1991 — 2007 |
Eastman, Alan R |
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. R55Activity Code Description: Undocumented code - click on the grant title for more information. |
Cell Death Induced by Anticancer Agents
DESCRIPTION: The goal of this proposal is to characterize the pathway of apoptosis. The approach of this proposal is to focus on the end result of apoptotic reactions, namely the activation of DNase-II and to define the potential effect of proteases and phosphatases, on the pathways of apoptosis. Apoptosis is a form of cell death induced as a consequence of many types of physiological, pathological, and cytotoxic insults. Results from this laboratory and others have shown that products of oncogenes and tumor suppressor genes can influence the apoptotic process and alter the outcome of therapeutic strategies. There is a major gap in the understanding of events occurring between the interaction with the primary cytotoxic targets and the eventual death of the cells. The approach of this laboratory is to identify events that occur in a dying cell and then to work back to the signals that regulate these events. The applicant focuses on DNA digestion as a frequent event occurring in a dying cell. Identification of the endonucleases involved will facilitate understanding of their activation by intracellular signals. Deoxyribonuclease-II (DNase II) has been identified as one of the endonucleases that potentially may be involved in apoptosis. DNase II cDNA has been cloned and antibody has been raised. The applicant proposes to perform studies in which DNase II will be either overexpressed or deleted in order to establish its role in apoptosis. Several isoforms of DNase II (30/31-, 26-, and 21-kDa isoforms) have been detected during apoptosis. The catalytic activity of these forms will be determined. The significance of endonuclease processing will be determined by genetic manipulation. The applicant proposes that intracellular acidification occurring during apoptosis may contribute to the apoptotic reaction. The acidification has been attributed to an alteration in the set-point of the Na+/H+ anti- port. The set-point is regulated by phosphorylation, suggesting protein kinases and phosphatases as possible regulators of apoptosis. Experiments have shown that inhibition of phosphorylation can protect cells from apoptosis. The applicant proposes to examine the regulation of protein phosphatase PP1, which has been implicated in the cascade of apoptosis. Proteases have also been implicated as regulators of apoptosis, consistent with the cleavage of DNase II. Markers of protease action (poly-ADP-ribose synthetase, terminin, and DNase II) and of phosphatase action (e.g. dephosphorylation of Rb) will be used to study this pathway. Inhibitors will be applied to each of the steps which will facilitate analysis of the temporal relationship between phosphatases, proteases, and endonucleases. Cell lines expressing bc1-2 will be used to locate steps that are modified by its action. Finally, the applicant will attempt to reconstitute apoptosis in vitro to enable the potential regulators of endonucleases and apoptosis to be determined.
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0.958 |
1994 — 2006 |
Eastman, Alan R |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Cancer Biology and Carcinogenesis
DESCRIPTION (provided by applicant): This application requests continued support for a training program in Cancer Biology that was begun in 1990. The program is designed to train predoctoral and postdoctoral fellows in the fundamentals of cancer research by participation in didactic courses, seminars and discussion groups, and in the performance of laboratory-based cancer research. The training program is integrated into the research programs of the Norris Cotton Cancer Center, thereby enhancing exposure to many facets of the disease. This is a multidisciplinary Training Program with 16 faculty draw n from six academic departments: Anesthesiology, Biochemistry, Engineering, Medicine, Microbiology, and Pharmacology and Toxicology. These faculty have an excellent training record, and are highly interactive both in their individual research efforts and through the programs of the Cancer Center. Predoctoral students are enrolled in one of four graduate programs: Cell and Molecular Biology (including Immunology), Chemistry, Engineering, and Pharmacology and Toxicology. Students will be recruited to the Training Grant after they have completed one or more years in these graduate programs, and have selected one of the Trainers as a mentor. This will allow their performance in first-year classes and research rotations to be used as additional evidence of their potential to succeed in a Ph.D. degree. Postdoctoral trainees will be engaged in research under the mentorship of a faculty adviser, but will have their research experience broadened by regular interactions with other faculty and fellows through conferences, seminars, and programmatic activities. Many of the trainees at both pre- and postdoctoral levels will engage in collaborative research with other listed trainers or with other members of the Cancer Center. This Training Program acts as an enhancement to the interactive environment that makes the Cancer Center a functional institution. Predoctoral trainees will generally be funded for three years, while postdoctoral trainees will be funded for two years. All trainees will be encouraged to obtain alternative extramural funding, thereby enhancing the overall number of trainees who can be supported. This mechanism also facilitates the recruiting of minority applicants as there is a more frequent turnover of positions, and hence funds can be assigned to any qualified minority as soon as we are able to interest him/her in the program. 2 T32 CA09658-11A1 3 Alan R. Eastman, Ph.D.
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0.958 |
1996 — 2000 |
Eastman, Alan R |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Cancer Biology and Carcinogensis
This application requests continue support for a training program in Cancer Biology and Carcinogenesis that was begun 4 years ago. The program is designed to train predoctoral and postdoctoral fellows in the fundamentals of cancer research by participation in didactic courses, seminars and discussion groups, and in the performance of laboratory- based cancer research. The training program is integrated into the research programs of the Norris Cotton Cancer Center, thereby enhancing exposure to many facets of the disease. This is a multidisciplinary Training Program with 14 faculty trainers drawn from six academic departments: Biochemistry, Chemistry, Microbiology, Pathology, Pharmacology and Toxicology, and Physiology. These faculty members have an excellent training record, and are highly interactive both in their individual research efforts and through the programs of the Cancer Center. Predoctoral students are enrolled in one of four graduate programs: Cell and Molecular Biology (including Immunology), Chemistry, Pharmacology and Toxicology, and Physiology. Students will be recruited to the Training Grant after they have completed one or more years in these graduate programs, and have selected one of the Trainers as a mentor. This will allow their performance in first year classes and research rotations to be used as additional evidence of their potential to succeed in a Ph.D. degree. Postdoctoral trainees will be engaged in research under the mentorship of a faculty adviser, but will have their research experience broadened by regular interactions with other faculty and fellows through conferences, seminars, and programmatic activities. Many of the trainees at both pre-and postdoctoral level will engage in collaborative research with other listed trainers or with other members of the Cancer Center. This Training Program acts as an enhancement to the interactive environment that makes the Cancer Center a functional institution. PredoctoraI trainees will generally be funded for 3 years, while postdoctoral trainees will be funded for two years. All trainees will be encouraged to obtain alternative extramural funding, thereby enhancing the overall number of trainees who can be supported. This mechanism also facilitates the recruiting of minority applicants as there is a more frequent turnover of positions, and hence funds can be assigned to any qualified minority as soon as we are able to interest him/her in the program.
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0.958 |
1999 — 2001 |
Eastman, Alan R |
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. |
Abrogation of Cell Cycle Arrest by Staurosporine Analogs
Caffeine has been known for many years to enhance the cytotoxicity elicited by DNA damaging agents such as cisplatin. The mechanism of this enhancement is through its ability to abrogate the S and G2 checkpoints that normally prevent a damaged cell from undergoing a lethal mitosis. Unfortunately, this therapeutic combination has never been realized because adequate concentrations of caffeine can not be obtained in a patient. A new compound, 7-hydroxystaurosporine (UCN-01), is at least 100,000 times more potent than caffeine in its ability to abrogate the cisplatin-induced S and G2 arrest, and causes a marked enhancement in cisplatin-mediated cell killing. Furthermore, the concentrations required appear to be well tolerated in animals. Experiments in human and rodent cell lines have established that this abrogation occurs only when the p53 tumor suppressor is defective. Thus, UCN-01 may selectively enhance chemotherapy in the tumor while sparing normal tissue. Unfortunately, the ongoing Phase I trial of UCN-01 has shown avid binding to human plasma proteins limiting or preventing its access to the tumor. This proposal addresses a solution to this problem based on the observation that a novel analog, K252a, does not bind to human plasma proteins yet still abrogates S phase arrest induced by cisplatin. However, it fails to abrogate the G2 checkpoint because when used alone it causes a G2 arrest. Two approaches are proposed. First, K252a will be used to selectively drive p53-mutant cells through S phase, at which time an S phase-specific drug such as irinotecan will be added; this may enhance cytotoxicity without the requirement for passage through mitosis. Second, based on results of a structure/activity analysis, it is proposed to synthesize novel analogs that it is predicted will abrogate both S and G2 arrest and enhance cytotoxicity while failing to bind to human plasma proteins. These drug combinations and analogs will be tested in cell culture models and in a transplantable murine tumor model. Concurrent mechanistic studies will be directed toward understanding the mechanism by which these analogs abrogate S phase arrest following cisplatin or irinotecan, and determine how wildtype p53 prevents abrogation of cell cycle arrest. These experiments should identify a drug combination that can be tested for its selective targeting to p53-defective tumors in future clinical trials.
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0.958 |
2002 — 2003 |
Eastman, Alan R |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Cell Survival Pathways and Inhibitors in Leukemia
DESCRIPTION (provided by applicant): Tumors characteristically exhibit mutations that enhance cell proliferation and survival. Two well-recognized cell survival pathways are RAF to MEK to ERK and PI3-kinase to Akt. Many inhibitors of these pathways are now in clinical trials or at earlier stages of development. However, early results suggest these inhibitors are more likely to suppress growth than kill the tumor cells. Our recent observations have demonstrated that such inhibitors may be more valuable when used in combination with more traditional anticancer agents. Specifically, it has been shown that a MEK inhibitor can dramatically enhance the rate of apoptosis induced by vinblastine in myeloid leukemia ML-1 cells and HL6O cells. However, U937 cells are insensitive to the MEK inhibitor but are sensitized to vinblastine by an inhibitor of PI3-kinase. These observations have led to the hypothesis that different leukemias preferentially use different survival signaling pathways, and that by defining which pathway a specific leukemia uses, effective drug combinations can be individualized for that patient. The goal of this project is to study freshly-isolated human leukemia cells and define the frequency with which they are sensitized to chemotherapy by inhibitors of these two cell survival pathways. The specific aims are to assay leukemia cells for phosphorylation of ERK and Akt as indicators of the signaling pathways used, and to combine inhibitors of these signaling pathways with vinca alkaloids ex vivo to determine the rate of induction of apoptosis. Additional experiments will determine whether normal leukocyte progenitors, which do not have an oncogene-enhanced cell survival pathway, are resistant to these drug combinations thereby suggesting such a therapy may be selective for the tumor. Finally, activation of Jun N-terminal kinase (JNK) will be assayed in leukemia patients receiving vincristine therapy, to confirm that this pathway is activated at drug concentrations tolerated by patients. Activation of the JNK pathway is necessary for the enhanced apoptosis induced by inhibitors of the Erk and Akt pathways. Successful completion of these aims will identify which leukemia patients might benefit from administration of inhibitors of these signaling pathways, and facilitate the design of clinical trials to test their efficacy in combination with other anticancer agents.
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0.958 |
2006 — 2008 |
Eastman, Alan R |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
2006 Molecular Therapeutics of Cancer Gordon Research Conference
[unreadable] DESCRIPTION (provided by applicant): This Gordon Research Conference on Molecular Therapeutics of Cancer, held annually since 1978 (initially under the name of Chemotherapy of Experimental and Clinical Cancer), provides a highly interactive forum for the presentation and discussion of novel drugs, drug targets and the preclinical and clinical development of novel therapeutics. Meeting participants represent a diverse range of interests, spanning the pharmaceutical industry, biotechnology companies, and clinical and academic institutions. The meeting seeks to promote advancements in the treatment of human cancer through the presentation of novel, unpublished work, and to focus on the ways these advancements can be brought to the service of patient care. The informality of the meeting venue, coupled with the GRC tradition of lively and extensive discussions, provides a unique opportunity for interactions between individuals from academia, industry and the clinical arena. The 2006 meeting will continue the trend of addressing new ideas, questions and solutions at the forefront of cancer therapy focusing on targets and strategies that have yet to be presented at larger national and international meetings. Topics will include: targeting the lipogenic pathways in tumors; cell cycle checkpoint regulation; targeting therapy to BRCA1/2 defective tumors; developmental gene regulation (Hedgehog, Wnt, Notch); impact of stem cells on therapeutic response; solving problems in gene and siRNA delivery; protein phosphatases as therapeutic targets, molecular prognosis, and novel therapeutic technologies (nanotechnology and imaging). [unreadable] [unreadable] [unreadable] [unreadable]
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0.958 |
2007 — 2011 |
Eastman, Alan R |
T32Activity Code Description: To enable institutions to make National Research Service Awards to individuals selected by them for predoctoral and postdoctoral research training in specified shortage areas. |
Cancer Biology and Molecular Therapeutics
[unreadable] DESCRIPTION (provided by applicant): This application requests continued support for a training program in Cancer Biology and Molecular Therapeutics that was begun in 1990. The program trains predoctoral and postdoctoral fellows in the fundamentals of cancer research by participation in didactic courses, seminars, discussion groups and performance of laboratory-based research. The training program is integrated into the research programs of the Morris Cotton Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center, thereby enhancing exposure to many facets of the disease. This is a multidisciplinary program drawing together 20 faculty with appointments in 7 different academic programs. The faculty have recently been brought together in a new Cancer Biology graduate program under an umbrella Program in Experimental and Molecular Medicine (PEMM). Predoctoral students are enrolled in the PEMM program in year 1 and then select one of five themes in which they undertake their thesis research, journal clubs and seminars. Students who select Cancer Biology then become the responsibility of the Cancer Biology Graduate Program for the remainder of their training. Required didactic work includes courses in Cancer Biology, Oncogenomics, and the Ethical Conduct of Research. Currently there are 43 PhD or MD/PhD students in the laboratories of the training faculty. Students are recruited to the Training Grant after they have completed one or more years in the graduate program, and have selected a faculty mentor. This allows their performance in first year classes and research rotations to be used as evidence of their potential to succeed in the PhD program. Postdoctoral trainees are engaged in fulltime research under the mentorship of a faculty adviser, but have their research experience broadened by regular interactions with other faculty and fellows through conferences, seminars and programmatic activities. There are currently 30 postdoctoral trainees in the laboratories of the faculty. Training grant funds are used to facilitate recruitment of postdoctoral trainees, who then are encouraged to obtain alternate extramural funding, thereby enhancing the ability of the program to recruit additional trainees. This mechanism also facilitates the recruitment of minority applicants as there is a more frequent turnover of positions, and hence funds can be assigned to any qualified minority as soon as identified. This training program has had an outstanding record of achievement since its inception, and this will be further strengthened by the focused training under the new Cancer Biology Graduate Program. This new direction for the program was achieved in major part by the established track record of this training program, and as a consequence we are requesting continued support at the current level of training positions. [unreadable] [unreadable] [unreadable] [unreadable]
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0.958 |
2007 — 2011 |
Eastman, Alan R |
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. |
Mechanisms of Resistance to Cell Cycle Checkpoint Kinase Inhibitors
[unreadable] DESCRIPTION (provided by applicant): DNA damaging anticancer agents induce arrest at various checkpoints throughout the cell cycle. This protective mechanism allows cells time to repair damage before progressing. UCN-01 (7-hydroxy-staurosporine) was identified as a potent inhibitor of the DNA damage-induced S and G2 arrest, thereby causing a marked enhancement in cell killing. UCN-01-mediated abrogation of normal cells is prevented by the p53 tumor suppressor protein. Thus, UCN-01 may selectively enhance chemotherapy in the tumor while sparing normal tissue. However, some p53-defective tumors are also resistant to UCN-01, while some p53-wildtype tumors are sensitive. This leads to the major question in this proposal: what are the determinants of response to checkpoint inhibitors? Aim 1 will focus on p53-defective tumor cell lines and investigate the role of Chk1 (inhibited by UCN-01) and other checkpoint kinases in arresting cell cycle progression. The response of various cell lines to different checkpoint inhibitors will be assessed. Three resistant tumor cell models will be analyzed for alternate kinases that explain their resistance to Chk1 and Chk2 inhibitors; candidate kinases include hSAD1, PLK3, MAPKAPK2 and JNK. To confirm the role of each kinase in checkpoint regulation, cell lines will be generated in which the kinase expression is prevented by siRNA. Aim 2 will address the question as to why some p53-wildtype tumors retain sensitivity to Chk1 inhibitors despite the fact that non-tumorigenic lines are resistant. Recent results demonstrate that p53 regulates the checkpoint through both gene activation (p21waf1) and repression (cyclin B) and that regulation of both of these proteins is defective in UCN-01-sensitive p53 wildtype tumors; p21 fails to be induced during S phase arrest, while cyclin B fails to be repressed during G2 arrest. The transcriptional and post-translational regulation of these two proteins will be studied and contributors to their differential regulation assessed. Experimental approaches will include dissection of the pathways through promoter analysis and chromatin immunoprecipitation assays. As novel checkpoint inhibitors enter clinical trial, the results of these studies will provide a basis upon which to stratify patients and thereby enhance the probability of developing a successful therapeutic regimen. For those tumors in which a response is not indicated, these experiments will likely identify alternate targets for drug discovery. [unreadable] [unreadable] [unreadable]
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0.958 |
2009 |
Eastman, Alan R |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
Molecular Therapeutics of Cancer Conference
DESCRIPTION (provided by applicant): The Molecular Therapeutics of Cancer conference has been held annually since 1978 (originally under the name of Chemotherapy of Experimental and Clinical Cancer). Since 2008, the conference has been organized by the Cancer Molecular Therapeutics Research Association. The conference continues to provide a highly interactive forum for the presentation and discussion of novel drugs, drug targets and the preclinical and clinical development of novel therapeutics. Meeting participants represent a diverse range of interests, spanning the pharmaceutical industry, biotechnology companies, and clinical and academic institutions. The meeting seeks to promote advancements in the treatment of human cancer through the presentation of novel, unpublished work, and to focus on the ways these advancements can be brought to the service of patient care. The informality of the meeting venue, coupled with the tradition of lively and extensive discussions, provides a unique opportunity for interactions between individuals from multiple disciplines. The 2009 meeting will be held at Stanford University and continue the trend of addressing new ideas, questions and solutions at the forefront of cancer therapy focusing on targets and strategies. Topics will include: targeting p53, systems biology and large datasets, oncogene addiction, DNA repair, novel protein therapeutics, targeting transcription factors, IGF-1 active drugs, and a discussion on whether the concept of cancer stem cells is useful in developing new therapies. Funds from NIH are used to facilitate attendance by pre- and post-doctoral fellows. These trainees are an integral part of the program, particularly during the interactive poster sessions. Four trainees are nominated to present in an oral session and are offered funding to attend the next annual conference. Public Health Relevance: Public Health Statement The Molecular Therapeutics of Cancer conference is an annual, three and a half day meeting designed to promote information exchange, discussion and collaboration among scientists interested in the chemotherapy of cancer. The primary goal of the conference is to promote translational research by bringing together investigators from both academic and industrial environments who are involved in preclinical and clinical drug development together with basic scientists working on potential new targets for cancer chemotherapy. A second goal is to enhance the training of pre-doctoral and post-doctoral students in the translation of preclinical science into clinical trials. This is achieved by facilitating trainee participation in this conference thereby providing exposure to this important research area that is frequently not provided in standard academic training programs.
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0.958 |
2009 — 2014 |
Eastman, Alan R |
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. |
Molecular Therapeutics Research Program
The goal of the Molecular Therapeutics Program (MT) is to foster the exchange of ideas, cooperation, and collaboration leading to translation of basic research focused on the identification and development of novel therapeutics into clinical applications, and to use basic research to answer clinical questions related to improving the treatment of cancer. The MT Program provides a forum for discussion and advancement of new developments in target identification, drug discovery, and mechanisms of drug action, and for translating these approaches into novel correlative and therapeutic clinical trials. The Program currently has 27 members from 7 departments and $8.2 millon in total funding, of which almost $4 million (61%) is from the NCI. The productivity over the past 5 years exceeds 240 papers, including 16% intra-program and 26% interprogram collaborative publications. Eighteen Program faculty participated in intra-program and 18 in interprogram collaborations, providing strong evidence of a highly interactive research program. Recent programmatic highlights include evidence for the role of the fatty acid synthase pathway as an independent marker of breast cancer progression, and the recognition that it can be targeted to suppress tumor growth. Other molecular targets under investigation include proteins in the Hedgehog signaling pathway, which is frequently activated in non-small cell lung cancer. New agents such as novel proteasome inhibitors and suppressors of the anti-apoptotic proteins Mcl-1 and Bcl-2 are under investigation, with the expectation of bringing these drugs to clinical trial at Morris Cotton Cancer Center. Novel treatment strategies developed in the MT Program that have been translated into Phase I clinical trials include the combination of cisplatin plus the Chk1 inhibitor UCN-01. In is study serial tumor biopsies were used to monitor biological activity in tumor tissue. Other investigators have developed novel technologies and complementary approaches to define predictive markers and therapeutic strategies, and an important goal of the MT Program is to test these ideas in correlative and therapeutic clinical trials at the NCCC. Also worthy of particular notice is a series of Phase I and II clinical trials in pancreatic cancer using chemoradiation in the neoadjuvant setting that has identified a promising treatment approach in this highly aggressive disease and demonstrates the Program's impact on disease outcome in cancer patients.
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0.958 |
2013 — 2017 |
Eastman, Alan R |
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. |
Mechanisms of Sensitivity to Cell Cycle Checkpoint Kinase Inhibitors
DESCRIPTION (provided by applicant): Many anticancer drugs target DNA resulting in activation of cell cycle checkpoints, arrest of proliferation, and repair, the consequence of which is recovery and survival of the tumor cells. Current efforts to enhance tumor cell killing include combining anticancer agents with inhibitors of DNA checkpoints. Chk1 has been identified as a critical kinase for cell cycle arrest and many inhibitors are currently in preclinical and clinical development; the current studies focus on the Chk1 inhibitor MK-8776. Recent results have identified a second critical function of Chk1 whereby it prevents the collapse of stalled replication forks. Accordingly, Chk1 inhibitors can dramatically sensitize cells to antimetabolites such as hydroxyurea and gemcitabine. Recently we discovered that stalled replication forks evolve to become more Chk1 dependent with time. This is critical to the development of Chk1 inhibitors as it impacts the timing of drug delivery in clinical trials. An additional observation s that some cell lines are hypersensitive to MK-8776 alone while others are completely resistant. The hypersensitive cell lines also require much less MK-8776 to sensitize them to hydroxyurea or gemcitabine. Accordingly, we hypothesize that a subset of tumors exist that will be highly responsive to the combination of MK-8776 plus either hydroxyurea or gemcitabine. This proposal will assess the variation in response to these drugs across a panel of cell lines and dissect the underlying mechanisms. The specific aims will 1) define the mechanism(s) for differential sensitivity of human tumor cell lines to MK-8776 as a single agent; 2) define the critical step(s) that occur at stalled replication forks that render them more Chk1 dependent with time; and 3) confirm the differential response of human cell lines when grown as xenograft tumors. In addition to establishing the underlying mechanisms, this research will define the optimum schedule of drug administration and biomarkers that can identify patients whose tumors are most likely to respond. This information will be critical for the design of clinical trils and selection of appropriate patients to treat.
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0.958 |
2015 — 2019 |
Eastman, Alan R |
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. |
Molecular Therapeutics (Mt)
Project Summary/Abstract: Molecular Therapeutics (MT) The goal of the Molecular Therapeutics (MT) Program is to identify therapeutic targets, drugs, and strategies, and to facilitate the translation of Dartmouth-investigator hypotheses into clinical trials. The research interests of the program faculty cover the full spectrum of investigations in molecular therapeutics and include synthesis of novel compounds as research tools and potential therapeutics; investigation of novel targets for therapy; assessment of predictors of disease progression or drug response; and proof-of-concept and therapeutic early phase clinical trials. The MT program currently has 30 members from 9 different departments whose research foci can be described under the following four scientific themes: (1) Synthesis and discovery of novel compounds and potential cancer drugs, (2) Interrogation of potential new targets and therapeutic strategies, (3) Development of biomarkers for cancer diagnosis and prediction of treatment response, and (4) Development of hypothesis-based cancer clinical trials. These four research themes do not exist as separate entities. There is extensive interaction between them, as novel drugs and compounds are used to interrogate novel targets, novel biomarkers are being identified, and these advances are being translated into molecular proof-of- principle clinical trials. The interactions across this spectrum are catalyzed by the interactive environment generated by activities of the MT program, its deep involvement in the Early Phase Trials Clinical Oncology Group (EPTCOG), and by the continual nurturing and mentoring of program members by the Program Co- Directors. This work results in extensive collaborations across the entire spectrum of molecular therapeutics, as evidenced by joint grants and publications. Major contributions of the program to the NCCC mission have been the facilitation of discoveries promising new therapeutic approaches, the translation of Dartmouth investigator hypotheses into clinical trials, and the accrual of patients to such studies. In addition, NCCC has made substantial commitment to improving the depth and breadth of research and clinical translation in the MT program through support of shared resources, financially supporting many of the costs associated with early- phase/proof-of-principle clinical trials, and strategic recruitment of new investigators. For example, over the past 5 years, the membership of the program has evolved with the successful recruitment of outstanding new faculty in the biological laboratory sciences (Miller, Kurokawa), chemistry (Micalizio, Wu), and in clinical/translational investigations (Danilov, Lansigan, Smith). More than 363 cancer-related articles have been published over the reporting period (54 [15%] in high impact journals), many of them representing intra- program (69=19%) or inter-program (107=29%) collaboration. These collaborations involve 29 MT program members and 63 NCCC members, almost equally distributed between the other 5 NCCC research programs. Total funding for the program currently is $8.0M, of which $6.0M is peer-reviewed and $3.4M is from NCI.
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0.958 |