Louis B. Nabors - US grants

DESCRIPTION (provided by applicant): Anti-integrin therapies that target specific mechanisms of tumor neovascularization and invasion present difficult problems in assessing their relative efficacy. Since the anti-angiogenesis effect may result in a significantly delayed or clinically inapparent anti-tumor effect when compared with that seen in therapies that target tumor cells directly, the most appropriate methods to assess an anti-angiogenesis effect need to be identified and validated. In patients with malignant brain tumors, it is procedurally high-risk, infeasible and unethical to obtain routine multiple tissue biopsies on a longitudinal basis to verify, at histopathological, cellular and molecular levels, that tumor vasculature is being appropriately targeted and adversely affected. The overall objective of this project will be to evaluate the capacity of several different non-invasive mechanisms and assays to correlate changes in vascularization of recurrent malignant gliomas in patients who will be treated with a novel anti-angiogenic drug, cyclic RGD (EMD121974). Our hypothesis is that specific non-invasive methodologies can be used to visualize and quantify the responses of tumor vasculature to an anti-angiogenesis therapy that focuses on a specific molecular target on activated endothelial cells. Under the auspices of the New Approaches to Brain Tumor Therapy (NABTT) consortium, we will conduct a dose-escalating Phase 1 Clinical Trial of EMD121974 (IND #59,073) using a novel anti-integrin drug supplied by CTEP. We propose to (1) determine the ability of dynamic contrast susceptibility (DCS) MR imaging to assess and quantify neovascularization responses to EMD121974 therapy at specific time points during the course of therapy; (2) perform specific in vitro assays on patient biofluids (blood, csf, urine, etc.) at these imaging timepoints that will assess antiangiogenic activity against endothelial cell function required for neovascularization (proliferation, migration, apoptosis) or glioma cells for invasion; and, (3) explore the utility of a labeled, targeted nanoparticle to quantify tumor and tumor-vascular burden in a mouse brain tumor model. Data from these studies will be critically important in developing, refining and validating non-invasive methodologies for timely assessment of specific anti-angiogenic therapies for malignant brain tumors in patients.

DESCRIPTION (provided by applicant): This proposal is being submitted as part of a cooperative agreement with other members of the New Approaches to Brain Tumor Therapy (NABTT) Consortium (Project Leaders: Henry Brem, M.D. and Stuart Grossman, M.D.; Coordinating Center, Johns Hopkins University), in order to design and conduct Phase I and Phase II treatment protocols for patients with anaplastic gliomas. The primary objective of this proposal is to improve the outcome for adult patients with primary brain tumors. We propose to address this goal by combining our clinical investigative strengths with those of the other members of the NABTT Consortium (Emory University, H. Lee Moffitt Cancer Center, Henry Ford Hospital, Johns Hopkins University, Massachusetts General Hospital, Wake Forest University, University of Alabama at Birmingham, University of Pennsylvania, and Cleveland Clinic). The particular strengths that our institution brings to the NABTT Consortium include: 1) a large number of patients with primary brain tumors and a well-developed referral network, 2) a brain tumor-dedicated multidisciplinary clinical team that has been in place for over ten years, 3) extensive clinical and laboratory resources, 4) a significant number of NIH-supported brain tumor laboratory research programs, including a recently-awarded SPORE in Neurological Cancer (P50 CA097247-01, Steven Rosenfeld, M.D., Ph.D., Principal Investigator), as well as a number of industrial-academia contacts for support of neuro-oncology research on campus, and 5) nationally-recognized expertise in cancer research, including biostatistics and data management, in functional neuroimaging, and in the conducting of institutional and cooperative phase I and II clinical trials. This proposal thus builds on our extensive clinical investigative expertise within the context of a well-established multi-institutional brain tumor treatment consortium.

DESCRIPTION (provided by applicant): This proposal is being submitted as part of a cooperative agreement with other members of the New Approaches to Brain Tumor Therapy (NABTT) Consortium (Project Leaders: Henry Brem, M.D. and Stuart Grossman, M.D.; Coordinating Center, Johns Hopkins University), in order to design and conduct Phase I and Phase II treatment protocols for patients with anaplastic gliomas. The primary objective of this proposal is to improve the outcome for adult patients with primary brain tumors. We propose to address this goal by combining our clinical investigative strengths with those of the other members of the NABTT Consortium (Emory University, H. Lee Moffitt Cancer Center, Henry Ford Hospital, Johns Hopkins University, Massachusetts General Hospital, Wake Forest University, University of Alabama at Birmingham, University of Pennsylvania, and Cleveland Clinic). The particular strengths that our institution brings to the NABTT Consortium include: 1) a large number of patients with primary brain tumors and a well-developed referral network, 2) a brain tumor-dedicated multidisciplinary clinical team that has been in place for over ten years, 3) extensive clinical and laboratory resources, 4) a significant number of NIH-supported brain tumor laboratory research programs, including a recently-awarded SPORE in Neurological Cancer (P50 CA097247-01, Steven Rosenfeld, M.D., Ph.D., Principal Investigator), as well as a number of industrial-academia contacts for support of neuro-oncology research on campus, and 5) nationally-recognized expertise in cancer research, including biostatistics and data management, in functional neuroimaging, and in the conducting of institutional and cooperative phase I and II clinical trials. This proposal thus builds on our extensive clinical investigative expertise within the context of a well-established multi-institutional brain tumor treatment consortium.

at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,

The overall purpose of the University of Alabama at Birmingham's application as a NeuroNEXT site is to continue to support the infrastructure and provide expertise to aid clinical neuroscience investigators in translating laboratory-based findings into clinical protocols. The Specific Aims for this Core are: 1) to provide for optimal support of investigators to undertake clinical research involving patients with diseases or disorders of the nervous system; 2) to provide patients with neurological diseases and disorders as well as referring physicians access to clinical research treatments; and 3) to facilitate the introduction of protocols derived from the translational research of the NIH, industrial partners, or academic centers into a national cooperative consortium of neuroscience clinical centers. The NeuroNEXT site at UAB is directed by Dr. L. Burton Nabors and Dr. Khurram Bashir, whom will provide overall leadership and administration of the NeuroNEXT site and will oversee its interactions with the Clinical Coordinating Center and Data Coordinating Center.

? DESCRIPTION (provided by applicant): Glioblastoma (GBM) is a primary malignancy of the central nervous system (CNS) that is universally fatal, extremely difficult to treat, and associate with tremendous burden to patients and caregivers due to the loss of neurological function. Aspects of the disease biology are being unraveled particularly the driver oncogenic events associated with the disease and the molecular subtypes. All reveal a complex tapestry suggesting downstream events of the classifying signatures are promoting a condition of extreme genomic instability. Our understanding of this altered state is limited and not in concordance with what biology teaches us, that this level of chromosomal instability should lead to mitotic catastrophe and cell death. Instead, we see a state of disease promotion and progression. We have reported on alterations occurring in the evolutionarily conserved cellular organelle, the centrosome induced by phosphoregulation of a RNA-binding protein, HuR (Human Antigen R). Aberrant regulation of HuR induces centrosome amplification, aneuploidy, and disease progression. It is our hypothesis that cytoplasmic localization and multimer formation drives the oncogenic behavior of HuR. We believe that insights into this novel area of regulation will provide insights into the mechanisms of genomic instability in cancer. We have proposed three specific aims to determine the importance of post-transcriptional regulation of centrosomes in the promotion of chromosomal instability. In Aim 1, we will extend our initial mechanistic insights to dissect the control mechanisms through which multimerization of HuR promotes instability with resultant tumor progression. In the second aim, we will develop compounds identified that have the capacity to alter HuR function specifically the acquisition of the states of cytoplasmic localization and multimer formation. In the last aim, we will characterize the impact of HuR inhibition in primary GBM cell lines in vitro and in vivo.

04 NEURO-ONCOLOGY (NO) PROGRAM ABSTRACT The Neuro-Oncology Program (04) has been a multidsciplinary, vertically integrated, basic, translational and clinical research program in the Comprehensive Cancer Center (CCC) since 1986. Its primary cancer focus includes molecular, cellular and systems biology of malignant glial tumors with a secondary emphasis on metastatic tumors to the brain and on malignant peripheral neuroglial tumors. The Neuro-Oncology Program membership has a strong presence in the UAB Comprehensive Neuroscience Center. The CCC Neuro- Oncology program serves a 5-state, Deep South region as a major, tertiary care referral center for patients with malignant and benign brain tumors and achieves its objectives through the support of the CCC and its shared facilities. The Neuro-Oncology Program is distinguished by: 1) A large number of patients with primary brain tumors and a mature 5-state referral network; 2) An active brain tumor-dedicated inter-disciplinary clinical team; 3) Extensive clinical and laboratory resources; 4) Significant extramural support for basic, translational, and clinical research, as well as a number of pharmaceutical industry-academia contracts for support of Neuro- Oncology research on campus; and 5) Nationally recognized expertise in conducting institutional and cooperative Phase I and II clinical trials utilizing agents developed through translational activities of the program. This program is a charter member of the Adult Brain Tumor Consortium (ABTC), the only NCI-funded adult brain tumor clinical consortium, and program members hold leadership positions in the Pediatric Brain Tumor Committee of the Children's Oncology Group. The Neuro-Oncology Program is multi-disciplinary with 20 primary members from 9 departments and 2 schools. Our members currently hold 28 active research grants, totaling $6,990,899 in direct costs annually, with 10 of those grants from the NCI totaling $680,818 annually in direct costs. During the current funding period, the membership published 169 peer-reviewed scientific papers, of which 32% were intra-programmatic and 29% were inter-progammatic brain tumor research. We conducted 66 interventional and 7 non-interventional IRB-approved clinical trials accruing 221 patients and 366 patients, respectively. In the current funding period, the Program has effectively harnesssed the CCC development of infrastructure and expertise to support systems biomedicine, bioenergetics, imaging and drug development. This has led to highly innovative research that has resulted in several seminal publications by the members of this program. The Neuro-Oncology Program will continue to advance basic and translational findings of its members' research to investigator-initiated Phase I and Phase II clinical trials for adult and pediatric patients with brain tumors.