The AACR Predoctoral Research Fellowships provide full-time graduate students a rare opportunity to invest in their future cancer research careers. The grant terms are flexible, allowing grantees to tailor their grant funds to fit their individual research funding and salary needs. Grantees may also transfer their funds to a postdoctoral fellowship position, should they advance in their careers during the grant term. These Fellowships foster basic, translational, clinical, and epidemiological research by scientists at the beginning of their careers in the cancer field.
2008-2011 AACR Centennial Predoctoral Fellowships 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-6Chi and Ly-6Clo 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)?; and 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 TAM during tumor development could be the basis of future therapeutic approaches that selectively modulates TAM which promote tumor growth and attenuate anti-tumor adaptive immune responses, while leaving immune-enhancing TAM intact."
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 percent 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 Predoctoral 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."
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 Predoctoral 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 hopeful that this research support will create avenues for developing novel and more effective cancer therapies."
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 Predoctoral 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."
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 carcinoma (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 two 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; and (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."