Thirteen Outstanding Young Investigators Receive Cancer Research Institute Postdoctoral Fellowship Award

The Fellowship Review Committee of the Cancer Research Institute’s Scientific Advisory Council, with the approval of the Institute’s Board of Trustees, has named 13 new postdoctoral fellows from its October 2008 application round, awarding more than $1.89 million in research funding through the Irvington Institute Fellowship Program of the Cancer Research Institute.

The 13 young research scientists are conducting basic and tumor immunology laboratory investigations under the guidance of leading immunologists and tumor immunologists at distinguished academic institutions throughout the United States, including Whitehead Institute for Biomedical Research, New York University School of Medicine, The Scripps Research Institute, Memorial Sloan-Kettering Cancer Center, and Yale University, among others. Since the fellowship program’s inception in 1971, 953 fellows have received valuable funding from the Cancer Research Institute. Many fellows have since gone on to become leaders in their field, including two who have won the Nobel Prize.

Peter Beemiller, Ph.D.
University of California, San Francisco
San Francisco, California

"As a cell biologist with a passion for fluorescent microscopy, I’m fascinated by the remarkable cell biology of immune cells. They can move very quickly, covering large distances in a very short time when they need to respond to an infection or the appearance of a tumor—they can do some pretty astonishing things. T cells, for instance, can respond to the presence of just a few antigen epitopes on a cell surface and, based on that little bit of molecular information, can decide very quickly to activate, proliferate, and attack any cells bearing the matching antigen. CRI funding allows me to concentrate my talents on the study of these nimble assassins of the immune system and explore how knowledge of their cellular biology may lead one day to new immune-based cancer therapies." 

Project Title: Actin cytoskeletal regulation of the T-cell receptor signalosome
Sponsor: Matthew F. Krummel, Ph.D.

Proper development, tissue repair, and immune system responses all require that cells respond appropriately to external stimuli. Cells are able to "sense" environmental triggers through signaling pathways, while failures in these pathways often lead to cancer, immunodeficiency, or allergies. These signaling pathways are controlled through interactions among a large number of proteins, resulting in complex regulatory networks that are both robust and sensitive. However, this complexity makes identifying therapeutic targets challenging. Proteins will often play multiple roles in signaling pathways, contributing to both the initiation and termination of a response. Dr. Beemiller will examine how three proteins (Cdc42', Rac', and Vav') known to have altered activity in a number of cancers contribute to both the activation and deactivation of the T-cell response to foreign antigens. Identifying how the proteins affect cell signaling could lead to therapies that manipulate and correct their activity. Dr. Beemiller aims to block signaling in a cancer cell or enhance signaling in immune cells to boost an immune response.

Micah J. Benson, Ph.D.
Immune Disease Institute, Inc. and Harvard Medical School
Boston, Massachusetts

"I am interested in immunology research mostly for the fact that it’s so medicinally applicable. One goal of mine is hopefully to impact human health and well-being with my research. My Cancer Research Institute fellowship gives me a head start and the financial ability to accomplish my goals. These days, financial resources for scientists are very difficult to come by, and my fellowship allows our lab to do more research. The CRI fellowship will also establish that I have successfully gone through very difficult leaps in my career path so far. I’ve landed a fellowship that’s very competitive and I’ve proven myself to a large extent." 

Project Title: Discovery of factors regulating immunoglobulin mRNA alternative splicing
Sponsor: Anjana Rao, Ph.D.

Multiple myeloma is an cancer of immune cells called plasma cells, which originate in the bone marrow and, when cancerous, secrete abnormal levels of antibody into the blood and lymphatic system. This secretion of antibodies into the circulatory systems results from clipping of the genetic template used to encode antibody. How the antibody template is clipped is currently unclear, and Dr. Benson is investigating whether a factor called hnRNPLL is involved in this process. He first will try to see whether multiple myeloma cells and non-cancerous plasma cells require hnRNPLL to generate secreted antibody. Secondly, he hopes to identify other factors required by these cell types to generate secreted antibody. Dr. Benson believes hnRNPLL to be essential for multiple myeloma cell function and that any factors identified in this study may serve as new targets in the treatment of human multiple myeloma.

Alex Christopher Engel, Ph.D.
University of California, Berkeley
Berkeley, California

"I've always been really excited about all the sciences - physics, chemistry, biology, ecology. I really see a lot of beauty in the world on a macro scale from going diving or going backpacking on mountains, and on a micro scale from looking at these miniscule cells under the microscope. I think that’s something that really excites me is just seeing the unifying beauty of the world that we live in."

Project Title: Mechanisms controlling localization and activation of intracellular Toll-like receptors
Sponsor: Greg M. Barton, Ph.D.

Harnessing the immune system to recognize and eliminate cancerous cells is a powerful strategy with significant clinical potential. Remarkably, over one hundred years ago, Dr. William B. Coley recognized that administration of inactivated bacterial products stimulates the immune system and increases the likelihood that patients will reject tumors. We now understand that these bacterial products bind directly to proteins called Toll-like receptors (TLRs). The localization, or cellular position, of TLRs is key to sensing bacterial and viral molecules. One important subgroup of TLRs is localized within cells in an intracellular compartment. Both the TLR and the microbial stimuli must be delivered to this location before the immune system can be activated. Dr. Engel will use a genetic screen to determine how these TLRs are delivered to their correct intracellular location. Specifically, he will identify the modifications that help distinguish these receptors from other proteins and ensure their correct delivery. He also aims to identify proteins that direct the transport of these receptors. Successful implementation of tumor immunotherapy would be significantly aided by an understanding of how to manipulate TLR activation. Gaining this understanding of how TLRs are transported will help in the design of TLR activating anti-cancer treatments.

Hiroaki Ito, Ph.D.
Benaroya Research Institute at Virginia Mason
Seattle, Washington

"This fellowship is important and valuable to me for my own status as an investigator as well as my career.  It is also essential for securing my salary without making it my mentor's responsibility. I can work hard to accomplish the aims of my research without losing my concentration due to funding concerns."

Project Title: Regulation of dendritic cell responses by ITAM-containing signaling adapters
Sponsor: Jessica A. Hamerman, Ph.D.

Dendritic cells (DCs) are a type of white blood cell that plays a key role in protecting the body from infection. Many tissues, such as the lung and intestinal tract, are continuously exposed to pathogens and have to be protected from infectious invasion. DCs catch pathogens and alert the immune system to the presence of infection by releasing inflammatory proteins and/or interacting directly with other immune cells such as T cells and B cells, which are required to eradicate the pathogen. Thus, DCs are a key point of control in the immune response. The response of DCs is tightly regulated because too strong a response to pathogens can lead to pathological conditions such as inflammatory and autoimmune diseases. Dr. Ito seeks to understand the molecular mechanisms of the regulation of DC responses against many pathogens without leading to autoimmunity. This work may lead to new DC-mediated immunotherapies applied for the treatment of autoimmune diseases and cancer. 

Rebecca Anna Johnson, Ph.D.
The Skirball Instute for Biomolecular Medicine at the NYU Langone Medical Center
New York, New York

"CRI support of my research at the Skirball Institute allows me to work with some of the best immunologists in the world--they're right here on the same floor as I am. I've got a background in DNA repair, and when I have questions about immunology, I just go ask one of them. I'm surrounded by DNA repair experts and leading immunologists, and that's really inspiring me to combine these two interests of mine."

Project Title: Isolated recombination signals as novel mediators of genomic instability
Sponsor: David B. Roth, M.D., Ph.D. 

Each day our cellular DNA is assaulted by a host of environmental factors such as ionizing radiation and toxic chemicals. These factors are capable of causing breaks in one or both strands of DNA. Double-strand breaks (DSBs) are particularly dangerous, as they can transform a normal cell into a cancerous one by causing rearrangements in the genome that alter the behavior of key genes. Mammalian cells have thus had to evolve complex systems to detect and repair different types of DNA damage. One such process, known as V(D)J recombination, allows developing lymphocytes to produce enough antigen receptors to guarantee that any foreign invader in the immune system can be met with an appropriately armed B or T cell. V(D)J recombination is carried out millions of times each day by two proteins found only in developing lymphocytes, which cut the DNA at very specific sequences known as recombination signal sequences, or RSS. The power of V(D)J recombination comes at a price: the formation of so many DSBs increases the chance of a mistake, such as the joining together of two pieces of DNA that don’t belong together. One type of mistake might involve the selection of the RSS or incomplete activity at one RSS. The mechanism responsible for these abnormal events is not known. It is an additionally important area of exploration because cancers such as lymphomas and leukemias appear to be caused in part by irregular V(D)J recombination. Dr. Johnson will study the role that DNA damage response plays in V(D)J recombination to gain greater insight into the causes of such cancers and into their prevention and cure.

Ralf M. Leonhardt, Ph.D.
Yale University
New Haven, Connecticut

Project Title: Characterization of TAP- and tapasin-independent MHC class I-restricted melanoma epitopes
Sponsor: Peter Cresswell, Ph.D.

Tumor cells display many strategies to evade the immune response and to escape cancer therapies. Alterations to the MHC class I antigen presentation pathway—essential to signaling danger to the immune system—occur in almost all types of malignancies, helping developing tumors avoid recognition by tumor-killing cells. Tumors can impair MHC class I antigen presentation by eliminating two important molecules, TAP and tapasin. Impaired MHC function may protect tumors from modern vaccination approaches. Even in the absence of either TAP or tapasin, a molecule called HLA-A2 has the ability to present antigens on the cell surface. Dr. Leonhardt hopes to optimize vaccination strategies in melanoma treatment by identifying and characterizing HLA-A2-restricted antigens that are efficiently presented even when the tumor disables MHC class I antigen presentation through elimination of TAP or tapasin. He is focusing on a melanoma-specific vaccine candidate that is currently used in several trials. Preliminary data show that the vaccine is efficiently presented by both TAP- and tapasin-deficient melanoma cells. Dr. Leonhardt will also perform a broad screen to identify more TAP- and tapasin-independent molecules. Assembly of the identified molecules into a vaccine may substantially improve current therapeutic approaches in skin cancer and other cancers involving tumors that have shut down MHC class I presentation. 

Haihui Lu, Ph.D.
Whitehead Institute for Biomedical Research
Cambridge, Massachusetts

"I think I’m a very optimistic person and I like challenges. In sports you learn some skills, you advance to a higher level, and you feel the accomplishment. I think it’s similar in research where you’re facing these situations where you don’t know what the outcome could be. You could have ten hypotheses, but you just don’t know what the answer really is. Then, you have to try a lot of different ways and go through a lot of trouble to find out which hypothesis is correct. I really like tackling problems and I like these challenges.”

Project Title: Heterotypic interaction between tumor associated macrophage (TAM) and breast tumor during epithelial-mesenchymal transition (EMT)
Sponsor: Robert A. Weinberg, Ph.D.

Cancer metastasis is a multistep process where cancer cells from a primary tumor site enter blood circulation, travel to distant organs, and grow into secondary tumors. Ninety percent of cancer-related deaths are caused by metastases. During the Epithelial-Mesenchymal Transition (EMT) process, cells from the primary tumor with very little motility can acquire the ability to invade and migrate, or metastasize. Inside tumors, cancer cells can also intermingle with macrophages, whose normal function is to elicit inflammation and induce an adaptive immune response that rapidly recognizes and kills invading pathogens. During metastasis however, tumor-associated macrophages (TAMs) are hijacked by the cancer cells to function in ways that promote tumor growth. TAMs also suppress the adaptive immune response, thereby assisting the tumors in evading immune surveillance and impairing the efficiency of cancer immunotherapy. Dr. Lu is studying the relationship between EMT and TAMs using breast cancer as a model. This understanding could provide diagnostic benefits by uncovering markers useful for the prediction of prognosis and drug response. It will also facilitate the development of novel cancer therapies by identifying new targets and increasing the efficiency of anticancer immunotherapy. 

Read a more in-depth profile of Dr. Lu's research, which we featured in our April 2009 issue of Cancer ImmuNews, the official e-newsletter of the Cancer Research Institute. 

Carsten Mim, Ph.D.
Yale University
New Haven, Connecticut

"The main point of my project is to understand how a signal gets from the cell surface into the cell itself. A lot of people focus on the actual transducing elements, which cause cancer at the end, but my project mostly focuses on how these elements actually get from the outside of the cell to the inside. I aim to understand this and to help to get an actual structural sense of these elements so that we can see what they look like and how they actually achieve what they actually achieve."

Project Title: Structural studies on BAR-proteins and their role in membrane remodeling
Sponsor: Vinzenz M. Unger, Ph.D.

To fully comprehend intercellular communication and antigen recognition, it is important to characterize events at the cell membrane during signaling. Endocytosis, or cellular engulfment of pathogens, is a highly regulated process that requires proper cellular membrane function to carry out its important protective activity. Dr. Mim seeks to gain a mechanistic understanding of cell membrane remodeling and cytoskeletal rearrangements that are involved in endocytosis. To accomplish this, he will study the structure of BAR proteins with a well-documented function in endocytosis using state-of-the-art imaging technology. Dr. Mim’s work will make important contributions to our understanding of the interface between cellular membranes, the cellular skeleton, and molecules that bind to the membrane during the endocytotic process. This new understanding could lead to therapies that enhance endocytosis during infection and cancer. 

Ngozi Rosalin Monu, Ph.D.
New York University Medical Center
New York, New York

Project Title: Mechanisms of antigen presentation by dendritic cells
Sponsor: Eduardo S. Trombetta, Ph.D., PharmD

One key difference between cancer cells and pathogenic microbes is that cancer cells share many similarities with normal tissues because they arise from normal tissue. One of the major challenges to cancer immunotherapy then is to develop precise immunotherapies that optimally exploit the differences between tumors and healthy organs. Dr. Monu’s research focuses on dendritic cell (DC) antigen presentation and how DCs prime T-cell responses. Her preliminary results indicate that manipulating the "digestibility" of antigens—or, the ability of DC to take up and present antigens—affects DC capacity to prime CD4+ and CD8+ T-cells for an immune response. Investigations into these results may establish broadly applicable approaches to T-cell responses to antigens. Dr. Monu envisions that the outcomes may be then further pursued in more detailed immunotherapeutic trials, either as vaccine formulations or for the ex vivo stimulation of T cells for adoptive cancer immunotherapy.

Carles Ubeda Morant, D.V.M, Ph.D.
Memorial Sloan-Kettering Cancer Center
New York, New York

"My sponsor has been studying immunology for many years and is very inspirational to my work. Also, there are other postdocs in my lab that are studying different aspects of immunology. Each person has specialized knowledge in several areas of immunology, which I think is pretty good because then we can combine our knowledge. If I am interested in some experimental results in which I am not an expert, here I have a lot of people that are experts in different areas of immunology. This is a very good environment for studying and answering some questions in immunology."

Project Title: Innate immune effect on intestinal microbial diversity
Sponsor: Eric G. Pamer, M.D.

In the intestine, one of the mechanisms of innate immunity is provided by epithelial cells. These cells express several receptors that can sense different bacteria and respond by producing antimicrobial molecules. Our gut contains billions of bacteria, also called commensal flora, which help us to digest food, but also protect us from infection. Clinical studies have shown that administration of broad-spectrum antibiotics increase colonization and infection with highly antibiotic resistant bacteria such as carbapenemase-producing Klebsiella (KPC) or Vancomycin-resistant Enterococcus (VRE). Recently, studies in Dr. Morant’s lab showed that depletion of commensal flora with broad spectrum antibiotics caused a decrease in the expression of at least one of these antimicrobial molecules and  allowed VRE to colonize the gut and disseminate. However, how changes in the commensal flora, like the ones induced after treatment with antibiotics or cancer chemotherapy, affect the expression of antimicrobial molecules and vulnerability to intestinal pathogens remains incompletely defined. Dr. Morant’s goal is to correlate the intestinal expression of antimicrobial molecules with the composition and density of the commensal flora. He will manipulate the commensal flora with specific and selective antibiotics and test the impact of antimicrobial molecule expression with the ability of VRE and KPC to spread in the intestine. He also will investigate the impact of specific receptors expressed by intestinal epithelial cells on the diversity and density of commensal flora. It has been proposed that mutations of these receptors are responsible for Inflammatory Bowel Disease (IBD), such as Crohn’s disease, and that this is due to changes in the composition of the commensal flora. A better understanding of how commensal flora is sensed by specific receptors, and how epithelial cells respond to them accordingly, will provide us with novel information about the mechanisms of IBD and will help us to find a treatment for such diseases. 

Read Pukkila-Worley, M.D.
Massachusetts General Hospital
Boston, Massachusetts

"I am an infectious disease physician and so I’m very interested in understanding how pathogens cause disease. The most exciting part about this system is that we can genetically manipulate both the host and the pathogen so that we can understand how this process happens. And the ultimate goal is to learn enough to create meaningful therapies that can help prevent and treat these diseases in humans."

Project Title: A Caenorhabditis elegans and Cryptococus neoformans model of the host-pathogen interaction
Sponsor: Eleftherios Mylonakis, M.D., Ph.D.

The environmental interaction between free living roundworms and fungi is evolutionarily ancient and provides selection pressure for the development of fungal virulence and adaptive host responses. Dr. Pukkila-Worley is using a systemic infection by the human pathogen Cryptococcus neoformans in the roundworm Caenorhabditis elegans to study fungal disease development and the innate immune response to infection. Maintenance of the cell wall in C. neoformans is particularly important for efficient yeast survival in stressful environments, such as within C. elegans. The protein Kin1 was identified in a C. elegans-C. neoformans screen and was subsequently found to affect cell wall structure in a manner important for the host response to cryptococcal infection. Dr. Pukkila-Worley seeks to identify components of this uncharacterized cryptococcal pathway and study their function in C. neoformans disease development. The C. elegans-C. neoformans model of the host-pathogen interaction also permits a novel genomic study that will help to identify genes with differential expression following exposure members of the Cryptococcus genus. Rigorous controls will allow Dr. Pukkila-Worley to identify C. elegans genes that are affected in response to fungal infection. Since host responses to pathogen invasion are strongly conserved throughout evolution, findings will likely be of direct relevance to higher order hosts, like humans.

MacLean C. Sellars, Ph.D.

"Having this award and being supported by CRI, knowing that I have a project which many smart people think is going to contribute to cancer immunology, reinforces my interest in going full force into cancer immunology. The other thing that is important for me is that when you have a fellowship like this, that is over a number of years, you can take chances and try new and exciting things. The fact that I know that I should be supported for three years really gives me the opportunity to go in-depth into this research and will make me a better researcher."

Project Title: Defining the transcription factor networks that control Th17 specification.
Sponsor: Dan R. Littman, M.D., Ph.D.

Interleukin (IL)-17 producing Th17 cells are a specialized type of immune cell that are critical to immune responses against bacteria and fungi, especially in the gut. However, Th17 cells are also thought to be a major cause of autoimmune and inflammatory conditions, ranging from multiple sclerosis to inflammatory bowel disease (e.g. Crohn’s disease). In addition, the inflammatory activity of Th17 cells likely contributes to cancer, as Th17 cells are associated with advanced gastric tumors and Crohn’s disease increases the risk of colon cancer. Recent studies indicate that Th17 cells are capable of killing melanomas and prostate tumors in animals, suggesting that under the right conditions they could be harnessed to fight cancer. Thus to effectively prevent and treat many autoimmune diseases and cancers, methods to regulate Th17 cell differentiation and function must be developed. One obstacle to this is that we know very little about the cell intrinsic events that instruct an immature T cell to become a Th17 cell rather than another type of T helper cell. A crucial step in this process is the establishment of the "Th17 transcriptional program": that is, the activation of "Th17 cell" genes (and thus Th17 cell functions) and the repression of "non-Th17 cell" genes (and thus non-Th17 cell functions). Dr. Sellars will help to define how proteins called transcription factors cooperate to control the Th17 transcriptional program. He will also determine how this transcription factor network regulates critical inflammatory genes in Th17 cells. Understanding the interactions in this transcription factor network may allow scientists to modulate Th17 cell development and function. This will in turn be crucial to designing new therapies to combat inflammatory diseases and cancer by suppressing Th17 cells, as well as to attack certain types of cancer by activating Th17 cells. 

Kittichoat Tiyanont, Ph.D.
Brigham and Women's Hospital
Boston, Massachusetts

"During my final years in grad school I became more interested in immunology. It’s quite fascinating to me to learn the clever ways that our immune system uses to fight invading microorganisms and disease, and try to help keep our body in good balance and healthy. When I was finishing my Ph.D., I became a little more interested in the structural aspects of cancer immunology. I want to see if we can use this information to help us develop better, more efficient therapeutics to attack these diseases."

Project Title: Inhibitors of Notch signaling
Sponsor: Stephen C. Blacklow, M.D., Ph.D.  

Notch receptors are important proteins, normally found on the surfaces of cells, which help control the normal development and function of many organ systems in the human body. They act like tiny switches in response to signals communicated by nearby cells. When the Notch switch becomes frozen in the "on" position as a result of excess stimulation or mutation, it promotes the development of wide range of cancers, some of which affect the human immune system. A major cancer caused by Notch malfunction is T-cell acute lymphocytic leukemia or T-ALL. This cancer results from an uncontrolled increase of the group of the white blood cells, called T cells, and primarily targets children and adolescents. Almost 50 percent of T-ALL patients have mutations that lock the Notch switch in the "on" state. Current drugs used to interfere with the Notch mechanism are not specific and are poorly tolerated because of their side effects and toxicity. Therefore, Dr. Tiyanont aims to develop better therapeutics to target the activation switch of the Notch receptor. In order to visualize the "on" and "off" states of the Notch switch, he plans to determine the three-dimensional shape of the Notch regulatory region bound to antibodies that trap the receptor in its "on" and "off" positions. He also plans to screen and identify drug-like compounds that can keep Notch in its "off" state. The knowledge obtained from this project will help to develop novel treatment for T-ALL and other diseases associated with abnormal Notch signaling.