AACR Research Fellowships foster 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.
2008-2011 AACR Centennial Postdoctoral Fellowship in Cancer Research
Kutlu G. Elpek, Ph.D.
Dana Farber Cancer Institute, Boston, MA
Project: 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 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."
2008-2011 AACR Centennial Postdoctoral Fellowship in Cancer Research
Heiko Enderling, Ph.D.
Caritas St. Elizabeth's Medical Center, Boston, MA
Project: 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 3-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."
2008-2010 AACR Centennial Postdoctoral Fellowship in Cancer Research
Catherine Guzzo, Ph.D.
Johns Hopkins University, Baltimore, MD
Project: 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."
2008-2011 AACR Centennial Postdoctoral Fellowship in Cancer Research
Ravindra Majeti, M.D., Ph.D.
Stanford University, Stanford, CA
Project: 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."
2008-2011 AACR Centennial Postdoctoral Fellowship in Cancer Research
Timothy Whitsett, Jr., Ph.D.
The Translational Genomics Institute, Scottsdale, AZ
Project: 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% 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.""
2008-2011 AACR-AstraZeneca-Prevent Cancer Foundation Fellowship for Translational Lung Cancer Research
Lauren A. Byers, M.D.
UT M.D. Anderson Cancer Center, Houston, TX
Project: Validation of a Proteomic Signature of Pemetrexed Resistance in NSCLC
"In non-small cell lung cancer (NSCLC), disease progression and therapeutic resistance can be driven by a variety of signaling pathways. Because of this, lung cancer patients vary greatly in their response to chemotherapies and targeted agents. We hypothesize that this molecular heterogeneity will be reflected in a tumor's proteomic signature prior to treatment, and that this signature can be used to predict sensitivity or resistance to a given drug. Using reverse-phase protein arrays (RPPA), a high throughput antibody-based technology, we previously compared proteins and phosphoproteins from key signaling pathways between pemetrexed-sensitive and -resistant NSCLC cell lines and derived a proteomic signature of pemetrexed resistance. We also identified several key signaling molecules associated with pemetrexed resistance that are potential therapeutic targets. In this project, we will validate this newly developed "pemetrexed response signature" in vitro and in vivo and test therapeutic targets included within the signature for their ability to abrogate pemetrexed resistance. Ultimately, we hope to translate these results into a clinical tool for predicting response to pemetrexed and to identify new biologically-based, rational drug combinations with pemetrexed. In the future, we plan to use this project as a model for testing our other drug-response signatures in NSCLC. Receiving the AACR-AstraZeneca-Prevent Cancer Foundation Fellowship for Translational Lung Cancer Research is a true honor. This award provides not only significant support for this project, but will also help me grow further as a translational researcher. I am also extremely grateful to my past mentors, Drs. Arnold Levine, Louis Staudt, and Louise Strong, and to my current mentors, Drs. John Heymach and Waun Ki Hong, who have been incredible role models and have shaped my development as a physician-scientist."
2008-2010 AACR George and Patricia Sehl Fellowship in Cancer Genetics Research
Keren Levanon, M.D., Ph.D.
Dana Farber Cancer Institute, Boston, MA
Project: The Fallopian Tube as the Field of Origin of Ovarian Serous Carcinoma
"Ovarian carcinoma is the leading cause of death from a gynecological malignancy. This is mainly due to the fact that the understanding of the pathogenesis of this disease has eluded scientists and clinicians for so long. Recently, we identified the field of origin of most serous carcinomas to be the fallopian tube fimbria, rather than the ovarian surface epithelium, and described the precursor lesion, termed ‘p53 signature', that precedes the development of serous cancer. For the first time, we are at a position to elucidate the endogenous and environmental risk factors, the molecular triggers, and the pathways to serous carcinogenesis and to progress toward suggesting an early detection method and strategies for targeted therapy. This project, with the generous support of the AACR and of the sponsorship of George and Patricia Sehl, has already yielded novel and unique tools for the investigation of the fallopian tube epithelium. My aim in the next two years is to unravel several key elements in the serous carcinogenic process, and pave the path towards introduction of new early detection biomarkers. Furthermore, I will attempt to propose new animal models of serous ovarian carcinoma, based on a transformed derivative of the true cell-of-origin. This model system will be a useful tool for investigation of targeted therapies, as they emerge. The motivation in this project is deep-rooted in my experience of the urgent need for progress in the care of ovarian cancer patients. It is an exciting and challenging turn point in my career as a medical oncologist who is also dedicated to basic and translational research of the best possible quality. I believe that the superb mentorship of Dr. Ronny Drapkin and the atmosphere in the Dana-Farber and Harvard Medical School communities, along with this fellowship grant, are the perfect conditions for fostering this important project."
2008-2010 AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis
Zoe Cournia, Ph.D.
Yale University, New Haven, CT
Project: MIF Inhibition as a Means to Suppress Tumor Growth and Angiogenesis
Macrophage migration inhibitory factor (MIF) is a tautomerase released by T-cells and macrophages, and acts as an immunoregulatory and proinflammatory cytokine. MIF is implicated in multiple aspects of tumor growth, including control of cell proliferation and promotion of angiogenesis. Deactivation of MIF by antibodies or inhibition of MIF binding its receptor, CD74, reduces cellular proliferation and attenuates tumor growth and angiogenesis. The aim of this pre-clinical project is to target and deactivate the MIF protein by small molecule inhibitors through a joint computational and experimental study. This goal will be achieved by computational structure-based drug design, synthesis of potential leads, and in vitro assaying for (a) MIF-CD74 inhibition and (b) tautomerase inhibition. Following the assays, the potent compounds will be further optimized with computational methods and re-assayed for enhanced inhibition activity. Apart from presenting an excellent opportunity for an efficient anti-cancer therapy, potent MIF inhibitors will improve our understanding of the MIF enzymatic activity and hence its implication in angiogenesis of tumor cells and metastases. In view of our limited knowledge of MIF biochemistry, we also propose to investigate the MIF tautomerization mechanism. Overall, the AACR Judah Folkman Fellowship will help to uncover new anti-cancer leads for further exploration through in vivo studies and animal models, as well as gain a fundamental understanding of MIF biochemistry. The proposed studies constitute a unique synergy between the Jorgensen laboratory, well-renowned for their computational drug design efforts, and the collaborating experimental Bucala group at Yale University. "I feel truly honored to be the first recipient of the AACR Judah Folkman Fellowship for Cancer Research in Angiogenesis. I would like to express my gratitude to my current mentor, Dr. Jorgensen, for his continuing support, inspiration, and confidence in my capabilities. I feel extremely privileged in being able to work with him in such an outstanding environment that fosters my development as a scientist in cancer research."
2008-2010 AACR-National Brain Tumor Foundation Fellowship, in memory of Bonnie Brooks
Heiko Wurdak, Ph.D.
Scripps Research Institute, La Jolla, CA
Project: Identification of Signals Regulating Brain Tumor Stem Cell Fate
"I aim to identify novel targets crucially involved in glioblastoma-derived stem cell fate. Glioblastomas are the most lethal brain tumors with a median survival rate of less than 12 months, which is due to resistance to radiation and other currently available treatments. Glioblastomas are diffuse tumors invading the normal brain tissue, which makes it impossible to completely remove the tumor via surgery. Tumor residues after surgery or radiation therapy therefore lead to quick relapse and regrowth of the tumor. Tumor recurrence has been recently attributed to a small fraction of cells within the tumor mass. These cells display characteristics of stem cells and are therefore called tumor stem cells or tumor initiating cells. However, conventional therapies target rapidly proliferating cells of the so called tumor bulk, rather than the tumor stem cells harboring high tumorigenic potential. Thus, specific treatments targeting tumor stem cells are required and novel tumor stem cell-specific targets need to be identified. I aim to identify small chemical molecules causing forced differentiation of tumor stem cells. To this end, libraries containing a large number of different chemical compounds will be screened for effective molecules (high throughput screening). Moreover, I aim to identify genes that are crucially regular to the tumorigenic potential of tumor stem cells. The screen will be done using RNA interference technology, a widely used tool to specifically silence gene function. A library of small interference RNAs eliciting gene-specific silencing will be used to target the "druggable" genome (all genes that encode disease related proteins and can be modulated by small chemical compounds). The role of newly identified small molecules and novel gene functions which are blocking self-renewal and lead to forced differentiation, and loss of tumorigenic potential of tumor stem cells, will be tested in a mouse model of glioblastoma. The proposed study should provide new insights into mechanisms of tumor stem cell self-renewal versus differentiation. In addition, novel targets and new therapeutic options for a more efficient treatment of recurrent glioblastomas might be discovered."
2008-2010 AACR-Prevent Cancer Foundation-AstraZeneca Fellowship in Translational Lung Cancer Research
Ji Luo, Ph.D.
Brigham and Women's Hospital, Boston, MA
Project: A Genome-Wide Analysis of Acquired Gefitinib Resistance in Lung Cancer
"A major challenge in cancer research is to identify new drug targets for the effective treatment of cancer. Targeted therapies against oncogenes which promote tumor growth have been especially effective. In particular, lung cancers with mutations in the epidermal growth factor receptor (EGFR) respond well to EGFR kinase inhibitors such as gefitinib and erlotinib. However, these tumors eventually develop resistance to these drugs. To better understand the mechanisms underlying this acquired resistance to EGFR inhibitors, I am applying our laboratory's latest barcoded shRNA library technology to interrogate the whole human genome for genes whose depletion could confer gefitinib resistance in lung cancer cells harboring EGFR mutations. This functional analysis will shed new light on the mechanisms of acquired gefitinib resistance and help identifying therapeutic approaches for the treatment of lung cancers.
A significant fraction of lung cancers, as well as other cancer types, are driven by the Ras oncogene. No targeted therapies are available for this class of aggressive tumors and drugging Ras itself has been technically difficult. To identify alternative drug targets for the treatment of Ras-driven tumors, I am applying our shRNA library in a genome-wide synthetic lethal screen to identify genes whose depletion selectively kills cancer cells with Ras mutations but not normal cells without Ras mutation. These genes and their protein products would represent a new class of drug targets for the treatment of Ras-driven tumors.
I thank the AACR for providing me with this fellowship to help me accomplish these research goals. I also wish to thank my mentor, Dr. Stephen Elledge, for his guidance and enthusiastic support of my research."
2007-2010 AACR-AstraZeneca-Cancer Research and Prevention Foundation Fellowship in Translational Lung Cancer Research
Daniel B. Costa, M.D.
Beth Israel Deaconess Medical Center, Boston, MA
Project: Transcription Factors in the Pathogenesis and Treatment of Lung Cancer
"Lung cancer leads cancer deaths and efforts to understand the molecular mechanisms involved in this malignancy are urgently necessary. Exciting current research has focused in oncogenes, such as the identification of epidermal growth factor receptor activating mutations and the development of oral small molecule tyrosine kinase inhibitors (erlotinib and gefitinib). However the study of tumor suppressor genes involved in lung cancer has lagged behind and no specific therapies targeting these genes have emerged to help patients. Dr. Costa's research will focus on studying genes necessary for normal lung development that act as tumor suppressors in non-small cell lung cancer (NSCLC). These are the transcription factors C/EBPα and Foxa2. Dr. Costa will study if these transcription factors are aberrantly expressed in tissue samples, linked to prospective clinical databases, from patients with NSCLC. It will be possible to correlate the expression of C/EBPα and Foxa2 with the tumors' pathological characteristics and the patients' clinical outcomes. His plan is also to identify the molecular mechanisms of down-regulation of these genes, by studying if epigenetic or genetic changes are culprits. The last step of the project consists of testing compounds that can either re-establish the function of these transcription factors or act through the pathways they are involved. Preliminary results have identified the synthetic triterpenoids as potential compounds that re-establish the C/EBP pathway and one of these triterpenoids is currently being evaluated as part of a phase I trial for patients with solid tumors at the Dana-Farber/Harvard Cancer Center's affiliated hospitals. The foreseeable clinical potentials of these studies are the identification of new prognostic markers in NSCLC and of new targets for early diagnosis and therapy of this deadly malignancy.
The AstraZeneca-Cancer Research and Prevention Foundation Fellowship in Translational Lung Cancer Research will be instrumental for Dr. Costa's career as a physician-scientist in Medical Thoracic Oncology and will allow him to continue his aspiration of translating findings from the laboratory to his patients afflicted with cancer. "I have been inspired by many individuals throughout my medical training. I would like to specially thank, first, my father, Dr. Fernando F. Costa, who is and has been my role model as a master clinician and scientist in my home country of Brazil. My interest for patient-based translational research was sparked by the mentorship of Dr. Bernard Forget at Yale University during my house-staff years. And most importantly, I am indebt to my current institution (Beth Israel Deaconess Medical Center) and mentor, Dr. Daniel Tenen, for trusting and stimulating my clinical and laboratorial pursuits. The future is very promising for translational research in lung cancer and efforts by the AACR in supporting young researches will continue to provide building blocks to enhance patient care and outcomes."
- View the list of Previous AACR Postdoctoral Research Fellowship Recipients