

The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world’s oldest and largest professional organization dedicated to advancing cancer research. The membership includes 31,000 basic, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowship and career development awards. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care. The AACR publishes six major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; and Cancer Prevention Research. The AACR also publishes CR, a magazine for cancer survivors and their families, patient advocates, physicians and scientists. CR provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.