The AACR Centennial Postdoctoral Fellowship in Cancer Research fosters basic, translational, clinical and epidemiological research by scientists at the beginning of their careers in the cancer field. They are open to postdoctoral fellows and clinical research fellows at an academic facility, teaching hospital or research institution who will be in the first, second or third year of their postdoctoral training at the start of the fellowship term. Fellowships support the salary and benefits of the fellow, with partial funds permitted to be designated to direct research expenses.
2008 GRANTEES
Kutlu G. Elpek, Ph.D.Postdoctoral Research Fellow, Dana-Farber Cancer Institute, Boston, MA
IL-15/IL-15Ralpha Complexes in Tumor Immunotherapy
"Accumulating evidence indicates that the immune system can recognize and destroy tumors by a process termed immunosurveillance. Cytotoxic leukocytes including CD8+ T cells and NK cells play major roles in immune-mediated destruction of malignant cells. The cytokine, IL-15, promotes the proliferation and effector capacity of CD8+ T cells, NK cells, and NKT cells, all of which express the IL-2/IL-15Rβ or CD122. Under physiological conditions, IL-15 is transpresented via the IL-15Rα chain on dendritic cells to CD122+ cells. Based on this observation, several recent studies have reported that the biological activity of IL-15 can be dramatically increased by complexing this cytokine to soluble IL-15Rα. Recently, we demonstrated that systemic delivery of IL-15/IL-15Rα complexes can trigger rapid but incomplete regression of established solid pancreatic tumors in RIP-Tag2 mice as well as transplantable tumors. Mechanistically, the complexes work by expanding tumor-resident CD8+ T cells and NK1.1+ cells, and endowing these cells with cytotoxic potential. Tumors can escape destruction by immune effector cells by recruiting populations of suppressive leukocytes, secreting inhibitory factors and altering the local vasculature. Such mechanisms may account for the incomplete tumor destruction in immunotherapy with IL-15/IL-15Rα complexes. My research focuses on identifying general properties of CD8+ T cells and NK1.1+ cells before and after exposure to IL-15/IL-15Rα complexes, and deciphering the molecular and cellular mechanisms by which tumors escape immune-mediated destruction. These studies will help us to understand the complex interactions between tumors and the immune system, and to develop more efficacious immunotherapeutic strategies for treating cancers as well as chronic infections. It is a great honor to be awarded by the AACR Centennial Fellowship at the start of my career. I am grateful to the AACR and my mentor Shannon J. Turley, Ph.D., for supporting me in this project and helping me build a research career in tumor immunology field."
Heiko Enderling, Ph.D.Postdoctoral Research Fellow, Caritas St. Elizabeth's Medical Center, Boston, MA
Paradoxical Proliferation-apoptosis-migration Dynamics in Tumor Progression
"Considering the complexities of therapeutic targeting and the extent to which individuals harboring tumor lesions remain asymptomatic and die of other causes, the role of intra-tumor and tumor-environment interactions may be underappreciated. Furthermore, given that tumors may be held in a dormant state marked by balanced cell proliferation and cell death, we now know that cancers can even exhibit self-limiting kinetics under certain circumstances. Understanding more fundamentally the cell kinetics that force early tumors into self-limited growth or even dormancy would clearly be valuable for future treatment planning. With an experimentally supported mathematical and computational model that accounts for the complicated interaction of three key parameters governing the growth of cancer cells, factors influencing tumor development through alterations to these kinetic parameters can be studied efficiently and correctly, unconstrained by the limits of our intuition. Preliminary studies have already yielded unexpected results. High levels of spontaneous cell death, for example, have been shown under certain circumstances to paradoxically increase the risk of migration-enhanced stem cell proliferation and advance tumor progression. A general conclusion to emerge from these studies is that influences that modulate cell migration and the liberation of cancer stem cells to areas of lower cell density may be decisive in the control of overall tumor growth and metastatic progression. Interestingly, cancer stem cells with their unlimited replicative potential were seen to drive tumor growth in our studies, while greater proliferation potential among their progeny was seen to inhibit it. This represents yet another counterintuitive result uncovered by the methodical tracking of cell kinetics. Under the supervision of my mentor Dr. Philip Hahnfeldt, and the generous support of this AACR Centennial Postdoctoral Fellowship in Cancer Research, I will develop a data-driven theoretical model that reveals the complete three-dimensional tumor response landscape expected from the interplay of proliferation potential, migration and cell death. From this, I seek a better understanding of the anomalous long-term tumor growth responses often observed in response to therapy. This approach will be a vital augment to existing dynamical models for tumor development and should provide valuable new insights into therapeutic response."
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Catherine Guzzo, Ph.D.Postdoctoral Fellow, Johns Hopkins University, Baltimore, MD
SUMO-Binding Proteins as Effectors and Regulators of SUMO Modification
"SUMOs (Small Ubiquitin-like MOdifiers) are ~100 amino acid proteins that are reversibly conjugated to other proteins in the cell, thereby regulating a wide range of essential functions. Many of the functions regulated by SUMOylation are intimately tied to processes directly relevant to cancer, including maintenance of genome integrity and cell cycle regulation. Studies in the past several years have, in fact, linked SUMOylation to a variety of human cancers, including leukemia, prostrate, breast and colon cancers. In addition, SUMOylation has a direct role in promoting cancer metastasis. Thus, developing a fundamental understanding of the signals and factors that regulate SUMOylation, as well as how SUMOylation affects protein function, has the potential to lead to important new insights into cancer development, diagnosis and also treatment. My research project focuses on understanding the role that SUMO-binding proteins play in determining the effects of SUMOylation, particularly in controlling DNA repair, cell growth and cell differentiation. This will allow us to better understand the mechanisms that regulate SUMOylation and thus delineate how SUMOylation functions in cancer progression. The AACR fellowship will provide valuable support for completing these important studies in the laboratory of Dr. Michael J. Matunis at the Johns Hopkins University."
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Ravindra Majeti, M.D., Ph.D.Clinical Fellow, Stanford University, Stanford, CA
Targeting of Human AML Stem Cell-Specific Cell Surface Molecules
"A growing body of evidence has added to our fundamental knowledge by demonstrating that human acute myelogenous leukemia (AML) is organized as a cellular hierarchy initiated and maintained by rare self-renewing leukemia stem cells (LSC). One implication of this cancer stem cell model is that in order to eradicate the leukemia and cure the patient, therapies must target and eliminate the leukemia stem cells. For the development of such LSC-targeted therapies, it is necessary to identify molecules that are preferentially expressed in LSC compared to their normal counterparts and that are critical for their function. My proposal seeks to investigate the pathogenic role of two cell surface molecules, CD47 and CD96, that we have found to be preferentially expressed on AML LSC. In addition, a major goal of this proposal is to generate monoclonal antibodies directed against these proteins that are capable of eliminating AML stem cells in vivo. CD47 serves as the ligand for SIRP-alpha on phagocytic cells, which in turn delivers an inhibitory signal for phagocytosis. We hypothesize that increased CD47 expression on human AML contributes to pathogenesis by inhibiting phagocytosis of leukemia cells. I will test this hypothesis by knocking-down expression of CD47 and through the use of a blocking monoclonal antibody. CD96 expression has been found on AML LSC from a majority of human samples assayed. I will examine the function of CD96 in leukemic pathogenesis through knock-down experiments and will additionally target CD96 with a monoclonal antibody we have developed. It is my ultimate goal that this research will directly lead to an antibody therapy for human acute myeloid leukemia that will improve long-term survival and, hopefully, cure these patients. I am very honored to receive the AACR Centennial Postdoctoral Fellowship, and would like to thank my past mentor Dr. Arthur Weiss and my current mentor Dr. Irving Weissman for all their support."
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Timothy Whitsett, Jr., Ph.D.Postdoctoral Fellow, The Translational Genomics Institute, Scottsdale, AZ
Suppression of the ING4 Tumor Suppressor Gene by Estradiol in Breast Cancer
"Breast cancer is the most commonly diagnosed cancer in women and remains a leading killer. It is well established that estrogen plays a critical role in the development of breast cancer. In tissue culture, estrogen has been shown to affect the survival, proliferation, and motility of breast cancer cells. While these effects are thought to contribute to the genesis, progression and metastasis of breast cancer, the underlying molecular mechanisms are not well understood at this time. We want to explore the possibility of interplay between estrogen and INhibitor of Growth family, member 4 (ING4), a tumor suppressor gene that our lab has shown to be deleted in up to 20 percent of all primary human breast tumors.
"We hypothesize that down-regulation of ING4 is a part of the mechanisms by which estradiol contributes to breast cancer growth, increased motility and metastasis. The specific aims of the proposed study are: 1) To decipher the molecular mechanisms of the ING4 down-regulation by estradiol in breast cancer cells; 2) To elucidate if estradiol-induced proliferation or motility of breast cancer cells is dependent on the suppression of ING4 in tissue culture; and 3) To determine the antagonistic relationship between estrogen and ING4 in the growth and metastasis of breast cancer in vivo utilizing a mouse xenograft model system. The results of this proposed study will provide insights into molecular mechanisms of estrogen-driven breast cancer growth, motility and metastasis. These mechanisms will provide novel targets for therapeutics in women with estrogen-dependent breast tumors. In addition, the results will also provide a basis to develop better therapies for the patients with tumors that involve suppression of ING4.
"Being awarded an AACR Centennial Postdoctoral Fellowship in Cancer Research is truly an honor and will allow me to conduct high-impact breast cancer research in the lab of Dr. Sue Kim. In addition, this fellowship is essential for building a strong foundation as a breast cancer researcher and allows me to pursue my research interests into the future."
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