1999 — 2003 |
Rudin, Charles M |
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. |
Genetic and Genomic Responses to Dna Damage
As more successful therapy for certain cancers has evolved, secondary malignancy has become an increasingly important concern. In addition, recent progress in supportive care for patients undergoing high dose chemotherapy, with hematopoietic growth factors or hematopoietic system cell support, has led to a dramatic increase in the number of patients treated with prolonged and high dose DNA-damaging therapy. A method for studying the molecular effects of such therapy has been designed using cells made resistant to programmed cell death by overexpression of the apoptotic inhibitor Bcl-xL. Differential mRNA display has been used to compare gene expression in the presence and absence of chemotherapeutic agents with various mechanisms of action. This technique has resulted in the identification of a number of transcripts specifically upregulated by prolonged exposure to DNA-damaging chemotherapy. Among the transcripts identified are members of a family of retrotransposable elements. The role of mobile elements and of other transcripts identified by this technique in the cellular response to DNA damage will be explored. Programmed cell death is a critical defense mechanism against the continued proliferation of cells suffering major DNA damage or chromosomal aberrancy. Major genomic rearrangements and aneuploidy are frequent events in cancer, suggesting that the signaling pathway from DNA damage to programmed cell death is defective in the majority of cancer cells. Defects in this response pathway may be critical in permitting the genomic alterations involved in carcinogenic transformation. A genetic screen for factors involved in this apoptotic signaling pathway is being performed using a retroviral cDNA library in mammalian cells exposed to DNA-damaging agents. Exposure to DNA-damaging chemotherapy is associated with induction of programmed cell death, or apoptosis, in chemosensitive tumors. Exposure to these agents has also been associated with characteristic chromosomal rearrangements of secondary malignancies. This proposal seeks to better define both of these molecular pathways, from DNA damage to programmed cell death, and from DNA damage to chromosomal aberrancy. Understanding the molecular basis of the various cellular responses to DNA damage is relevant to the design of both chemopreventative and therapeutic anticancer strategies.
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0.958 |
2003 — 2004 |
Rudin, Charles M |
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.) |
A Pharmacogenetic and Pharmacodynamic Study of Erlotinib
DESCRIPTION (provided by applicant): Erlotinib (OSI-774) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. OSI-774, like other EGFR-directed therapies, is associated with toxicities including skin rash and diarrhea. The molecular basis of these toxicities, and the basis for the high degree of interpatient variability in toxicity, has not been determined. Basal layers of both the epidermis and the gastrointestinal mucosa express EGFR, and EGFR signaling has been implicated in physiological regulation in these tissues. Skin toxicity in patients treated with EGFR-directed therapies may be of particular clinical relevance as several recent studies have suggested that skin rash may correlate with anti-tumor activity. We hypothesize that inhibition of EGFR-dependent signal transduction in non-malignant tissues may be responsible for OSI-774 toxicity, and may be a clinically relevant indicator of potential anti-tumor efficacy. This study will involve the administration of OSI-774 at a fixed starting dose in approximately 64 subjects with advanced solid tumors. Several analyses will be performed to assess potential causes of interpatient variability in toxicity. Length of a CA dinucleotide repeat polymorphism in the first intron of the EGFR gene has been strongly correlated with relative expression of EGFR. Specific Aim 1 will be a pharmacogenetic analysis, testing the hypothesis that length of this sequence polymorphism may serve as a predictor of OSI-774 toxicity in vivo. Specific Aim 2 will be a pharmacodynamic analysis, evaluating relative EGFR expression and activation, as well as expression and activation of the downstream mitogen activated kinases ERK1 and ERK2 in skin biopsies prior to and following administration of OSI-774. These analyses will test the hypothesis that CA dinucleotide repeat length correlates with relative degree of suppression of EGFR-dependent signaling. Specific Aim 3 will be a pharmacokinetic analysis, evaluating whether polymorphisms in the CYP3A5 metabolizing enzyme gene correlate with measures of OSI-774 metabolism. Together these analyses will characterize potential factors influencing interpatient variability in OSI-774 toxicity. A clear understanding of the basis of variability in the toxicity of OSI-774 and similar EGFR-directed agents might ultimately guide use of the currently available agents to patients most likely to benefit. Defining the basis of this toxicity could also promote the development of EGFR-directed agents that may avoid such toxicity or that may be effective in a broader spectrum of cancer patients.
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0.958 |
2007 — 2008 |
Rudin, Charles M |
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.) |
Phase I/Ii Study of Ms-275 and 5-Azacytidine in Patients With Advanced Non-Small @ Johns Hopkins University
[unreadable] DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is the most common cause of cancer death in the U.S. Most NSCLC patients die of recurrent progressive disease after primary therapy. There are no available therapies for recurrent lung cancer associated with long-term disease-free survival. New therapies for NSCLC, particularly for recurrent disease, are a critical need. Epigenetic gene silencing mediated through aberrant DNA methylation and histone deacetylation is a key contributor to lung carcinogenesis. Preclinical studies by our group have shown that combined inhibition of DNA methyl transferases (DNMT) and of histone deacetylases (HDAC) synergistically induces re-expression of tumor suppressor genes epigenetically silenced in cancer. Clinical studies at our institution of the DNMT inhibitor 5AC in combination with HDAC inhibitors phenylbutyrate or MS- 275 in hematologic malignancies have resulted in remarkable clinical activity associated with reversal of epigenetic changes in key tumor suppressor genes silenced in these diseases. We propose to test the efficacy of combined epigenetic targeting in patients with advanced, recurrent NSCLC using 5AC and MS-275 on a schedule shown to be well-tolerated and associated with significant activity in patients with hematologic malignancies. The trial will include correlative analyses designed to evaluate whether therapy is associated with re-expression of genes we have found to be frequently epigenetically silenced in lung cancer. The aims of this project include the following: SA1: To assess safety, characterize toxicities, and determine the maximum tolerated dose of 5AC with MS-275 in patients with recurrent advanced NSCLC. SA2: To determine the objective response rate of 5AC and MS-275 in patients with recurrent NSCLC. SA3: To determine the pharmacokinetic profile of 5AC and MS-275 in patients with recurrent NSCLC. SA4: To assess the pharmacodynamic effects of 5AC and MS-275 on DNA methylation, histone acetylation, and gene re-expression in patients with recurrent NSCLC through analysis of blood, sputum and tissue biopsies. Lung cancer is the most common cause of cancer death in both men and women, responsible for over 160,000 deaths annually in the U.S. This project will study a novel therapeutic strategy in patients with lung cancer, based on reversing the aberrant silencing of regulatory genes in cancers. If successful, this approach could alter the poor prognosis of individuals with this disease. [unreadable] [unreadable] [unreadable]
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0.908 |
2012 — 2016 |
Rudin, Charles M |
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. |
Clinical Research Office @ Johns Hopkins University
The Clinical Research Office (CRO) provides numerous services to faculty and staff conducting oncology research at the Sidney Kimmel Comprehensive Cancer Center (SKCCC). The CRO has a key leadership role in the SKCCC research infrastructure, with the CRO Director overseeing and integrating activities among the several Clinical Research Cores. The Program Managers of the seven disease-specific research Programs and the SAC lab Manager have a dual-reporting relationship to both the Research Program Directors and the CRO Manager. This allows for a centralized research infrastructure yet at the same time allows disease-specific Programs flexibility based on the disease(s) being studies. Centralized and integrated CRO electronic resources include (1) a Clinical Research Management System (CRMS) tracking real time accrual to all oncology research studies, (2) a Protocol Library containing all active protocols, consents, order sets, and related documents, (3) a Pharmacy Research Orders Tracking/Approval System (POTS), (4) the Protocol Review and Monitoring System-Clinical Research Review Committee (PRMSCRC) Electronic Forum tracking documents, scientific review comments, and meeting outcomes from the weekly pre-PRMS-CRC (pre-Protocol Review and Monitoring System) and CRC (Protocol Review and Monitoring System) meetings, (5) a Standard Operating Procedures website for housing recommended clinical research methods and procedures, (6) a Regulatory Documents Warehouse to provide centralized access to common regulatory documents including clinical investigator CVs and laboratory certifications, and (7) an external SKCCC Clinical Trials website to facilitate web-based clinical trials searches by the community. Education provided by the CRO includes an introductory research course for all new research staff involved in oncology clinical trials, CRMS training, and continuing research education for research faculty and staff. The CRO provides regulatory expertise regarding FDA regulations and Investigational New Drug (IND) submissions, and internal regulatory oversight and guidance for all investigator-initiated trials. Quality assurance services are an essential component of the CRO via auditing and monitoring and developing standard operating procedures. The CRO acts as a liaison with the Johns Hopkins Institutional Review Boards, outside auditors and regulatory agencies. In 2010, there were 499 active research studies, including 319 therapeutic (354 Intervention) clinical trials. Accruals in 2010 totaled 6,386; including 5,036 to non-intervention studies and 1,350 to intervention trials. Lay: The Clinical Research Office (CRO) provides a centralized infrastructure for the conduct of clinical trials, including formal education programs, regulatory expertise, auditing, and databases such as a Protocol Library; a Clinical Research Management System (CRMS) for tracking enrollment, and a Pharmacy Orders Tracking System (POTS). The CRO plays a key role in integrating activities among the other clinical research cores. SKCCC Managed Shared Resource Current Grant Year Reporting Period: January 1, 2010 to December 31, 2010.
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0.908 |
2012 — 2016 |
Rudin, Charles M |
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. |
Protocol Review (Crc) @ Johns Hopkins University
The Protocol Review and Monitoring System Clinical Research Review Committee (PRMS-CRC) of the Sidney Kimmel Comprehensive Cancer Center (SKCCC) at Johns Hopkins is responsible for reviewing the scientific merit, priorities, and progress of the clinical research of the Center. Committee approval is required prior to opening a protocol in the Cancer Center. The Committee also has the authority to close protocols that do not demonstrate adequate scientific progress. On average, in 2010 each week the Committee reviewed three new studies, one resubmitted study with PRMS-CRC recommended changes, and two studies for annual progress and performance. The CRC is our Protocol Review and Monitoring System (PRMS).
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0.908 |
2019 — 2021 |
Carbone, David P. Ramalingam, Suresh S Rudin, Charles M |
UG1Activity Code Description: To support single project applications conducting clinical evaluation of various methods of therapy and/or prevention (in specific disease areas). Substantial federal programmatic staff involvement is intended to assist investigators during performance of the research activities, as defined in the terms and conditions of the award. NOTE: The UG1 is the single-component companion to the U10 which is used for multi-project applications only. |
Ecog-Acrin Thoracic Maligcies Integrated Translational Science Center
PROJECT SUMMARY/ABSTRACT The ECOG-ACRIN Thoracic Integrated Translational Research Center (EA-ITSC) comprises a team of accomplished researchers with a proven track record of collaborative work to improve outcomes for patients with lung cancer. The EA-ITSC, funded in 2014 by the NCI (U10) at the same time as the formation of the National Clinical Trials Network (NCTN), has played a major role in developing novel approaches for risk stratification, molecular testing, and treatment of lung cancer. This group has also been responsible for guiding the development of biomarker-driven clinical trials initiated by the ECOG-ACRIN Thoracic Malignancies Committee. Our highly collaborative team approach includes sharing specimens across institutions, conducting pilot projects that are of direct relevance to NCTN trials and guiding the translational research components of all newly developed ECOG-ACRIN thoracic malignancies trials. Our overarching goal is to develop novel biomarkers to enhance the efficacy of immunotherapy, overcome resistance to targeted agents and to identify combination treatment approaches to enhance the efficacy of existing therapies in lung cancer within the context of the NCTN. With this application, we propose to continue our research work with direct relevance to the NCTN, with the following specific aims: 1) To develop genomic, epigenomic, and proteomics approaches to enhance biomarker discovery efforts in ongoing and planned ECOG-ACRIN studies; 2) To conduct pilot studies on existing ECOG- ACRIN and institutional lung cancer tumor specimens that will lead to prospective NCTN clinical trials; and 3) To guide the development of translational research components of ECOG-ACRIN Thoracic trials and promote collaborations with lung cancer SPORE and P01 institutions. The EA-ITSC will have a robust pilot projects program from years 2-6 of this award that will invite participation from all the NCTN network groups, institutions with lung cancer SPORE and P01 awards, to bring the best science to NCTN clinical trials.
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0.923 |
2020 — 2021 |
Lewis, Jason S (co-PI) [⬀] Poirier, John Thomas [⬀] Poirier, John Thomas [⬀] Rudin, Charles M |
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. |
Immuno-Pet Imaging of High-Grade Neuroendocrine Lung Tumors Using 89zrrovalpituzumab, a Dll3-Targeting Monoclonal Antibody @ New York University School of Medicine
PROJECT SUMMARY/ABSTRACT Small cell lung cancer (SCLC), is a high-grade pulmonary neuroendocrine tumor that accounts for ~16% of all lung cancer cases diagnosed annually in the United States. In most patients, SCLC is metastatic at the time of presentation; patients with extensive stage disease have a poor prognosis with survival measureable in months, and an average 5-year survival of <5%. New therapeutic strategies are desperately needed to improve clinical outcomes for these patients. A novel antibody drug conjugate (rovalpituzumab tesirine; Rova-T) targeting Delta like ligand 3 (DLL3), a highly tumor-selective cell surface protein, has demonstrated impressive clinical benefit in early phase clinicial trials in patients with extensive stage small cell lung cancer. Among evaluable patients with DLL3+ baseline samples, as measured by IHC, a 39% overall response rate and 75% clinical benefit rate were observed, highlighting both the therapeutic potential for targeting DLL3 and the utility of DLL3 assessment. While DLL3 IHC has demonstrated diagnostic utility, this data is presently collected from archived tissue specimens, which may not serve as ideal reference points to help make the best decisions in the clinic at the time of treatment; indeed, many patients with apparent DLL3 positivity failed to respond and many patients were not evaluable. A more reliable, dynamic, real time, non-invasive yet quantitative method to evaluate the in vivo status of antigen expression on tumors will greatly improve patient selection for this agent in the clinic. We propose development of an immuno-PET diagnostic agent comprising 89Zr labeled rovalpituzumab. Specific Aim 1 builds upon promising preliminary imaging data. We are already able to obtain high-contrast immune-PET images using non-specific amine labeling and site-specific maleimide bioconjugation. We will improve upon this approach by developing more stable thiol-clickable methylsuflone chelators for 89Zr to minimize kidney uptake. Specific Aim 2 will be centered on the study of the in vivo toxicology and pharmacology of 89Zr-Rova as well as the preparation and submission of an FDA Investigational New Drug application for the clinical trial. The goal of Specific Aim 3 will be the first-in-human clinical trial of 89Zr-Rova for the PET imaging of patients with small cell lung cancer concurrently enrolled on a clinical trial of the therapeutic ADC Rova-T. This 30-patient trial will be focused on the clinical safety and efficacy of 89Zr as a predictor of response to Rova-T. This proposal will strengthen the already close working relationship between Memorial Sloan Kettering scientists and clinicians and Stemcentrx, Inc. toward the development of 89Zr-labeled rovalpituzumab. This novel imaging agent will render diagnostic value to the DLL3-targeting ADC by allowing it to serve as a contemporaneous diagnostic tool and act as a scout for future radiotherapeutics.
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0.922 |