| Program Leader: D. Chakravarti, PhD |
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Program Co-Leader: C. Horvath, PhD |
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The Hormone Action and Signal Transduction (HAST) in Cancer Program of the Robert H. Lurie Comprehensive Cancer Center (RHLCCC) is a basic research program that includes both basic and clinical investigators who are exploring the mechanisms by which normal and transformed cells respond to hormones and growth factors. The program leader is Debabrata (Debu) Chakravarti, PhD, an expert in transcriptional regulation and nuclear hormone signaling who focuses on the mechanisms of physiological control of nuclear hormone receptor signaling through co-regulators and chromatin modifications and abnormalities of these mechanisms in cancer. This is an interdepartmental program composed of 19 faculty from 8 departments and 2 schools. Between January 2001 and September 2006 there have been 359 cancer-relevant publications from the current program members. Fifty-two (14%) of these publications represent intra-programmatic collaborations and 83 (23%) represent inter-programmatic collaborations. Total current cancer-relevant peer-reviewed funding is $4,551,322 (direct) with $1,896,639 (direct) from NCI and $2,654,683 (direct) from other peer-reviewed sources. The program goals are focused on how hormones and growth regulatory factors interact with their cognate receptors, mediate downstream signal transduction events resulting in changes to the cell physiology, and how these events are altered in a cancer cell. This is achieved by a coordinated and focused effort of the program investigators toward a unified understanding of the context in which normal cells become neoplastic and the mechanisms that perpetuate the aberrant cell phenotype over time. A basic understanding of the mechanism of abnormal cancer cell signaling can be utilized to specifically target tumors for therapy and enhance our knowledge of the efficacy or resistance to anticancer therapeutics as well as development of new therapeutics. The previous critique of this program noted excellent to outstanding merit, but stressed a need for some more cancer relevant research. Evolution of cancer-related research in member laboratories, recruitment of new faculty including the current program co-leaders, the inclusion of cancer investigators from other basic science and clinical programs, and the elimination of scientists not directly engaged in cancer research has now dramatically strengthened the cancer focus of this program while continuing and even surpassing its already established strengths in basic science. Program members are highly interactive and collaborative, both intra- and inter-programmatically, on a spectrum of projects including translational initiatives.
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Hormones and growth factors act as key extracellular regulators of basic cell biological processes such as proliferation, survival, apoptosis, differentiation and migration. Control of these processes is essential for normal development and maintenance of tissue homeostasis. Hormones exert their effects by interacting with specific receptor proteins and receptor binding is the first step in the molecular cascade of events leading to biological actions. It is also clear now that aberrant cellular activation by altered expression or activity of receptors or their ligands is a frequent oncogenic strategy. Hormone-receptor interactions that are associated with human cancers are under intense investigation by members of the HAST Program. Interactions of peptide hormones with cell surface receptors (Band, Clevenger, Lupu, Mayo, Woodruff,) and steroid hormones with nuclear and non-nuclear receptors (Budunova, Bulun, Chakravarti, Jameson, Kim, Rodriguez, Rosen) are being investigated with a focus on elucidating the mechanisms by which ligands and their receptors interact to potentiate disease states. Better definition of the role of ligand-receptor interactions and subsequent participation of coregulatory proteins in the oncogenic process also validates these for targeted anticancer therapies, another area of pursuit by the group. In addition, a better definition of the role of ligand-receptor interactions in tumor progression is also being pursued in the context of chemoprevention (Bulun, Budunova, Kim, Rodriguez).
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Ligand-receptor interactions trigger a number of cytoplasmic as well as nuclear signaling pathways that directly control normal cellular functions, including cell proliferation and differentiation, cell cycle progression, apoptosis and cell migration. Consequently, aberrant signaling due to altered expression and/or mutational activation or inactivation of signaling proteins has emerged as key element of oncogenic transformation. The role of crucial signaling pathways such as MAPK, JNK/p38, PI 3-kinase and small G-proteins in normal and neoplastic signaling is being investigated by members of the program with a particular focus on hormonal regulation of developmental processes (Budunova, Clevenger, Jameson, Linzer, Mayo, Woodruff), signaling by protein kinases involved in solid tumor and leukemia/lymphoma pathogenesis (Band, Bentram, Freyman, Lupu, Mayo, Platanias, Pelling, Rosen, Stein, Woodruff), transcriptional and non-genomic mechanisms of nuclear hormone receptor function and its control by co-activators and co-repressors, and chromatin associated proteins (Budunova, Bulun, Chakravarti, Clevenger, Jameson, Mayo, Rodriguez, Rosen, Woodruff), in vivo genetic model systems to investigate tumor-relevant signaling mechanisms (Band, Budunova, Bulun, Mayo, Stein, Iwasaki, Woodruff,) and signaling pathways downstream of mutant signaling receptors or intermediates (Band, Jameson, Platanias, Rosen). By targeting the signal transduction pathways that are causally linked to abnormal growth, differentiation, migration and survival of a tumor cell, the oncogenic process can be halted, leading to the elimination of the tumor. Finally, in vitro and in vivo models to screen for inhibitors of specific oncogenic signaling pathways as well as to identify newer signaling components through genome-scale strategies are being developed by the program investigators (Band, Bulun, Chakravarti, Jameson, Pelling, Platanias, Rosen, Woodruff). Collectively, these studies will help elucidate how specific ligands regulate cellular responses, elucidate how aberrations of signaling pathways may play a vital role in the pathogenesis of cancer and other human diseases, identify signaling mechanisms that can be targeted in neoplastic cells, and help develop model systems for high-throughput screening for new inhibitors of signaling pathways for therapeutics development.
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The levels and activities of ligands and receptors as well as their signaling intermediates are tightly regulated to ensure physiological responses. Alterations in these regulatory mechanisms can thereby deregulate cellular responses to hormone and growth factors, promoting oncogenic behavior. Members of the program are investigating the role of phosphorylation/dephosphorylation, ubiquitination and other post-translational modifications (Band, Bentram, Budunova, Bulun, Chakravarti, Clevenger, Jameson, Linzer, Lupu, Mayo, Pelling, Platanias, Rodriguez, Rosen, Stein, Woodruff), DNA- and histone ( chromatin)-based modifications such as methylation and acetylation (Bulun, Chakravarti, Clevenger, Jameson, Linzer, Lupu, Mayo, Platanias, Rosen, Woodruff) and other mechanisms that control the intensity and duration as well as the nature of signals downstream of productive ligand-receptor interactions, and how these control mechanisms are altered in neoplastic cells. In addition, subcellular trafficking events that control the proper localization of receptors and signaling proteins as well as their post-activation degradation through endocytic or proteasomal pathways are under active investigation (Band, Budunova, Bulun, Clevenger, Jameson, Linzer, Lupu, Mayo, Pelling, Platanias, Rosen, Stein, Woodruff). Insights derived from the identification of cellular pathways that endow a normal cell with the ability to process exogenous information into coordinated responses will permit a more comprehensive understanding of how these responses are altered in tumor cells. Importantly, these insights should help the investigators in designing translational efforts to target regulatory components of signaling pathways and also provide extended molecular signatures for molecular diagnosis and prediction of therapeutic responses.
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Targeted anticancer therapy is designed to interrupt abnormal signaling in cancer cells. It is now clear that additional biochemical pathways are impacted by these agents and often these can play critical roles in the sensitivity or resistance of cancer cells to targeted therapies. Recent success with hormonal and chemoprevention strategies against cancer has also highlighted the need to investigate the signaling mechanisms by which prevention strategies work so that safer agents can be found and potential side effects associated with chemoprevention can be avoided. Finally, elucidation of mechanisms by which anticancer agents impact germ cells has emerged as a key issue for younger women and children with cancer to preserve their fertility. Members of the HAST program are actively pursuing these themes. Mechanism of action of hormonal or chemical preventive agents (Bentram, Bulun, Kim, Lupu, Pelling, Rodriguez, Rosen), molecular basis of the activity of targeted therapeutic agents against cancer cells (Band, Bulun, Lupu, Platanias, Rosen, Woodruff) and strategies to preserve fertility based on an understanding of signal transduction pathways in ovarian development coupled with an understanding of anticancer agent impact on signaling pathways (Rodriguez, Mayo, Woodruff) are being pursued by the group. In addition, members of the program (Band, Pelling, Platanias, Rodriguez, Rosen, Woodruff) are involved in collaborative efforts with other programs of the Cancer Center to translate the conceptual knowledge in signal transduction into novel therapeutics and detection strategies using Nanotechnology solutions through the CCNE initiative of the NCI recently awarded to the Cancer Center. These new initiatives have been critically facilitated by the strong interactions provided by the HAST program.
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