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 Predoctoral Fellowship in Cancer Research
Martin Etzrodt, M.Sc.
Massachusetts General Hospital, Boston, MA
Project: Real Time Imaging of Innate Immunity in the Tumor Microenvironment
"Tumor-associated macrophages (TAM) constitute a major part of the tumor mass in many cancers. TAM display a multitude of functions that can either promote or inhibit tumor growth. Their myleoid precursors - the circulating monocytes - have been considered very ‘plastic' until they migrate to their destination tissue. Recent studies, however, indicate that monocytes comprise at least two subsets (i.e., Ly-6C hi and Ly-6C lo cells) ‘committed' to specific function. At present, the role of monocyte heterogeneity in cancer is unknown. However, pioneering studies in mouse models of cardiovascular disease indicate that circulating Ly-6Chi and Ly-6Clo monocytes promote disparate processes once recruited in destination tissue.
In my Ph.D. project I aim to study the consequences of monocyte heterogeneity in the context of cancer. Specifically, I will ask the following questions: 1) What is (are) the direct precursor(s) of TAM, and is there differential participation of monocyte subsets? 2) What is the involvement of monocyte/TAM subsets during tumor progression (initiation, invasion, angiogenesis)? 3) Does elimination of distinct monocyte/TAM subsets result in measurable anti-cancer effects?
To answer these questions, I will use sophisticated tumor mouse models that recapitulate human disease and utilize two recent advances in molecular imaging, namely: 1) novel biocompatible nanomaterials developed at the host institution that are capable of in vivo labeling of defined cell types and molecular activities, and 2) a set of noninvasive imaging modalities such as intravital multiphoton microscopy, fluorescence mediated tomography and magnetic resonance.
A profound knowledge of the individual role and the spatio-temporal distribution of TAMs during tumor development could be the basis of future therapeutic approaches that selectively modulatesTAM which promote tumor growth and attenuate anti-tumor adaptive immune responses, while leaving immune-enhancing TAM intact."
2008-2011 AACR Centennial Predoctoral Fellowship in Cancer Research
Raymond E. Moellering, B.S.
Harvard University, Boston, MA
Project: Direct Inhibition of Notch Signaling in Cancer
"My doctoral work draws upon areas of chemical biology and chemical synthesis to address emerging questions in cancer biology. Specifically, I am interested in developing new synthetic approaches that will allow pharmacologic access to regions of biological space that are currently considered "un-druggable." Transcription factors, the proteins that directly regulate gene expression, are classic examples of inaccessible biological targets due to their reliance on extensive protein-DNA and protein-protein interactions. As these interaction surfaces generally lack suitable binding sites for small molecules they have historically been resistant to drug discovery efforts. Furthermore, due to their broad influence over cellular proliferation and differentiation, if and when they become deregulated, cancer often follows. The Notch transcription factor complex is no different, as gain-of-function mutations have been discovered in more than 50% of T-cell Acute Lymphoblastic Leukemia (T-ALL) cases and elevated pathway activity has been reported in numerous other cancers. The aim of my current research has been to employ a novel chemical approach to directly disrupt the assembly of the active Notch transactivation complex, which consists of the intracellular domain of Notch1 (ICN1), the DNA-binding protein CSL and a co-activator MAML1. Leveraging genetic and structural insights known about the complex, I have designed alpha-helical synthetic peptides that have been stabilized via side-chain olefin metathesis and are capable of preventing complex formation. Prevention of complex formation subsequently inhibits Notch target gene expression and downstream oncogenic signals. With the generous support of an AACR Centennial Pre-doctoral Fellowship I now plan to optimize the potency, specificity and pharmacologic properties of these ligands through structure-based medicinal chemistry. Biochemical and cell-based assays will be employed to characterize the inhibitory potential of resulting compounds. Finally, I plan to develop and implement a bio-luminescent murine model of Notch-driven T-ALL to explore the anti-cancer effects of advanced lead molecules in vivo. In addition to expressing my gratitude to the AACR for this award, I would like to thank my previous mentors Dr. Eugene Mash and Dr. Robert Gillies, as well as my current mentors Dr. Gregory Verdine and Dr. James Bradner for their guidance and enthusiastic support of my interdisciplinary research interests and continuing development as a scientist."
2008-2011 AACR Centennial Predoctoral Fellowship in Cancer Research
Andrey S. Poleshko, M.S.
Fox Chase Cancer Center, Philadelphia, PA
Project: Identification and Evaluation of Key Mediators of Epigenetic Silencing
"Epigenetic silencing directs transcriptional shutoff of specific genes during development and cellular differentiation. This process is mediated by epigenetic marks including DNA methylation and a variety of posttranslational histone modifications (e.g., methylation). Errors in placement or removal of epigenetic marks may drive epigenetic silencing and tumorigenesis. Inhibitors of DNA methyltransferase (DNMT) and histone deacetylase (HDAC) enzyme families can reverse epigenetic silencing and produce anti-tumor effects, possibly through reactivation of silent tumor suppressor genes (so-called epigenetic therapy). As these inhibitors show little specificity within enzyme families, their precise mechanisms of action are not well understood. My research focuses on validation of the underlying concept of epigenetic therapy and identifying new silencing factor targets. Specifically, the goal of my work is to use an RNAi-based, gene-by-gene knockdown approach to identify new epigenetic regulators. A genome-wide siRNA library screen will be employed to identify host factors that are involved in the maintenance of epigenetic silencing, and the roles of these factors in epigenetic regulation of tumor suppressor gene silencing will be assessed. Being awarded an AACR Centennial Pre-doctoral Research Fellowship in Cancer Research is a great honor and will provide support for my current research, as well as establish a strong foundation for my future research career. I believe that the mentorship of Dr. Anna Marie Skalka and Dr. Richard Katz, along with this fellowship, will provide personal benefits that I will appreciate for many years to come. In addition, I am hopefully that this research support will create avenues for developing novel and more effective cancer therapies."
2008-2011 AACR Centennial Predoctoral Fellowship in Cancer Research
Vivian Lee Weiss, B.A.
Johns Hopkins University, Baltimore, MD
Project: Improving Cancer Therapy: Modification of High and Low Avidity T Cells
"Vaccines are considered one of the most important contributions to the prevention of infection. Vaccines activate the immune system to recognize and eradicate the foreign antigens of viruses and bacteria. Recent scientific findings suggest that the immune system can be exploited to recognize cancer antigens as if they were viral proteins. In fact, two cancer vaccines have now been approved for the prevention of hepatomas and cervical cancers, respectively. Unfortunately, so far, vaccines have not had success in treating existing cancers. It is now clear that developing cancers use multiple mechanisms to turn off the immune system. Therefore, in order to improve on the efficacy of vaccines for the treatment of cancer, it is important to first understand these tumor-suppressing mechanisms. It has been shown that T cells are often detected in cancer bearing hosts, but are dysfunctional and unable to effectively clear the tumor. One reason for an ineffective immune response is that tumor antigens are often similar to the proteins within the normal cell. To avoid autoimmune disease, the highest potency (high avidity) T cells specific for self antigens are either eliminated from the T cell repertoire or down regulated during their development in the thymus. Recent studies have shown that higher avidity T cells are detectable in patients with cancer, but are indeed inactivated and unable to mediate tumor clearance. Lower avidity T cells represent another available population of T cells that have the potential to target cancer cells, but are functionally incapable of effective tumor killing on their own. We are using the HER-2/neu transgenic (neu-N) mouse model of spontaneous mammary tumors to understand the mechanisms that control both high and low avidity T cells. To elucidate the mechanisms regulating high and low avidity T cells, we created high and low avidity T cell receptor transgenic mice specific for the immunodominant epitope of the HER-2/neu antigen expressed by the mammary tumors in the HER-2/neu transgenic mice. We will use these mice to evaluate the activation and proliferative capacity of each T cell population in the tumor bearing mice under conditions of tumor-induced immune tolerance and T cell activation. Finally, we will test our hypothesis that over-expression of the post-transcriptional regulator, miR-181a, will increase the tumor killing capabilities of the low avidity T cells. Results from these studies will elucidate the mechanisms of T cell regulation and should directly translate into improved clinical strategies for cancer treatment with immune based therapies. I am honored to receive the AACR Centennial Pre-doctoral Research Fellowship in Cancer Research, as this support will provide me the opportunity to complete my research thesis on post-translational modifications of tumor-specific T cells. I would also like to thank my mentor, Dr. Elizabeth Jaffee, whose encouragement and guidance has been invaluable for this project and who serves as a role model for students pursuing a career as a physician scientist."
2008-2011 AACR Centennial Predoctoral Fellowship in Cancer Research
Wen Xue, M.S.
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
Project: Probing Tumor Suppressor Gene Networks in Hepatocarcinomas by in vivo RNAi
"My research project will extend our understanding in the genetics and treatment of liver cancer. Hepatocellular carcinomas (HCC) is one of the most lethal and prevalent malignancies worldwide. I will use in vivo RNA interference (RNAi) technology and mouse models to characterize new tumor suppressor gene pathways in HCC. My research plan includes 2 directions: (1) using stable in vivo RNAi to validate a candidate tumor suppressor gene called deleted in liver cancer 1 (DLC1) on chromosome 8p22 and to study its downstream signaling pathway; (2) using genomic deletion based shRNA library to screen for novel tumor suppressor genes in HCC. These works can provide important insights into the molecular basis of liver cancer. We also believe this novel approach will identify promising drugable genes/pathways in HCC and will lead to improved HCC therapies."
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.""
2008-2010 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-Amgen, Inc. Fellowship in Clinical/Translational Cancer Research
Christopher A. Maher, Ph.D.
University of Michigan, Ann Arbor, MI
Project: The Role of microRNAs in Prostate Cancer Progression
"MicroRNAs (miRNAs) are a class of short single-stranded non-coding RNAs that are known to be involved in critical processes such as development, differentiation, apoptosis, and proliferation through transcriptional or post-transcriptional modification of target messenger RNA (mRNA) transcripts. Recently, expression profiling studies revealed miRNA gene signatures associated with diagnosis, staging, progression, and prognosis in a variety of cancers. In addition, over 50% of miRNAs have been associated with fragile sites and genomic regions susceptible to amplification or deletion in cancer suggesting that miRNAs can act as oncogenes or tumor suppressors. Therefore, the underlying hypothesis of this research is that in advanced stages of prostate cancer a subset of miRNAs will have altered expression, either through chromosomal aberrations or transcriptional regulation, thereby modifying their regulatory roles and subsequently enabling the progression of cancer. To address this, I will collect, integrate, and analyze mRNA and miRNA microarrays, microarray-based Comparative Genomic Hybridization (aCGH), and high-throughput small RNA sequencing of normal, tumor, and metastatic prostate samples. First, I intend to elucidate gene signatures associated with early and late stages of prostate cancer progression through integration of miRNA profiling and deep sequencing of small RNAs. Subsequent integration of matched aCGH data will reveal those miRNAs in the gene signatures whose expression was altered due to genomic aberrations. Furthermore, elucidating biologically relevant downstream targets for miRNAs within these gene signatures will provide insight into their regulatory networks and reveal putative therapeutic targets. While I will be using prostate cancer as a model for further experimental validation, I expect a subset of these miRNAs will be acting as oncogenes or tumor-suppressors in a broader range of cancers and therefore could have significant translational impact in diagnosis, prognosis, and therapy. I am honored to be awarded an AACR-Amgen Fellowship in Clinical/Translational Cancer Research as it will enable me to pursue my research and grow as a translational scientist. I am also grateful to my past mentors, Drs. Lincoln Stein, Doreen Ware, and Winston Hide, and my current advisor, Dr. Arul Chinnaiyan, who have been outstanding role models and invaluable throughout my training as a scientist."
2008-2010 AACR-Amgen, Inc. Fellowship in Clinical/Translational Cancer Research
Kimberly A. Brown, Ph.D.
Memorial Sloan-Kettering institute for Cancer Research, New York, NY
Project: Identification of Androgen Receptor E3 Ubiquitin Ligases in Prostate Cancer
"The identification of novel prostate cancer therapeutics is a significant clinical need because current hormone therapies eventually fail, leading to a drug-resistant and fatal disease termed castrate-resistant prostate cancer. Men with castrate-resistant prostate cancer often exhibit an increase in androgen receptor (AR) protein levels. Previous work in our laboratory show that this increased level of AR is necessary and sufficient for the progression of prostate cancer to castrate-resistant disease and its function is necessary to sustain tumor growth. In addition to castrate-resistant prostate cancer, AR is expressed in nearly all prostate tumors and AR expression is necessary for tumor maintenance. Taken together, these data suggest that AR plays a critical role in hormone-sensitive and castrate-resistant prostate cancer and remains an important target for prostate cancer therapeutics. My research focuses on identifying alternative approaches to current hormone therapies by targeting AR protein stability. Specifically, the goal of my current proposal is to identify novel AR E3 ubiquitin ligases and to understand the role of AR E3 ligases in castrate-resistant prostate cancer. This research will allow us to better understand the underlying mechanism of prostate cancer development and has great potential to translate into beneficial treatments for people living with prostate cancer. Being awarded an AACR-Amgen, Incorporated Fellowship in Clinical/Translational Cancer Research is an honor and will allow me to conduct high-impact prostate cancer research in the laboratory of one of the leaders in clinical and translational cancer research. In addition, this fellowship is essential for building a strong foundation as a 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."
2008-2009 AACR Anna D. Barker Fellowship in Basic Cancer Research
Bernard A. Ayanga, Ph.D.
UT M.D. Anderson Cancer Center, Houston, TX
Project: Investigating The Mechanism of p63 and p73 In The DNA Damage Response
"p53, an important tumor suppressor gene in human cancer, is mutated in more than 50% of tumors. It controls cellular stress responses by converting upstream signals such as DNA damage, hypoxia, and oncogene deregulation into critical biological endpoints, such as cell cycle arrest and apoptosis. p53 family members, p63 and p73, have remarkable structural similarities to p53, but the roles of these homologues in tumor suppression are controversial. This is due to the existence of multiple isoforms for both p63 and p73. Isoforms containing transactivation domain (TA) and those without (ΔN) exist. These isoforms have been shown to have opposing activities whereby the ΔN isoforms act as dominant negatives against p53, TAp63 and TAp73. Our lab has shown previously that p63 and p73 are required for p53 dependent apoptosis in the developing central nervous system (CNS) of the mouse and in E1A MEF cells after DNA damage. A long- standing question in the p53 field is what molecules regulate p53's ability to induce cell cycle arrest or apoptosis in response to DNA damage. Our work showing the interdependence on the p53 family members in the DNA damage response has begun to shed light on this question. Although we have shown that p63 and p73 regulate p53's ability to selectively activate cell cycle arrest or programmed cell death (apoptosis), the mechanism for this interplay between the p53 family members remains elusive. The goals of my research are to investigate the mechanism by which the p53 family members p63 and p73 influence whether p53 induces cell cycle arrest or cell death in response to DNA damage. Our lab has previously shown that in the absence of p63 and p73, p53 (while still capable of inducing cell cycle arrest) is unable to induce apoptosis in response to DNA damage. The hypothesis to be tested in this research is that p63 and p73 recruit proteins that modify histones at the promoters of p53-target proapoptotic genes, allowing for the expression of these genes in response to DNA damage. The plans are to test this hypothesis by conducting chromatin immunoprecipitation (ChIP) experiments, as well as to identify the cofactors that associate with p63 and p73 to promote gene transcription. I also plan to generate mice that conditionally knock out the TAp73 and DNp73 alleles and assess the outcome of this on p53-mediated apoptosis after DNA damage in cells lacking the TAp73 and the DNp73 isoforms of p73. I also plan to examine various human cell lines that carry mutations in p53 and determine whether the cells that are resistant to DNA damage (chemotherapy) have a defect in histone modification at the promoters of proapoptotic target genes. These studies will shed light on the complex p53 family and how apoptosis, an important anti-tumorigenic pathway, is induced in response to DNA damage. This research has wider implications for the development of chemotherapeutic agents that target tumors with mutations in the p53 pathway."
2008-2009 AACR-Astellas USA Foundation Fellowship in Basic Cancer Research
Florian C. Bassermann, M.D., Ph.D.
New York University, New York, NY
Project: Deregulation of SCF-Dependent Ubiquitylation in the Development of Multiple
"Multiple myeloma (MM) is the second most common hematologic malignancy in the United States which results from the clonal amplification of plasma cells. The recent clinical success of the proteasomal inhibitor bortezomib (VelcadeTM) in the treatment of MM has highlighted the importance of the ubiquitin-proteasome system in this disease. The mechanisms of how this system is deregulated in MM have however remained largely elusive. My research will focus on an E3 ubiquitin ligase termed SCFFbxo9, which was found to be overexpressed in MM in an "oncogene like" manner (i.e. copy number-correlated expression and significant overexpression versus normal plasma cells). Using a mass spectrometric-based approach, I will identify the regulatory network and substrates of SCFFbxo9 and investigate how these pathways are altered in MM. The investigation of ubiquitin-mediated degradation processes, which are specifically deregulated in MM, are anticipated to serve as a platform from which to identify new "drugable" targets that will represent the basis for more specific therapies in the treatment of this disease."
2008-2009 AACR-Astellas USA Foundation Fellowship in Basic Cancer Research
Ting Chen, Ph.D.
The Rockefeller University, New York, NY
Project: Identification and Characterization of Stem Cells in Skin Cancers
"My research will focus on the hair follicle stem cells (SCs) and their role in tumorigenesis. SCs are natural units of tissue repair and homeostasis; this has led to the postulate that mutant SCs may be at the root of cancerous tissues. If so, this small population of cells would need to be targeted for effective cancer therapies. As a prerequisite to exploring the potential of therapies directed at cancer SCs, it is necessary to identify and characterize putative cancer SCs and ascertain how they differ from normal adult SCs. Skin epithelium is an excellent model tissue for studying this problem because its SC populations are spatially and temporally well defined, and they can be propagated in tissue culture. Multiple signal pathways tightly control the quiescence and activation of hair follicle SCs. Stabilizing mutations in β-catenin result in pilomatrichomas. Inhibition of BMP signal pathway by loss of the BMP receptor 1A leads to activation of the hair follicle SC compartment and tumor formation. My goals are to apply the molecular insights I gain on these models to a fundamental understanding of the relationship between stem cells activation and tumorigenesis. The fellowship from AACR will be invaluable in helping me achieve these objectives. In 2007, I joined Dr. Elaine Fuchs's lab at the Rockefeller University. She brought me to the dynamic field of epidermal stem cells and has been instrumental in fostering my development as a stem cell biologist and the creation of a collaborative and inspirational atmosphere in her lab at the Rockefeller University."
2008-2009 AACR-Astellas USA Foundation Fellowship in Clinical/Translational Cancer Research
Akil A. Merchant, M.D.
Johns Hopkins University, Baltimore, MD
Project: Hedgehog Signaling in Normal and Malignant Hematopoiesis
"Aberrant activation of the Hedgehog (Hh) signaling pathway has been described in a wide variety of human cancers. The essential role this pathway plays in regulating stem cells during normal embryonic development and adult tissue homeostasis suggests that Hh signaling similarly modulates cancer stem cells (CSC). We have begun to study Hh signaling in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) and have found that components of the Hh pathway are highly expressed within primary clinical samples from both these diseases. Furthermore, inhibition of Hh signaling significantly reduces clonogenic leukemia growth in vitro, whereas conditional pathway activation in the myeloid compartment of transgenic mice produces a block in differentiation and bone marrow dysplasia reminiscent of MDS. We hypothesize that a better understanding of Hh signaling in AML and MDS will lead to the development of novel therapies with the potential to inhibit leukemic CSC and improve long-term outcomes. Therefore, we propose to: 1). Define the role of aberrant Hh signaling in regulating the cell fate decisions of leukemic CSC; 2). Establish the in vivo anti-leukemic activity of novel Hh inhibitors; and 3). Examine the effects of deregulated Hh activation on normal hematopoiesis."
2008-2009 AACR-Bristol-Myers Squibb Oncology Fellowship in Clinical Cancer Research
Panagiotis Konstantinopoulos, M.D., Ph.D.
Beth Israel Deaconess Medical Center, Boston, MA
Project: The Nrf2/Keap1 Pathway as Mediator of Platinum Resistance in Ovarian Cancer
"The major limitation to the successful treatment of epithelial ovarian cancer (EOC) is the development of resistance to platinum compounds. In order to gain insight into the mechani