2002 — 2006 |
Sharpless, Norman Edward |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Melanoma in P16ink4a and P19arf Deficient Mice @ University of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Malignant melanoma (MM) is a singular challenge to modern oncology as it is one of the few human cancers in which the age-adjusted incidence has increased throughout the last decade, and it is notoriously refractory to therapy. The genetics of MM in humans suggest two general classes of lesions, receptor tyrosine kinase (RTK) activation, and deletion of the Ink4a/Arf locus at 9p21. Mice with melanocyte specific overexpression of H-Ras (a signaling intermediate of several RTKs) and Ink4a/Arf loss have been previously shown to develop melanoma with high penetrance and short latency. The Ink4a/Arf locus, conserved in mouse and humans, encodes two distinct proteins, p16INK4a and p19ARF, both of which regulate critical tumor suppressor pathways, and each may play a substantive role in human melanoma. Mutational analysis of human tumors and melanoma- prone kindreds clearly establish p16INK4a as a suppressor of melanoma formation, while the role of p19ARF in human tumors is less clear. Previous work in the mouse, however, shows p19ARF, through its regulation of p53, to be a critical tumor suppressor gene in a wide range of tissues. I propose to define genetically the relative importance of these two proteins in murine melanoma using two novel but as of yet uncharacterized strains of knockout mice. Using standard gene targeting techniques coupled with CRE recombinase mediated excision of the remnant selectable marker (PGK-Neo), I have produced two independent knockout (KO) strains with specific deletion of either p16INK4a or p19ARF. The work described in this proposal involves the characterization in vitro and in vivo of the p16INK4a specific KO, with a particular emphasis on melanocyte biology and melanoma formation. To c o mplement the in vivo analysis of the effect of p16INK4a loss on tumorigenesis, I will cross the p16INK4a KO to a p53-deficient background to look for increased tumor formation and change in tumor spectrum. Melanocyte growth from both p16INK4a and p19ARF null mice will be characterized in vitro, with particular emphasis on their relative transformability. Finally, I will attempt to develop a well-defined murine model of melanoma by crossing the p16INK4a and p19ARF specific KO mice to H-RAS overexpressing mice, in the hope of establishing which of the proteins, or perhaps both, is the critical mediator of melanoma susceptibility in mice in vivo. Such a model could then serve as a foundation for future studies of melanoma progression and therapy, and the results of this work will have implications for the treatment of human MM.
|
1 |
2004 — 2014 |
Sharpless, Norman Edward |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of P16ink4a in Mammalian Aging @ University of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): It has been suggested that the beneficial, anti-cancer functions of certain tumor suppressor mechanisms such as senescence may untowardly contribute to aging. In this model, genes that prevent cancer also compromise organismal fitness by limiting tissue regeneration and repair. Several lines of evidence suggest the tumor suppressor p16INK4a, a potent mediator of senescence, is a strong candidate for such a molecular effector of aging. First, mice lacking p16INK4a are tumor prone but otherwise developmentally normal; suggesting p16INK4a is majorin vivo function is to abrogate neoplasia. Additionally, we and others have shown that significant p16INK4a expression is not detected in young rodents and humans, yet is widely expressed in older mammals. As the only known function of p16INK4a is to induce cell cycle arrest, this increased p16 INK4a expression may play a significant role in the impaired tissue regeneration and stem cell function characteristic of aging. In support of this hypothesis, our recent data from the study of p16INK4a-/- animals demonstrates that mice lacking p16 INK4a possess a resistance to certain aging phenotypes. For example, p16INK4a-/- mice demonstrate attenuation of the physiologic age-associated decline of function of T-cells and pancreatic islets. In particular, this latter phenotype produces enhanced glucose tolerance and resistance to an islet cell toxin in adult p16INK4a -/- mice. In specific aim I, we propose to characterize rigorously the expression of p16INK4a in several tissue compartments in young and aged mice through real-time PCR, immunohistochemical and RNA in situ approaches. This data will inform specific aim II, in which we plan to study further several aging phenotypes (e.g. longevity, glucose tolerance, hematopoetic stem cell function, immune function, bone density, wound healing, graying, etc.) in mice lacking p 16INK4a compared to normal littermate controls. For these experiments, we have backcrossed p16INK4a deficient animals to a homogeneous and more tumor-resistant genetic background (C57Bl/6), allowing for the study of p16INK4a -/- mice at older ages. In specific aim III, we will seek to provide genetic confirmation that p16INK4a expression contributes to aging through the generation of low copy-number BAC transgenic mice that over-express p16INK4a under the control of its endogenous promoter. The aging phenotypes of these animals will be characterized in a way analogous to specific aim II. Through these approaches, we will examine the in vivo tissue and age-specific effects of p16INK4a expression, and delineate its contribution to a variety of mammalian aging phenotypes.
|
1 |
2007 — 2011 |
Sharpless, Norman E |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Murine &Human in Vivo Models of Melanoma Formation @ Univ of North Carolina Chapel Hill
Project 3 utilizes human and murine model systems to address the links between signature genetic events in melanoma progression (p16INK4a loss and N-RAS/B-RAF mutation) and the DMAdamage response in melanocytes. This project combines analyses of novel murine models of melanoma with a comprehensive molecular and immunohistochemical study of a large, clinically annotated human melanoma database. In specific aim 1, we combine two different RAS alleles, conditionally inactivatable p53 and p16INK4a alleles, and an inducible, melanocyte-specific CRE allele to produce new murine models of melanoma that are highly faithful to the human genetics of this tumor. In these models, all oncogenic events are restricted to the melanocytic compartment, and include somatic inactivation of p16/p53 or somatic activation of K-RAS, Two of the alleles (Tyr-CRE-ER-T and conditional p16INK4a) are newly characterized and unpublished. In specific aim 2, we combine these novel murine models of melanoma with neonatal UV-B exposure to facilitate in vivo melanomagenesis. Specific aim 2 also includes a detailed immunohistochemical analysis of the kinetics of the expression of markers of the DNA damage response and senescence with or without UV- B treatment in the setting of RAS activation, p16INK4a loss and/or p53 loss. This specific aim employs a similar approach to analyze human dermal reconstructs in immunodeficient mice with and without UV exposure using reagents supplied from projects 1 and 2. In specific aim 3, we extend our analysis of human primary formalin-fixed and paraffin-embedded melanocytic lesions to identify the relationship among RAS/RAF/p16INK4a mutation, ERK MAP kinase activation, senescence and the DNA damage response in the progression from nevus to metastatic tumor. This specific aim includes a comprehensive immunohistochemical analysis of several markers of the DNA damage response and senescence, as well as a mutational analysis of N-RAS, B-RAF and p16INK4a. This specific aim is powered (250 melanocytic lesions from nevus to metaststic melanoma) to account for molecular heterogeneity in primary tumors but still uncover biologically significant relationships among these signature genetic events, the DNA damage response and melanoma progression. We expect this work will further our basic understanding of human melanoma progression as well as identify new clinjcal predictors of disease progression and outcome.
|
1 |
2011 — 2016 |
Sharpless, Norman E |
K12Activity Code Description: For support to a newly trained clinician appointed by an institution for development of independent research skills and experience in a fundamental science within the framework of an interdisciplinary research and development program. |
Unc Oncology Clinical Translational Research Training Program @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): In this application, the University of North Carolina at Chapel Hill (UNC) Divisions of Adult and Pediatric Hematology/Oncology, the Department of Radiation Oncology, the UNC Lineberger Comprehensive Cancer Center (LCCC) and the Division of Gastroenterology and Hepatology propose to renew funding for the UNC Oncology Clinical/ Translational Research Training Program (OCT-RTP). All four of the components will contribute mentors and research resources to the proposed training program, and all components except UNC-LCCC will contribute scholars. OCT-RTP will admit two scholars per year. The PI, Dr. Norman Sharpless, is Professor of Medicine and Genetics, a member of the Hematology/Oncology division, and is the LCCC Associate Director for Translational Research. Dr. Sharpless has extensive experience in cancer research in the areas of murine models, novel therapeutics, Phase I trials and commercialization of intellectual property. Dr Thomas Stinchcombe, Associate Professor and Hematology/Oncology fellowship program director, has newly assumed the role of Program Director. The program's objectives are to establish a highly motivated and rigorously trained cadre of physician clinical researchers who are competitive in seeking research support and who will become successful, independent patient-oriented cancer investigators. Training resources that will be available for the OCT-RTP include: the Lineberger Comprehensive Cancer Center, the North Carolina Cancer Hospital, the UNC School of Medicine K30 Clinical Research Curriculum and the UNC Program on Ethnicity Culture and Health Outcomes. The goals of the OCT-RTP are to increase the quality and quantity of patient-oriented research, including all phases of clinical research and particularly that involving a translational component. The foundation of the proposed training program will be the participation of highly qualified basic science and clinical mentors assigned to each scholar with mentoring activities coordinated by a mentor integration panel. An internal advisory committee that includes senior faculty from each of the four components will select and monitor the progress of scholars, while an external advisory committee will review the program annually. Since its inception, the OCT-RTP has enrolled six Scholars who records are detailed in the progress report. Our mentorship panel has evolved as some faculty members have left and new faculty have been recruited. One external advisory board member has rotated off and been replaced by A William Blackstock MD. Facilities and resources for the program have evolved to insure even stronger support for this program since its initial funding.
|
0.988 |
2012 — 2016 |
Sharpless, Norman E Wong, Kwok Kin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
In Vivo Murine Models of Metastasis For Therapeutic Testing @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Metastasis is the most lethal feature of human cancers, but the molecular processes that govern metastatic spread are not well understood. One of the major obstacles in this crucial area of cancer research is the lack of faithful genetic de novo cancer model that results in regional and distant metastases. Xenograft models based on cancer cell lines cannot fully recapitulate the intricate interplay in the complex microenvironment of stromal and cancer cells. In addition, the necessity of using immuno-compromised mice for xenograft transplants precludes elucidation of the likely critical interaction between the primary cancer and the immune system in cancer progression. The Sharpless and Wong laboratories have recently generated de novo mouse lung cancer and melanoma models driven by activated oncogenic Kras and concurrent tumor suppressor Lkb1 loss that has a >60% penetrance of regional and distant metastases. We demonstrated that loss of Lkb1 function is crucial in the promotion of cancer invasion and metastasis and dissected the signaling pathways that are crucial to this process. We have now further improved this genetic model by incorporating a p53 mutant allele into the Lkb1/Kras mutant mice. Compound mutant mice with Kras driven lung cancer or melanoma that have concurrent Lkb1 and p53 loss have distant hematogenous metastases (100% penetrance), thus demonstrating distinct and separate tumor suppressor functions for Lkb1 and p53. Distant organs harboring metastases include lymph nodes, spleen, kidney, liver, bone and brain, recapitulating the full spectrum of metastatic sites observed in association with human lung cancers and melanoma. With this proposal, we wish to further characterize and refine these metastatic cancer models and incorporate in vivo non-invasive imaging markers (luciferase and enhanced green fluorescent protein) into these compound mutant mice to permit tracking of the location of micro- metastasis non-invasively using the latest in vivo non-invasive imaging techniques. These models will then be used to test targeted therapeutics that can kill these cancers and inhibit metastatic spread. With collaborators in the UNC Center for Integrative Chemical Biology and Drug Discovery, we will also develop small molecule tool compounds that will enhance metastatic behavior by inhibiting Lkb1 activity. These studies will yield important insights into primary and acquired resistance of these cancers to the various treatments to help facilitate better treatment strategies.
|
0.988 |
2014 |
Sharpless, Norman E |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Cigarette Warning Labels: Research Synthesis and Impact On Smoking Behavior @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): Tobacco use is the leading preventable cause of death in the United States. Legislation empowers the FDA to regulate the manufacture, marketing, and distribution of tobacco products, and requires new warnings on cigarette packs to communicate the risks of smoking. In this supplement to an existing P30 research grant, we seek to synthesize the literature and expand the ecological validity of the controlled laboratory experiments examining the warnings' impacts. To accomplish this, we will conduct a meta-analysis of the existing experimental literature on cigarette pack warnings (Aim 1). In addition, we will conduct a large-scale RCT in which we label cigarette packs that smokers use every day with text or graphic warnings to examine the impact on smoking behavior (Aim 2). This new approach combines the strengths of laboratory experiments and field studies in evaluating warnings to achieve strong generalizability and internal validity. Participants will be 2,250 adult smokers ages 18-65 from North Carolina and California. The proposed studies will additionally examine whether the impact of cigarette pack warnings on smoking behavior differs for low-income versus higher-income smokers.
|
0.988 |
2014 — 2015 |
Sharpless, Norman E |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Cancer Center Core Support Grant @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): The UNC Lineberger Comprehensive Cancer Center requests renewal of its National Cancer Institute (NCI) Center Core Support Grant (CCSG) for Years 36-40. Over the past CCSG cycle, the Center has grown in funding, membership, facilities and productivity. NCI funding has increased from $45M to $64M and total cancer-related extramural funding rose from $150M to $220M yearly. The Center's 295 members (up from 235) span the basic, clinical and population sciences; all areas have seen an increase in faculty funding and research productivity. A tradition of interaction among disciplines, fostered by a proactive matrix cancer center at a highly-regarded public university provides an outstanding venue for integrating forward-looking interdisciplinary cancer research. Cancer center members hold 34 multi-investigator program grants and 26 training grants. Faculty additions in the physical and pharmaceutical sciences created new opportunities in drug discovery and delivery. Substantial investment in faculty, equipment and bioinformatics dramatically expanded our cancer genetics research effort; UNC was again selected as a site of The Cancer Genome Atlas. Thirty-eight clinical researchers were recruited, strengthening our multidisciplinary cancer care and research teams. Our publication rate in top clinical oncology journals increased by four-fold. Accruals to therapeutic trials, including investigator-initiated trials, more than doubled to 850 and 434 respectively. Our population scientists initiated new endeavors in cancer communication, dissemination, survivorship, and molecular epidemiology. Groundbreaking observations in breast cancer minority disparity research have emerged from the Center's epidemiology and clinical programs. The formation of transdisciplinary teams stimulates progress toward implementing the Center's and NCI's strategic objectives. Major events include opening the North Carolina Cancer Hospital, a new clinical structure that nearly triples patient care space, and new basic science buildings. The Center's significant and continued expansion, including 20 faculty recruitments now in progress, is driven by remarkable institutional support including direct support for cancer research from the state legislature. The UNC Lineberger requests funding for nine scientific programs, 20 shared resources, two staff investigators, and for leadership, planning and evaluation, administration, and developmental research. The increased CCSG budget will support technological and operational expansion of cores and faculty recruitment in the basic, translational, clinical, and population sciences. With these funds, a talented faculty integrated through cancer center mechanisms will make advances in the prevention, early detection, and treatment of cancer in North Carolina and the nation.
|
0.988 |
2014 — 2017 |
Kim, William Y. Sharpless, Norman E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
(Pqd5) Predicting Anti-Cancer Efficacy Through Tumor Profiling @ Univ of North Carolina Chapel Hill
DESCRIPTION (provided by applicant): An experimental issue hampering our ability to understand the therapeutic refractoriness of melanoma and other human cancers has been a lack of validated and faithful models for efficacy testing. Historically, promising anti-cancer compounds have been tested for preclinical efficacy in vitro and then in mouse 'xenograft' models prior to human testing. In xenograft systems, human cancer cell lines are grown under the skin of immunocompromised mice, and then xenograft-bearing animals are treated with intended therapies. These models are not physiologic, and have a poor track record of predicting therapeutic success. Recent changes have made it possible to test would-be cancer therapies in genetically engineered murine models (GEMMs) of cancer, which provide several advantages to xenograft models. Studies conducted in the UNC Mouse Phase I Unit (MP1U) have shown that testing in GEMMs can better replicate human pharmacokinetics and efficacy prediction, and results from these studies can provide timely data for clinical trials. In this proposal we will study the therapeutic efficacy of several novel anti-cancer drugs slated for human trials in patients with melanoma, using our credentialed GEMMs. We will chose for testing, regimens that are currently being testing in human clinical trials, including anti-immune system targeted therapeutics, which are not able to be tested in xenograft models. Through the use of several well selected and validated GEM models of melanoma harboring different 'driver' genetics, we will identify somatic events associated with response to specific therapeutic agents. Responding and refractory tumors will be tested using genomic analysis of RNA and DNA to provide a further understanding of therapeutic response. We will then compare the predicted efficacy of these agents in GEMMs to results from 12 ongoing or planned human clinical trials, to empirically determine the ability of these murine 'co-clinical' trials to predit efficacy in human patients with melanoma.
|
0.988 |
2015 — 2017 |
Sharpless, Norman E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
The Role of P16ink4 in Mammalian Aging @ Univ of North Carolina Chapel Hill
? DESCRIPTION (provided by applicant): Work from our lab and others has established that expression of the p16INK4a tumor suppressor mechanism plays a critical role in mammalian aging. The expression of p16INK4a in the setting of certain cellular stresses and tissue pathology clearly plays a beneficial role in limiting important age-associated conditions associated with excess proliferation such as cancer and atherosclerosis. The activation of p16INK4a throughout life, however, is associated with the accumulation of cells that have undergone senescence, a permanent form of growth arrest, which is also associated with the elaboration of pathogenic, pro-inflammatory cytokines. Therefore, the beneficial cancer-preventing expression of p16INK4a compromises some aspects of organismal fitness with aging by limiting the regeneration and repair of certain self-renewing compartments. During the prior ten years of this proposal, our group, with collaborators, has provided significant evidence for this model. In 2004, we showed that p16INK4a is a faithful biomarker of mammalian aging. In 2006, we showed that p16INK4a-deficient animals demonstrate a resistance to some aging phenotypes in pancreatic ß-cells, neural stem cells and hematopoietic stem cells, while transgenic animals expressing excess p16INK4a demonstrate an accelerated functional decline with aging in these compartments. In 2009, we developed an approach to measuring p16INK4a expression with aging in humans, and employed this assay to show the age-promoting effects of tobacco use, physical inactivity, chronic HIV infection, and cytotoxic chemotherapy in people. We also identified a highly common polymorphism in humans that strongly affects p16INK4a expression and is associated with atherosclerotic disease. In 2011, we showed an important effect of p16INK4a expression on the physiology of aging B- vs. T-lymphocytes, and provided an explanation for how p16INK4a expression limits atherosclerotic disease. Finally, in 2013, we reported in Cell that p16INK4a expression with aging does not predict malignancy risk in mice, and showed that locus activation results in vivo from cell-non-autonomous mechanisms. In the renewal of this proposal, we seek to extend these prior observations to further enhance our understanding of how p16INK4a influences mammalian aging. In specific aim I, we employ novel reporter and p16CRE alleles to study whether p16INK4a expressing cells are always senescent in vivo. In specific aim II, we will examine the effects of depleting p16INK4a-expressing cells on tumorigenesis and aging using a genetic or immune approach. In specific aim III, we will examine the effects of alterations in the cellular epigenetic state on expression f p16INK4a and somatic stem cell function with aging. Through these approaches, we will further delineate the contribution of p16INK4a expression and cellular senescence to mammalian aging.
|
0.988 |
2016 — 2017 |
Sharpless, Norman E |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Cancer Center Support Grant @ Univ of North Carolina Chapel Hill
? DESCRIPTION (provided by applicant): The overarching goals of the Cancer Cell Biology Program are: (i) to understand, at the molecular and cellular levels, mechanisms underlying tumor initiation, progression, metastasis and resistance to therapeutic treatment, and (ii) to identify and validate new targets for cancer therapy. Insight derived from these studies, when integrated with research and development from other programs, will provide targets and guidance for the development of strategies for therapeutic intervention of cancer. Toward these two goals, the Program faculty investigates various aspects of cancer cell biology, including growth factors and receptors; angiogenesis and vascular biology; apoptosis; cell cycle regulation; chromatin biochemistry and transcriptional regulation; cell microstructure and function; DNA replication and repair; metabolism; regulatory RNA; and signal transduction. Led by two co-leaders with complementary expertise, Yue Xiong and James Bear, the program organizes these different areas into four major research themes: (1) Cell Cycle, (2) Cell Signaling, (3) Cell Movement and Organization, and (4) Epigenetics and Chromatin Biology. The major emphasis of the Program is to foster integrated research that spans these inter-related themes, enhancing the research and translational capabilities of program investigators through the establishment, expansion and utilization of appropriate core facilities, and promoting interactions with investigators from other LCCC basic, clinical and population sciences programs. The Cancer Cell Biology Program consists of 45 members who are associated with 7 basic science and 4 clinical departments at UNC-Chapel Hill. During the last funding period, program members have published 644 cancer-related articles (30% collaborative). In 2014, our program members held 101 grants and $27.3M (total cost) in annual extramural funding, including 24 grants and $5.8M (total costs) from the NCI.
|
0.988 |
2016 — 2017 |
Sharpless, Norman E |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Developmental Funds (Core 002) @ Univ of North Carolina Chapel Hill
ABSTRACT Developmental Funds support the Lineberger Comprehensive Cancer Center (LCCC) mission directly through the provision of resources and indirectly by leveraging institutional and philanthropic assets. Collectively, these resources expand and enhance cancer research across LCCC in the basic, clinical, population and translational sciences. During the last five years, these funds have been used to make key recruitments, to launch innovative ideas, and to make technical advances within our Shared Resources. Through these expenditures, the LCCC bolstered interdisciplinary and translational research efforts. By objective criteria, e.g. extramural grants funded, and junior faculty garnering national awards, our recruitment and retention efforts have been a stunning success. Our range of pilot project awards have initiated new research across the clinical, population, translational, and basic spectrum, again yielding success in seeding extramural grant funding, broad collaborations, and cancer related publications. The funds provided for Shared Resources have developed new techniques, particularly those translating fundamental discoveries into clinical applications. A decision by NCI three years into this cycle allowed expenditures of Developmental Funds for projects outside the borders of the United States. We were please to utilize this capability to fund pilot projects in our initiatives in sub-Saharan Africa that have led to significant NCI grant funding. While we retained the capability of using Developmental Funds for bridge funding, we did not utilize any Development Funds for this in the last cycle. As has been the case over the last decade, Developmental Funds have been key in the growth of the Center's scientific and clinical impact. LCCC requests $50,000 increase in this category, to $700,000 per year, in this renewal application, justified by past success and needs for a growing Center. We will continue to use these funds in recruitment, pilot projects, and Shared Resource development and retain the potential for interim (bridge) funding.
|
0.988 |
2016 — 2017 |
Elam, Amanda (co-PI) [⬀] Mitin, Natalia Muss, Hyman Sharpless, Norman E |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Biomarkers of Molecular Age to Predict the Toxicity of Cancer Chemotherapy @ Univ of North Carolina Chapel Hill
? DESCRIPTION (provided by applicant): Although the age-adjusted survival of cancer patients has improved over the last decade, with US population aging, there will be a sharp rise in total numbers of new cancer diagnoses and cancer morbidity through 2050. The vast majority of these new cases will be in patients over the age of 65. Treatment of cancer in the elderly is complicated by the increased risk of treatment-related toxicities, which are currently difficult to predict due to the lack of reliable, clinical use models and chronological age is not an accurate predictor of toxicity risks. Development of a molecular marker of aging would help clinicians to predict a patients' risk of treatment- related toxicity with higher certainty. Work in the Sharples lab has revealed that the cellular senescent factor, p16INK4a, can be used as a faithful biomarker of molecular age and physiologic reserve in humans. Importantly, data from our recent clinical trial demonstrate that p16INK4a expression correlates with the occurrence of life- threatening grade 3/4 toxicities and hospital admission in patients' ?50 years of age with early stage breast cancer receiving combination docetaxel and cyclophosphamide therapy (TC). Therefore, we propose to develop and validate the use of p16INK4a biomarker as a predictor of TC-induced toxicities and related hospitalizations to guide choice of chemotherapy regimen (drugs and dosage) and to alert clinicians to consider appropriate prevention strategies. Accurate prediction of patients at risk (or lack of risk) of adverse events such as neutropenic fever could result in substantial healthcare cost savings by targeting growth factor treatment to those at highest risk of myelosuppression. Additionally, we believe that our p16INK4a assay could be incorporated into existing oncological practice without the need for extensive clinical trial validation and physician education, immediately impacting patient care. Completion of the work proposed here, will allow us to develop analytical performance data necessary for CLIA approval and solidify evidence of clinical utility for toxicity risk assessment in breast cancer patients necessary for commercialization and market adoption.
|
0.988 |
2016 — 2017 |
Sharpless, Norman E |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Planning and Evaluation (Core 001) @ Univ of North Carolina Chapel Hill
ABSTRACT The LCCC internal and external advisory groups provided invaluable guidance in planning and evaluation of all the major initiatives. The new Director continued to expand the decision-making and advisory groups to include: · The Senior Leadership Team, which is composed of the Director and (8) Associate Directors,meets weekly to evaluate progress in strategic LCCC initiatives. · The Program Planning Committee, which meets bi-weekly to evaluate progress of all important initiatives and includes institutional and Research Program Leaders, plus the Senior Leadership Team. · The Internal Advisory Board, which is comprised of institutional leaders including the Chancellor; the Deans of the schools of Medicine, Pharmacy, and Public Health; and external advisors, and which meets with the Director at least quarterly. · The Scientific Advisory Board (SAB), which is comprised of expert external advisors, and which was expanded with the addition of 7 new members in 2014 to provide additional expertise in specific areas such as cancer genomics, tumor immunology, administration, patient advocacy and biostatistics. There are now 16 members on the SAB with complementary expertise in basic, clinical, translational, and population sciences and administration. The SAB meets annually or more often, at the UNC LCCC. With careful planning and critical input from advisory groups, the Director initiated a new 5 year strategic planning process, reorganized Center Research Program membership, Shared Resource Leadership, and created working groups and committees to continue improving oversight and governance. These coordinated teams of advisors provide critical advice and guidance, both annually in the fall and ad-hoc as required, ensuring that LCCC most effectively set priorities and pursues objectives that promote basic, clinical, prevention and translational research at the Center.
|
0.988 |
2016 — 2017 |
Sharpless, Norman E |
P30Activity Code Description: To support shared resources and facilities for categorical research by a number of investigators from different disciplines who provide a multidisciplinary approach to a joint research effort or from the same discipline who focus on a common research problem. The core grant is integrated with the center's component projects or program projects, though funded independently from them. This support, by providing more accessible resources, is expected to assure a greater productivity than from the separate projects and program projects. |
Administration (Admin Core) @ Univ of North Carolina Chapel Hill
ABSTRACT The Lineberger Comprehensive Cancer Center (LCCC) Administrative Core includes the Senior Leadership Team (SLT) and Center Administraion. The SLT establishes the overall strategic direction and research mission for LCCC and center Adminstration operationalizes this vision. The SLT includes the Director and Associate Directors of Clinical; Basic; Population Science; Translational Research; Education and Training; and Administration that meet weekly to consider all matters impacting LCCC. Center Administration provides infrastructure to promote the cancer research activities of its 300 members, with a particular focus on facilitating transdisciplinary and translational cancer research. The Administration supports the Director, Senior Leaders, Program Leaders, Shared Resources Directors and LCCC Members in carrying out the Center mission through effective strategic planning and evaluation, operational management, and centralized resources. LCCC Administration (72 FTE/$14M) oversees the largest research operation at the University including a $156M budget (FY14) including grant and fiscal management and other administrative services for 134 faculty members and 15 Shared Resources. Many of these reside in center-controlled space (153,000 nsf) which the administrative staff also manages. The administrative staff is responsible for Human Resources and administering partial salary support for over 1200 FTEs. Administrative responsibilities include: management of Center finances, personnel, grants and contracts, purchasing, and philanthropy; provide administrative and financial oversight LCCC shared resources; oversee space utilization and common equipment; facilitate recruitment efforts; manage center membership; and coordinate and facilitate pilot award programs and Center planning and evaluation activities (leadership and programmatic meetings, seminars, annual symposia and retreats, and internal and external board meetings). The administrative staff also supports communication to the 300 LCCC members and the University as a whole as well as educating citizens and legislators regarding Center activities across the state. The Administrative Core monitors and reports on member accomplishments, funding, cancer-related activity to the membership committee and SLT as a part of the annual membership evaluation. The conduct of surveys and evaluation for planning is also a function of the central administrative staff. The Administrative Core functions are overseen by two leaders with 30 and 15 years' experience at UNC Lineberger and a dynamic new Associate Director for Administration. For Year 40, the Center requests a committed level of $737,324 to support 6.45 FTEs plus costs for supplies, travel, and other operational expenses to support the Administrative Core. The center Administration portion ($455,089 and 5.2FTE) represents 9% of the overall CCSG budget request and 3% of the Administration operating budget ($14M). The requested budget for Administration is equivalent to the 2010 budget despite increased Center funding, space, and personnel.
|
0.988 |