2001 — 2004 |
Recht, Lawrence D |
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. |
Stem Cell Plasticity After Blastocyst Implantation
DESCRIPTION (provided by applicant): Several recent studies indicate that tissue-derived stem cells can not only differentiate into cells of the tissue from which they are obtained, but also those from other tissues. We have been interested in the range of differentiative capacity (which we term plasticity) of CNS derived stem cells and hypothesized that one way to assay this would be to implant these cells into blastocyts and assess incorporation into the resulting mice later in development. Our results indicate a robust incorporation of these cells into extraneural tissues including bone marrow, where they express lineage markers of differentiated hematopoietic cells, bone muscle and GI tract. We believe this model provides a unique insight into stem cell plasticity because of the high efficiency of implantation and production of apparently normal pups. We propose to follow-up our studies by addressing the following specific aims: 1) We will determine whether incorporation of stem cells into blastocysts varies as a function of stem cell subpopulation or type, we will create a retorviral library of neural stem cells to assess whether specific subpopulations exist as well as comparing neural stem cells with marrow stromal cells in their ability to incorporate into blastocysts; 2) We will determine whether incorporation of neural stem cells into other tissues renders them functional by performing bone marrow transplantation of cells obtained from chimeric pups into lethally irradiated mice and assessing whether neural stem cells can repair a embryonically lethal genetic defect in bone; and 3) We will assess whether neural stem cells retain their functional capacity to develop into olfactory interneurons after blastocyst transplantation and determine whether their implantation at the blastocyst stage can repair mice with an absence of myelin.
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0.958 |
2006 |
Recht, Lawrence D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Peritumoral Brain Edema in Patients With Malignant Brain Tumor |
0.958 |
2007 |
Recht, Lawrence D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Dexamethasone-Sparing Study Comparing Herf to Placebo |
0.958 |
2007 |
Recht, Lawrence D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Hcrf For Patients With Malignant Brain Tumor Who Require High-Dose Dexamethasone |
0.958 |
2007 |
Recht, Lawrence D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Peritumoral Brain Edema in Patients With Primary Malignant Glioma;(Hcrf) to Dex |
0.958 |
2007 — 2008 |
Recht, Lawrence D |
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.) |
Quantifying Cortical Neuron Production After Transplantation
[unreadable] DESCRIPTION (provided by applicant): The cerebral cortex controls mammalian behavior essentially through processing sensory input to then coordinate efferent activity via projection to subcortical structures. Anatomically, it is composed of a complex six-layer laminar structure. Sensory information processing occurs in the more superficial layers; cortical projection neurons (CPNs) arise in the deep layers and project axons either to other parts of the cortex or to subcortical areas, thus representing the most important cellular modulators of cortical output. Reestablishment of a CPN's complex, specific connectivity would therefore be an important goal of any repair strategy for cortical injuries. Recently, there has been much interest in using cellular therapy to replace neurons, usually through implantation of embryonic stem cells (ES cells). Although these cells can be readily induced to differentiate into neurons, it remains to be established whether there are qualitative differences between various differentiating strategies and types of neurons seen after transplantation. Our own studies assessing two pools of in vitro conditioned neuronal ES cells revealed an unexpected qualitative difference in their capacity to form CPN's after transplantation into neonatal cortex. Thus, while one cell pool produced virtually no CPN's, the other produced a robust subcortical projection that was remarkably anatomically appropriate. Furthermore, by serial comparisons of these two pools of cells, we were able to establish that this behavior was driven by a relatively small subset of transcription factors that function during development to produce the CPN population. These findings therefore raise the possibility that one can specifically modulate the neuronal phenotype of a cell repair treatment prior to transplantation through induction (or inhibition) of finite numbers of genes in vitro. In this R21 proposal, we propose to optimize the production of this specific neuronal cell subset through enriching the cell subpopulation for markers associated with CPN production. Additionally, we will assess the necessity and sufficiency of the identified genes in this process through either inducing their activity in the non- CPN producing pool of cells or silencing them in the CPN producing pool. With the results obtained, we will then be in a better position to assess whether this strategy has the capability of effecting functional improvement, thus moving it closer to eventual utility in the clinic, primarily as a treatment of cortical birth injuries. Brain injuries represent a significant public heath problem that is not only quality of life diminishing but also extremely costly. Improving recovery from these devastating problems is therefore of great relevance. Embryonic stem cells represent possibly the best potential cell type for use in brain transplantation. The ability to control the neuronal differentiation of these cells so that they can produce specific cell subsets should therefore be of great value in developing better therapeutic strategies for this problem. [unreadable] [unreadable]
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0.958 |
2007 |
Recht, Lawrence D |
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.) |
Spo 33555: Cdon: a Novel Marker of Neural Stem Cells
[unreadable] DESCRIPTION (provided by applicant): Stem cell activity has been reported in various adult tissues and organs, including some discrete regions within the adult brain. The identification of a pool of cells within the mammalian CNS with the properties both to self-renew as well as differentiate into all neural cell types has generated much excitement in the neurobiology community because of its relevance to brain regeneration, injury and neoplasia. Our ability to harness the regenerative capacity of stem cells to reduce the burden of neurological disease and damage hinges on understanding the fundamental biology of these cells. Making progress in adult stem cell research is dependent on clearly identifying and isolating discrete cell populations, characterizing these cells, as well as on deciphering signals in the surrounding environment that instruct these cells whether to remain as stem cells or to differentiate. We previously isolated a cell surface receptor, CDOn, whose expression pattern strikingly coincides with regions in the adult central nervous system associated with stem cell activity. Interestingly, the loss of this gene function results in a microform of holoprosencephaly. The purpose of the experiments proposed here are to explore the possibility that CDOn receptor expression delineates the sup-population of slowly cycling stem cells in the adult brain. We plan to establish the identity of the cells in the stem cell niche that express CDOn and to substantiate the potential usefulness of CDOn expression as a marker for specifically isolating these cells in vitro and in vivo. Because CDOn is a receptor, we believe that revealing the identity of cells in the stem cell niche that express the CDOn receptor in comparison to cells that do not will yield insights into how cells respond differently to extrinsic cues within the microenvironment of the stem cell niche. [unreadable] [unreadable] [unreadable]
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0.958 |
2008 |
Recht, Lawrence D |
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.) |
Cdon: a Novel Marker of Neuronal Stem Cells
[unreadable] DESCRIPTION (provided by applicant): Stem cell activity has been reported in various adult tissues and organs, including some discrete regions within the adult brain. The identification of a pool of cells within the mammalian CNS with the properties both to self-renew as well as differentiate into all neural cell types has generated much excitement in the neurobiology community because of its relevance to brain regeneration, injury and neoplasia. Our ability to harness the regenerative capacity of stem cells to reduce the burden of neurological disease and damage hinges on understanding the fundamental biology of these cells. Making progress in adult stem cell research is dependent on clearly identifying and isolating discrete cell populations, characterizing these cells, as well as on deciphering signals in the surrounding environment that instruct these cells whether to remain as stem cells or to differentiate. We previously isolated a cell surface receptor, CDOn, whose expression pattern strikingly coincides with regions in the adult central nervous system associated with stem cell activity. Interestingly, the loss of this gene function results in a microform of holoprosencephaly. The purpose of the experiments proposed here are to explore the possibility that CDOn receptor expression delineates the sup-population of slowly cycling stem cells in the adult brain. We plan to establish the identity of the cells in the stem cell niche that express CDOn and to substantiate the potential usefulness of CDOn expression as a marker for specifically isolating these cells in vitro and in vivo. Because CDOn is a receptor, we believe that revealing the identity of cells in the stem cell niche that express the CDOn receptor in comparison to cells that do not will yield insights into how cells respond differently to extrinsic cues within the microenvironment of the stem cell niche. [unreadable] [unreadable] [unreadable]
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0.958 |
2008 |
Recht, Lawrence D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Clinical Trial: Peritumoral Brain Edema in Patients With Primary Malignant Gliom
(11Beta,16alpha)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione; 1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone; 16Alpha-methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione; 16Alpha-methyl-9alpha-fluoro-delta1-hydrocortisone; 16Alpha-methyl-9alpha-fluoroprednisolone; 9Alpha-fluoro-11beta,17alpha,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione; 9alpha-Fluoro-16alpha- methylprednisolone; ACTH-Releasing Factor; Aacidexam; Active Follow-up; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Ambene; Amplidermis; Anemul mono; Antimicotico; Aquapred; Arm; Astrocytoma, Grade IV; Auxiloson; Azona; Baycuten; Baycuten N; Brain Edema; Brain Swelling; CRF-41; CRH; CRISP; Cell Communication and Signaling; Cell Signaling; Clinical; Clinical Trials; Clinical Trials, Unspecified; Computer Retrieval of Information on Scientific Projects Database; Corson; Corticoliberin; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone-41; Cortidexason; Cortisumman; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.p.; Dectancyl; Deenar; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dex-4; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexace; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dose; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; ENPT; End Point; EndPointCode; Endpoints; Enrollment; FLR; Failure (biologic function); Fluoro-9alpha Methyl-16alpha Prednisolone; Fluorodelta; Fortecortin; Funding; Gammacorten; Glioblastoma; Grade IV Astrocytic Neoplasm; Grade IV Astrocytic Tumor; Grant; Hexadecadrol; Hexadrol; Human; Human, General; Institution; Intracellular Communication and Signaling; Intracranial Edema; Investigators; KPS; Karnofsky; Karnofsky Index; Karnofsky Performance Status; Karnofsky Performance Status Scale; Karnofsky Scale; Label; Lokalison-F; Loverine; Malignant; Malignant - descriptor; Malignant Glial Neoplasm; Malignant Glial Tumor; Malignant Glioma; Malignant Neuroglial Neoplasm; Malignant Neuroglial Tumor; Man (Taxonomy); Man, Modern; Measures; Methylfluorprednisolone; Millicorten; Mymethasone; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neurologic; Neurologic Examination; Neurological; Neurological Examination; Ocasa; Orgadrone; Patients; Performance; Predni-F; Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)-; Protocol; Protocols documentation; QOL; Quality of life; Randomized; Relative; Relative (related person); Research; Research Personnel; Research Resources; Researchers; Resources; Safety; Score; Signal Transduction; Signal Transduction Systems; Signaling; Source; Spersadex; Spersadox; Steroid Compound; Steroids; Symptoms; Therapeutic; Time; Toxic effect; Toxicities; United States National Institutes of Health; Upper arm; Visit; Visumetazone; Week; auricularum; biological signal transduction; clinical investigation; corticotropin releasing hormone; day; enroll; failure; follow-up; glioblastoma multiforme; randomisation; randomization; randomly assigned; response; spongioblastoma multiforme; tumor; week trial; wet brain
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0.958 |
2008 |
Recht, Lawrence D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Clinical Trial: Hcrf For Patients With Malignant Brain Tumor Who Require High-Do
(11Beta,16alpha)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione; 1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone; 16Alpha-methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione; 16Alpha-methyl-9alpha-fluoro-delta1-hydrocortisone; 16Alpha-methyl-9alpha-fluoroprednisolone; 9Alpha-fluoro-11beta,17alpha,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione; 9alpha-Fluoro-16alpha- methylprednisolone; ACTH-Releasing Factor; Aacidexam; Active Follow-up; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Ambene; Amplidermis; Anemul mono; Antimicotico; Aquapred; Auxiloson; Azona; Baycuten; Baycuten N; Blinded; Brain Edema; Brain Swelling; CRF-41; CRH; CRISP; Cancer of Brain; Cell Communication and Signaling; Cell Signaling; Chronic; Clinical; Clinical Trials; Clinical Trials, Unspecified; Computer Retrieval of Information on Scientific Projects Database; Corson; Corticoliberin; Corticotropin-Releasing Factor; Corticotropin-Releasing Factor-41; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone-41; Cortidexason; Cortisumman; Daily; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.p.; Dectancyl; Deenar; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dex-4; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexace; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Dose; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Drugs; Fluoro-9alpha Methyl-16alpha Prednisolone; Fluorodelta; Fortecortin; Funding; Gammacorten; Grant; Hexadecadrol; Hexadrol; Human; Human, General; Institution; Intracellular Communication and Signaling; Intracranial Edema; Investigators; KPS; Karnofsky; Karnofsky Index; Karnofsky Performance Status; Karnofsky Performance Status Scale; Karnofsky Scale; Label; Lokalison-F; Loverine; Malignant Tumor of the Brain; Malignant neoplasm of brain; Man (Taxonomy); Man, Modern; Measures; Medication; Methylfluorprednisolone; Millicorten; Mymethasone; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neurologic; Neurological; Ocasa; Orgadrone; Patients; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Physicians; Placebo Control; Predni-F; Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)-; Protocol; Protocols documentation; QOL; Quality of life; Randomized; Research; Research Personnel; Research Resources; Researchers; Resources; Safety; Score; Signal Transduction; Signal Transduction Systems; Signaling; Source; Spersadex; Spersadox; Steroid Compound; Steroids; Symptoms; Title; Toxic effect; Toxicities; United States National Institutes of Health; Visit; Visumetazone; auricularum; biological signal transduction; clinical investigation; corticotropin releasing hormone; drug/agent; follow-up; randomisation; randomization; randomly assigned; wet brain
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0.958 |
2008 |
Recht, Lawrence D |
M01Activity Code Description: An award made to an institution solely for the support of a General Clinical Research Center where scientists conduct studies on a wide range of human diseases using the full spectrum of the biomedical sciences. Costs underwritten by these grants include those for renovation, for operational expenses such as staff salaries, equipment, and supplies, and for hospitalization. A General Clinical Research Center is a discrete unit of research beds separated from the general care wards. |
Clinical Trial: Dexamethasone-Sparing Study Comparing (Herf) to Placebo
(11Beta,16alpha)-9-fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-diene-3,20-dione; 1-Dehydro-16alpha-methyl-9alpha-fluorohydrocortisone; 16Alpha-methyl-9alpha-fluoro-1,4-pregnadiene-11beta,17alpha,21-triol-3,20-dione; 16Alpha-methyl-9alpha-fluoro-delta1-hydrocortisone; 16Alpha-methyl-9alpha-fluoroprednisolone; 9Alpha-fluoro-11beta,17alpha,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione; 9alpha-Fluoro-16alpha- methylprednisolone; Aacidexam; Active Follow-up; Adexone; Adverse effects; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Ambene; Amplidermis; Anemul mono; Antimicotico; Aquapred; Auxiloson; Azona; Baycuten; Baycuten N; Blinded; CRISP; Cell Communication and Signaling; Cell Signaling; Clinical Trials; Clinical Trials, Unspecified; Computer Retrieval of Information on Scientific Projects Database; Corson; Cortidexason; Cortisumman; Daily; Data Element; Decacort; Decadrol; Decadron; Decalix; Decameth; Decasone R.p.; Dectancyl; Deenar; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Deterioration; Dex-4; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexace; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasone; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Disorder of muscle, unspecified; Dose; Double-Blind Method; Double-Blind Study; Double-Blinded; Double-Masked Method; Double-Masked Study; Drops; Drugs; ENPT; End Point; EndPointCode; Endpoints; FLR; Failure (biologic function); Fluoro-9alpha Methyl-16alpha Prednisolone; Fluorodelta; Fortecortin; Funding; Gammacorten; Grant; Hexadecadrol; Hexadrol; Institution; Intracellular Communication and Signaling; Investigators; KPS; Karnofsky; Karnofsky Index; Karnofsky Performance Status; Karnofsky Performance Status Scale; Karnofsky Scale; Label; Lokalison-F; Loverine; Measures; Medical; Medication; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Methylfluorprednisolone; Millicorten; Monitor; Muscle Disease; Muscle Disorders; Muscle disease or syndrome; Muscular Diseases; Mymethasone; Myopathic Conditions; Myopathic Diseases and Syndromes; Myopathic disease or syndrome; Myopathy; Myopathy, unspecified; NIH; National Institutes of Health; National Institutes of Health (U.S.); Neoplasm Metastasis; Nervous System Physiology; Neurologic Examination; Neurologic function; Neurological Examination; Neurological function; Ocasa; Orgadrone; PBO; Patients; Performance; Pharmaceutic Preparations; Pharmaceutical Preparations; Placebo Control; Placebos; Predni-F; Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11beta,16alpha)-; QOL; Quality of life; Randomized; Relative; Relative (related person); Research; Research Personnel; Research Resources; Researchers; Resources; Safety; Score; Secondary Neoplasm; Secondary Tumor; Sham Treatment; Signal Transduction; Signal Transduction Systems; Signaling; Source; Spersadex; Spersadox; Steroid Compound; Steroids; Symptoms; Time; Treatment Side Effects; Tumor Cell Migration; United States National Institutes of Health; Visit; Visumetazone; Week; auricularum; biological signal transduction; cancer metastasis; clinical investigation; day; drug/agent; failure; follow-up; muscular disorder; nervous system function; randomisation; randomization; randomly assigned; sham therapy; side effect; therapy adverse effect; treatment adverse effect
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0.958 |
2014 — 2018 |
Recht, Lawrence D Spielman, Daniel M (co-PI) [⬀] Spielman, Daniel M (co-PI) [⬀] |
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. |
Metabolic Therapy of Gbm Guided by Mrs of Hyperpolarized 13c-Pyruvate
DESCRIPTION (provided by applicant): In addition to their abnormally high proliferative rates, cancer cells universally demonstrate an abnormal metabolism that is characterized by an overutilization of glycolysis (GLY) relative to the more energy efficient mitochondrial oxidative phosphorylation (OXPHOS). Originally described over 80 years ago by Warburg, this altered metabolism, more recently termed metabolic reprogramming, is now viewed as a hallmark of cancer [1], and appears intimately tied to the proliferative state. The novel clinical implicationof these observations on tumor metabolism is that they suggest that a potential anticancer strategy lies in reverting this metabolism towards normal levels, i.e., forcing OXPHOS. Although this would not result in cell kill per se, it should result in stabilization of growth with minimal toxiity. However, although a number of targets exist for which active drugs can be directed, we contend that the major obstacle towards taking this to the clinic is the inability to measure cancer metabolism in the intact organism. The recent development of hyperpolarized 13C magnetic resonance spectroscopy (MRS) enables for the first time the real-time investigation of in vivo metabolism with more than a 10,000-fold signal increase over conventional 13C methods. Using 13C-labeled pyruvate (Pyr) as a substrate allows us to quantitatively follow the in vivo fate of pyruvate, which occupies a key nodal point in the metabolic pathway in which glucose is either converted to lactate (Lac; reflecting GLY) or acetyl CoA (generating bicarbonate [Bic] in the process; reflecting OXPHOS). With this technology, it is therefore possible to measure the 13C labeling of lactate and bicarbonate following the bolus injection of hyperpolarized [1-13C]-Pyr, thus permitting a Lac/Bic ratio to be calculated, which we propose to study as a marker of therapeutic response. Bevacizumab (BEV; Avastin®) is a monoclonal antibody (mab) that binds vascular endothelial growth factor (VEGF), thus inhibiting angiogenesis. It is widely used in a number of tumor types, including glioblastoma multiforme, the most malignant of the primary brain tumors. Although it can have dramatic initial effects, its duration tends to be relatively short-lived and associated with the development of refractory tumor progression. Although an intimate relationship between flow and metabolism is well documented, there has been little study of the impact of BEV on tumor metabolism. We have proposed that BEV acutely disrupts tumor metabolism at the tissue level, such as to force OXPHOS, and that this transient effect correlates with tumor stabilization [2]. By improving Bic detection to enable quantitation, we have observed a marked decrease in Lac/Bic ratio in transplanted glioblastoma tissue after anti-VEGF therapy, an effect that can be seen within three hours of administration, providing initial support for this counterintuitive hypothesis. Considering that despite extensive study into its antiangiogenic effects, neither a reliable early clinical marker of BEV effect nor o resistance development has been elucidated, our results offer a new and exciting direction for improving the impact of this very valuable oncotherapeutic. This project represents a collaboration between a group that has been on the cutting edge of this technology with the P.I., a clinician scientist who is familiar with clinical trials as well as laboratory models of brain cancer. Glioblastoma multiforme (GBM), the most commonly occurring primary brain tumor, is an excellent prototypical cancer with which to assess metabolic therapies because of its high rate of GLY and treatment refractoriness. However, it is important to note that the derived findings should apply to all cancer. Our experiments are designed in such a way that by the end of this funding period, we will have refined this technology so as to perform imaging with high resolution as well as to assess molecules such as glutamate which are deeper into the OXPHOS pathway (SA1), determine the time course and dose relationships of the BEV effect in transplanted glioblastoma (SA2), assess the impact of anti-VEGF therapy on metabolic symbiosis (SA3) and assess whether these findings extrapolate to a more clinically relevant model in which brain tumors develop spontaneously after exposure to a neurocarcinogen in utero (SA4). These experiments therefore should move us close to our ultimate goal of linking BEV's treatment impact with an optimal lactate/bicarbonate ratio that can be used clinically not only as a measure of therapeutic efficacy, but also as a therapeutic goal. The recent awarding of funds to purchase a clinical grade polarizer at Stanford should also us to accelerate the translation of findings from bench to bedside.
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0.958 |
2016 — 2020 |
Recht, Lawrence D |
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 and Monitoring System (Core-014)
PROJECT SUMMARY ? PROTOCOL REVIEW AND MONITORING SYSTEM Overview The Protocol Review and Monitoring System (PRMS), referred to at Stanford as the Scientific Review Committee (SRC), has been operational at Stanford University since 2005. Each year we have reviewed our operations and implemented improvements in order to ensure that studies conducted at the Stanford Cancer Institute (SCI) are of the highest scientific merit, feasible to conduct and employ resources appropriately. SCI's SRC is charged with providing peer review of all institutional and national clinical research protocols involving cancer patients at Stanford. The patient and other populations from which SCI studies are drawn include those in the Stanford Clinical Cancer Center, Stanford Health Care at large including outreach sites, Stanford Children's Health and the Cancer Prevention Institute of California. Scientific review applies to all phases of clinical therapeutic intervention, behavioral clinical trials, tissue and body fluid research, and diagnostic trials that impact medical decision making for the treatment of cancer patients. Particular attention is paid to reviewing investigator-initiated clinical trials, and especially those for which there is no other peer-review mechanism. The primary focus of scientific review is on the scientific merit of the study. However, the SRC is also responsible for ensuring that studies conform to the research objectives and priorities of SCI. Scientific review is performed in addition to the review of ethical issues carried out by Stanford's Administrative Panels on Human Subjects in Medical Research, also called Institutional Review Boards (IRBs). Both the SRC and the IRB must approve any study prior to subject enrollment. SCI ensures that its clinical research studies are of true scientific merit, high quality, have access to an adequate patient population and meet requisite statistical benchmarks. To accomplish these objectives, the SRC is charged with providing scientific peer review of all research protocols involving cancer patients treated at SCI. The SRC also has the authority to review and approve or deny all trials involving subjects with cancer. The SRC is also responsible for annual reviews of studies and has the authority to suspend or close studies due to low accrual, stopping rule violations, change in scientific relevance or other scientifically-based reason.
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0.958 |
2020 — 2021 |
Recht, Lawrence D Spielman, Daniel M [⬀] Spielman, Daniel 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. |
Imaging Biomarkers For Glioma Treatment Response
ABSTRACT Alteration of metabolism so as to favor a preponderance of glycolysis (GLY) relative to oxidative phosphorylation (OXPHOS) is considered a hallmark of cancer. Known originally as the Warburg effect, and now considered part of the larger concept of metabolic reprogramming, these cellular changes represent a way for cancer tissue to support rapid proliferation by preserving carbon skeletons for biomass production. Understanding the mechanisms that underlie this metabolic shift is an active area of research. In the context of therapeutics, insights from recent studies provide strong support that this reprogramming phenotype is necessary and sufficient to support the cancer process, thus providing a basis for highly novel therapeutic strategies in which either blocking or reversing metabolic reprogramming is the goal. Furthermore, malignant gliomas, highly glycolytic cancers exceedingly resistant to conventional treatments, seem particularly suited to approaches that can subvert this phenotype, and we believe the most crucial obstacle to moving such therapies to clinic has been the inability to reliably measure in vivo response to such metabolic therapies. The scientific premise of this proposal is that hyperpolarized 13C (HP13C) magnetic resonance imaging (MRI) offers great promise in fulfilling this clinical need. Pyruvate (Pyr), located at a crucial juncture in the brain glucose metabolic pathway where it can be either reduced to lactate (Lac) or converted to acetyl CoA + CO2, which is then converted to bicarbonate (Bic), has the potential to be used as a HP13C surrogate marker of the balance between GLY and OXPHOS. Following the bolus injection of HP [1-13C]Pyr, we propose that the observed 13C-Lac/13C-Bic (Lac/Bic) ratios can be used as a quantitative biomarker of a changing balance between these two metabolic processes, thus providing key information on glucose?s metabolic fate complementary to the uptake information provided by more commonly available 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET). Here, we propose to add simultaneous FDG-PET/HP13C/MRI measurements to an upcoming Phase II clinical trial of malignant glioma treated with BPM31510 (Berg LLC), a nano-suspension of Coenzyme Q10 showing high accumulation in cancer cell mitochondria and having marked antitumor activity in multiple in vivo models (both alone and in combination with chemotherapeutic agents) with in vitro evidence strongly suggesting the effect is mediated via increasing OXPHOS (i.e., reversing the Warburg effect). Our overall goal is to assess the potential synergy of combining information on glucose uptake, as provided by FDG-PET, and glucose metabolism, as provided by HP13C, for tumor characterization, assessment of therapeutic response, and prediction of patient outcome. If successful, the results from this pilot study would provide the critical preliminary data to justify larger follow-up studies of the use of these imaging biomarkers with anticancer metabolic therapies.
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0.958 |