2002 — 2005 |
Maity, Amit |
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. |
Regulation of Vegf in Tumors by Ras, Egf and Pten @ University of Pennsylvania
DESCRIPTION (provided by applicant): Vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, is often overexpressed in cancers. In many in vivo models, inhibition of VBGF function arrests tumor growth. While hypoxia has long been recognized to be a potent inducer of VEGF, VEGF can also be expressed in normoxia. Recent evidence indicates that angiogenesis can develop in tumor masses before they have grown to a size large enough to contain hypoxic regions, suggesting that angiogenic factors may be expressed by these tumors under normoxic conditions. In contrast to the induction of VEGF rnRNA under hypoxia whose mechanism is known to involve the hypoxia-inducible factor-1 (HIF-1), the upregulation of VEGF in normoxia is much less well understood. The overall aim of this grant is to study mechanisms of VEGF upregulation in normoxia by alterations commonly found in cancers: specifically, epidermal growth factor receptor (EGFR) activation and mutations in Ras and PTEN. VEGF mRNA levels and promoter activity in U87 human glioblastoma cells are increased by EGFR stimulation. Introduction of wild type PTEN into U87 cells, in which PTEN is inactivated, decreases VEGF mRNA levels and promoter activity. Specific Aim 1 will focus on defining the elements in this pathway, which appears to be PI(3) kinase dependent but independent of HIF- 1. H-ras transformation of Rat 1 fibroblasts leads to a six-fold increase in VEGF mRNA expression in normoxia. Furthermore, the level of HIF-1alpha protein is increased in normoxic Rat1-ras cells, an unexpected finding given that HIF-1alpha has traditionally been thought to only be induce under hypoxic conditions. The focus of Specific Aim 2 is to determine whether this increase in HIF- 1 alpha causes the increase in VEGF expression under normoxia. Aim 2 will also examine the signaling pathways that link Ras activation, HIF-1alpha and VEGF expression. These experiments will lead to a better understanding of HIF-1 alpha regulation, mechanisms of VEGF overexpression in cancers, and the effects of EGFR activation and Ras and PTEN mutations on gene expression.
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0.915 |
2006 — 2010 |
Maity, Amit |
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. |
Regulation of Vegf/Hif-1 by Akt: Implications For Radiotherapy @ University of Pennsylvania
DESCRIPTION (provided by applicant): Our long-term goal is to determine mechanisms by which the PI3K/AKT pathway, which is commonly activated in human cancers, increases expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-la (HIF-la). We also wish to understand what role this may play in the efficacy of EGFR inhibitors, which are currently being used in the clinic. VEGF, a key mediator of angiogenesis, is often overexpressed in human cancers. Hypoxia has long been recognized to be a potent inducer of VEGF expression through the transcription factor HIF-1. We have found that the PI3K/AKT pathway plays an important role in VEGF regulation through at least two different mechanisms. First, the PI3K/AKT pathway increases transcription by increasing binding of the transcription factor Sp1 to the VEGF proximal core promoter. Secondly, the AKT pathway can increase the expression of HIF-1a, which can also lead to increased VEGF transcription, particularly in hypoxia. In Specific Aim 1 we will explore the mechanisms by which AKT leads to increased Sp1-mediated transactivation of the VEGF promoter. In Specific Aim 2 we will study the potential role of glycogen synthase kinase-3p (GSK-3J3), a downstream target of AKT involved in protein translation, on increasing HIF-1 a. A number of drugs are currently being tested in the clinic that may work in part through the mechanisms described above. EGFR inhibitors (e.g. gefitinib, erlotinib) decrease PI3K/AKT signaling and we have found that these inhibitors also decrease HIF-1a and VEGF expression. Our preliminary data suggest that gefitinib may increase tumor oxygenation, which should lead to increased radiosensitization. Therefore, in Specific Aim 3 we will study the effects of EGFR inhibition on HIF-1 a and VEGF expression and on tumor oxygenation in vivo and the effects on radiosensitivity. LAY SUMMARY: We will study how the expression of VEGF, an important mediator of blood vessel growth, is increased in human tumors. The clinical importance of these studies is that EGFR inhibitors currently being used in the clinic may work though these pathways to increase the oxygenation of tumors. Increased oxygenation should make tumors more sensitive to radiation;therefore, our studies may be important in helping to optimize the combination of EGFR inhibitors with radiation.
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0.915 |
2014 — 2018 |
Lin, Alexander Maity, Amit |
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. |
Using 18f-Ef5 Pet to Measure Hypoxia Modulation by Nelfinavir in Larynx Cancer @ University of Pennsylvania
DESCRIPTION (provided by applicant): Radiation therapy (RT) is commonly used to treat solid tumors~ however, even with sophisticated treatment planning and dose delivery, the local control for many cancers remains poor. One clear example is high-risk (human papilloma virus (HPV)-negative), locally-advanced head and neck squamous cell carcinoma (LA-HNSCC), where local recurrences are common and cause significant morbidity and death. One factor strongly associated with local recurrence following RT in LA-HNSCC is tumor hypoxia. Consistent with this, hypoxia modification has been shown to improve local control and overall survival in patients with HNSCC, particularly in those with HPV-negative disease. We have found in pre-clinical models that nelfinavir (NFV), a HIV protease inhibitor with a long history of use in the clinic, decreases tumor hypoxia, which may increase extrinsic radiosensitivity. Additionally, NFV increases intrinsic radiosensitivity, as measured by clonogenic survival assays. We hypothesize that this may be related to the drug's ability to decrease glucose uptake. Aim 1 is a phase II clinical trial of NFV in combination with RT and concurrent cisplatin chemotherapy for patients with HPV-negative, locally advanced larynx cancer, which has a poor prognosis with standard chemoradiation. Outcomes will be compared to historical controls receiving standard therapy (5-yr disease- free survival 40%) to determine whether there is any improvement with the addition of NFV. We will assess the effect of NFV on hypoxia and tumor glucose metabolism via 18F-EF5 and 18F-FDG PET/CT scanning, respectively. We will measure the effect of NFV on the PI3K/Akt pathway by assessing phosphorylation of Akt and downstream proteins in peripheral blood mononuclear cells (PBMC). Correlation between clinical outcome and response via imaging or PBMCs may allow us to predict which patients are likely to respond to NFV, and to enrich our population for a future phase III randomized trial. Our approach may lead to a novel approach to treating HNSCC with radiation, which could be extended to other cancer types treated primarily with radiation. In the subsequent aims we will investigate two aspects of NFV action that are highly relevant to the ideas being tested in the clinical trial in Aim 1. In Aim 2 we will determine whether the effect of NFV on O2 consumption is mediated by Akt inhibition and whether the drug affects mitochondria function. If we find that the O2 effect is mediated by Akt, then measuring changes in hypoxia may be a surrogate for measuring Akt inhibition in this setting. In Aim 3, we will determine whether the effect of NFV on decreasing glucose uptake is mediated by Akt inhibition, which would have implications for using 18F-FDG-PET/CT scanning to assess the efficacy of PI3K/Akt inhibitors in general. We will also investigate whether the decrease in glucose uptake in response to NFV leads to impaired anti-oxidant capacity by decreasing flux through the oxidative pentose phosphate cycle (OPPC), which we hypothesize contributes to the drug's ability to increase intrinsic radiosensitization.
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0.915 |
2015 — 2019 |
Koumenis, Constantinos (co-PI) [⬀] Maity, Amit |
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. |
Improving Radiation Response by Targeting O2 Metabolism Via the Pi3k/Mtor Pathway @ University of Pennsylvania
DESCRIPTION (provided by applicant): Radiation therapy is commonly used to treat solid tumors including head and neck squamous cell cancer (HNSCC); however, many patients still fail locally. Therefore, we need to find new ways to increase its effectiveness. We have been investigating inhibitors of the PI3K/mTOR pathway. In preliminary studies we found that NVP-BEZ235, a dual PI3K/mTOR inhibitor, and NVP-BKM120, a PI3K inhibitor, radiosensitize cells in vitro and induce autophagy, which we hypothesize is a cytoprotective response rather than a mode of cell death. In Aim 1 we will test this hypothesis in vitro using BKM120 and also in vivo with flank and orthotopic tumors in nude mice. We will use both genetic approaches (knocking out key autophagy genes) and pharmacologic approaches (chemicals that inhibit autophagy, Spautin1 and chloroquine). We also have preliminary data that multiple drugs that inhibit PI3K/mTOR signaling including, the 2 above and GDC-0980, GDC-0068, and RAD001, decrease O2 consumption rate (OCR) in vitro. We have also shown that BEZ235 decreases tumor hypoxia in vivo; thereby, leading us to propose a new model by which oxygenation within tumors may be modulated to increase cell killing after radiation. In Aim 2 we will investigate the mechanism(s) by which these drugs decrease OCR. We have 2 hypotheses, the first of which is that they increase Ser293 phosphorylation of the E1? subunit of pyruvate dehydrogenase (PDH), which is a critical gatekeeper of mitochondrial respiration. Phosphorylation of PDH E1? inhibits its function, hence reduces entry of pyruvate into the citric acid cycle and consequently decreases OCR. Our second hypothesis is that drugs that inhibit mTOR downregulate the expression of mitochondrial proteins that are involved in cellular respiration. In Aim 3 we will investigate whether the decrease in O2 consumption by PI3K/mTOR inhibition leads to increased radiation sensitivity in vivo. One of the ways we will do this is by using the drug GDC-0980, which does not affect intrinsic (in vitro) radiosensitivity but does reduce OCR. Hence, if this drug leads to increased radiation response in vivo, it is likely through effects on oxygenation. In Aim 3 we will also continue our screen of a 426 chemical compound library of FDA- approved agents to search for other agents that decrease OCR. We will then test the top candidates (in terms of degree of reduction of OCR) for their effects on tumor hypoxia in vivo and determine whether they have an additive effect with PI3K/mTOR inhibitors on decreasing hypoxia. Successful completion of these aims will set the stage for PI3K/mTOR inhibitors currently being tested in the clinic to be used in combination with radiotherapy for HNSCC and generate new leads for translational drugs that impact upon tumor cell oxygen metabolism.
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0.915 |
2017 — 2021 |
Maity, Amit Minn, Andy J Vonderheide, Robert H [⬀] Wherry, E. John (co-PI) [⬀] |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Radiation and Checkpoint Blockade For Cancer Immune Therapy @ University of Pennsylvania
The long-term goal of this P01 is to understand the intersection of radiation biology and cancer immunology and to translate this research into better therapies with curative potential for patients with cancer. Radiation therapy (RT) can systemically impact the immune system, and recent clinical success of PD1 and CTLA4 immune checkpoint blockade (ICB) has given rise to our overarching hypothesis that the immune stimulatory effects of RT can expand the spectrum of clinical responsiveness when combined with dual ICB across multiple histologies. Our preliminary data and investigative approach bridges studies in both patients and animal models. To achieve our goals, we have developed three Projects, which require close coordination of projects and cores. In Project 1, we will determine the clinical and immunological impact of treating patients on two clinical trials: (i) nivolumab (PD1 mAb) and ipilimumab (CTLA4 mAb) with or without hypofractionated RT (HFRT) in a randomized phase II study in metastatic melanoma; and (ii) and tremelimumab (CTLA4 mAb) and durvalumab (PDL1 mAb) with HFRT at two dose schedules in metastatic pancreatic, lung, and breast carcinoma. In Project 2, we will determine the role of RT in establishing cancer immunity, evaluating the mechanism of anti-viral signaling through pattern recognition receptors and non-coding RNA and examining dendritic cell biology and CD40 activation. In Project 3, we will define the genetic and epigenetic basis of resistance to RT and ICB and examine PDL1 independent pathways to overcome this. Biomarkers revealed in Projects 2 and 3 will be examined using human samples from the clinical trials in Project 1. The Cores for this P01 are essential for our progress including provision of administration support for collaboration (Core A), a state-of-the-art platform for small animal radiation (Core B), and bioinformatics and biostatistical approaches to drive deep learning from data generated in all Projects (Core C). The potential for paradigm shifting impact is to transform the indication of RT from ?local therapy? to key part of a novel ?systemic? immune therapy for meaningful efficacy against metastatic and advanced cancer.
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0.915 |
2020 |
Maity, Amit |
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. |
Radiobiology and Imaging Research Program @ University of Pennsylvania
Project Summary The Radiobiology and Imaging Program has been continuously approved by the NCI Cancer Center Support Grant since 1987. The Program seeks to improve patient outcomes through the advanced understanding of how ionizing and non-ionizing radiation interacts with cancer and normal tissues. The Programmatic goals are to: (1) Study molecular mechanisms of radiation response and identify targets to improve radiotherapy. (2) Elucidate mechanisms underlying use of Photodynamic Therapy (PDT) and translate to the clinic. (3) Develop methods for measuring and altering tumor oxygenation and metabolic status; understand the molecular events governing cell death by IR and physiological stresses. (4) Develop novel techniques to image the interaction between radiation, PDT and tissues. (5) Understand the biological effects of protons to inform their effective clinical use. The Program was rated as ?Exceptional? at the time of the 2010 CCSG renewal application and is led by Constantinos Koumenis, PhD, Professor and Director of the Research Division of Radiation Oncology and Amit Maity, MD, PhD, Professor of Radiation Oncology. Drs. Maity and Koumenis are NCI-funded researchers who bring their scientific vision to this Program, which is focused on basic and translational research and the development of investigator-initiated trials. Since the last renewal, the Co- Leaders have recruited new junior and senior scientists, enhanced collaborative peer-reviewed funding and increased the number of investigator-initiated clinical trials involving radiotherapy and imaging. Moreover, Drs. Koumenis and Maity have steered the Program towards new areas of emphasis including combined radiation and immunotherapy modalities and precision medicine and they have expanded the incorporation of imaging modalities into basic and translational efforts. Through this process, they increased interactions with the Immunobiology, Cancer Therapeutics, Breast Cancer and Cancer Control Programs. A major development has been the substantial expansion of both translational and clinical studies of proton therapy. Program members represent six departments from four schools at Penn. During the past five years, translational research has continued to be a major focus. The 33 Program members have $7.7M in research grant funding (annual direct costs), of which $7.5M is peer-reviewed and $3.7M is NCI-funded. There were a total of 405 cancer-related publications authored by Program members during the project period. Of these, 19% are intra- Programmatic, 28% are inter-Programmatic and 53% are multi-institutional.
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0.915 |
2021 |
Maity, Amit |
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. |
Radiobiology and Imaging Program @ University of Pennsylvania
PROJECT SUMMARY ? Radiobiology and Imaging Program (RBI) The Radiobiology and Imaging Program (RBI) seeks to advance the understanding of the interaction of ionizing and non-ionizing radiation with cancer and normal tissues. RBI addresses the cancer burden within our catchment area through collaboration with our Community Outreach and Engagement (COE). Scientific Aims are to: 1) Develop and characterize agents to improve cancer therapy with radiation; 2) Investigate radiobiological or imaging methods of altering or interrogating the immune environment to improve therapeutic response; 3) Gain a deeper understanding of the tumor microenvironment (TME) and metabolism with the aim to leverage this understanding to improve therapeutic response; 4) Develop novel imaging to optimally guide cancer care; and 5) Understand the biological effects of protons to optimize their clinical use and determine which patients will benefit most from proton beam therapy. The Program is led by Amit Maity, MD, PhD, Professor and Executive Vice-Chair of the Department of Radiation Oncology, and Daniel Pryma, MD, Associate Professor of Radiology and Chief of the Division of Nuclear Medicine. Drs. Maity and Pryma are NCI-funded researchers who bring their scientific vision to this Program, which is focused on basic and translational research and the development of investigator-initiated trials. Since the last renewal, the Program Leaders recruited new junior and senior scientists, enhanced collaborative peer-reviewed funding, and more than doubled accruals to interventional clinical trials, especially investigator-initiated trials (which constitute 91.6% of interventional accruals). Drs. Maity and Pryma expanded the Program's focus on imaging modalities and theranostics and further enhanced the integration and interplay between radiobiology and imaging in RBI. A major development has been the substantial expansion of both translational and clinical studies of proton therapy. RBI has critical interactions with other ACC Programs including Tumor Biology, Immunobiology, Cancer Therapeutics, Breast Cancer, Cancer Control, Tobacco and Environmental Carcinogenesis, and Pediatric Oncology. The 44 Program members represent seven departments from four schools at Penn. RBI members have $12M in research grant funding (annual direct costs), of which $10.9M is peer-reviewed and $7M is NCI-funded. There were 654 cancer-related publications authored by Program members during the project period. Of these, 27% are intra-Programmatic, 35% are inter-Programmatic and 64% are multi- institutional. RBI has 36 R01-equivalents. Program members accrued 1,476 subjects to interventional trials, and 3,611 subjects to non-interventional trials.
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0.915 |