Grant Number:	1R01CA131151-01A1 Interpret this number
Primary Investigator:	Sarkar, Fazlul
Organization:	Wayne State University
Project Title:	RO1: a Novel and Targeted Approach to Inhibit Invasion and Angiogenesis
Fiscal Year:	2008

DESCRIPTION (provided by applicant): Among many solid tumors, pancreatic cancer (PC) has the worst prognosis and it is the fourth leading cause of all cancer deaths in the United States, which could be partly due to the ability of PC cells to orchestrate in "turning-on the switch" for migration, invasion, angiogenesis and metastatic processes during the early course of the disease. The development of PC is strongly favored due to initiation of inflammatory events as suggested by the presence of extensive desmoplastic stroma (fibrogenesis) found in human PCs, partly contributed by PDGF over-expression, generation of reactive oxygen species (ROS) and activation of NF-:B. In addition, activation of EGFR and Notch-1 signaling also leads to the activation of NF-:B and, in turn, regulates NF-:B downstream signaling molecules such as COX-2, MMP-9, uPA and VEGF, among others, that are known to be causally associated with migration, invasion, angiogenesis and metastasis, ultimately leading to poor survival of patients diagnosed with PCs. While conducting experiments using a non-toxic dietary chemopreventive agent, 3,3'-diindolylmethane (DIM), especially BR-DIM (hereafter known as B-DIM, a formulated DIM with greater bioavailability supplied by BioResponse, Inc.), we found that B-DIM is a potent inhibitor of PDGF-D (a recently identified PDGF), EGFR, Notch-1 and NF-:B which, in turn, inhibits MMP-9, uPA, PGE2 and VEGF secretion in B-DIM treated cells. Based on our results, we hypothesize that the use of B-DIM will serve as a novel approach by which the processes of cell migration, invasion and angiogenesis could be inhibited. We will test our hypothesis by accomplishing the following three specific aims. In aim-1, we will thoroughly investigate the consequence of B-DIM treatment of PC cells in vitro by analyzing the effect of B-DIM on PDGF-D, EGFR, Notch-1, NF-:B, uPA, MMP-9, VEGF, COX-2 (PGE2) in preventing cell growth, tumor cell migration, invasion and apoptosis, and the effect of B-DIM on angiogenesis tested by using conditioned media from B-DIM treated cells in vitro and also by plug assay in vivo. In aim-2, we will investigate the molecular mechanism(s) and the specific contribution of PDGF-D, EGFR, Notch-1, NF-:B, uPA, MMP-9, VEGF and COX-2 in mediating the biological activity of B-DIM in PC cells in vitro by applying knock-down and over-expression approaches. In the third specific aim, we will test the in vivo anti-tumor activity of B-DIM using an orthotopic PC model in SCID mice as well as in transgenic mouse models, and test whether the anti- tumor activity could be correlated with the down-regulation of EGFR, NF-:B, uPA, MMP-9, VEGF, PDGF-D and COX-2 in tumor tissues. Moreover, we will test whether the inactivation of these signaling pathways could lead to sensitization of PC cells to conventional therapeutic agents. The completion of the proposed study will provide mechanism-based evidence in support of the use of B-DIM for preventing PC cell growth, migration, invasion and angiogenesis, and induction of apoptotic cell death. PUBLIC HEALTH RELEVANCE: Our results could aid in designing innovative preventive and/or therapeutic approaches for saving lives of patients diagnosed with this deadly disease. This project is focused on elucidating the mechanism by which a chemopreventive agent (B-DIM) could prevent pancreatic tumor invasion and angiogenesis, resulting in the inhibition of tumor progression. We hypothesize that B-DIM will down regulate PDGF-D signaling among others, which in turn will inactivate PDGF-D downstream signaling, resulting in the inhibition of cell growth, invasion and angiogenesis, and the inhibition of tumor progression. We will test our hypothesis by three specific aims using molecular approaches and animal model studies.




The Role of Nutraceuticals in Pancreatic Cancer Prevention and Therapy: Targeting Cellular Signaling, MicroRNAs, and Epigenome.
Authors: Li Y. , Go V.L. , Sarkar F.H. .
Source: Pancreas, 2015 Jan; 44(1), p. 1-10.
PMID: 25493373
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Deregulation of miR-146a expression in a mouse model of pancreatic cancer affecting EGFR signaling.
Authors: Ali S. , Ahmad A. , Aboukameel A. , Ahmed A. , Bao B. , Banerjee S. , Philip P.A. , Sarkar F.H. .
Source: Cancer Letters, 2014-08-28 00:00:00.0; 351(1), p. 134-42.
EPub date: 2014-05-16 00:00:00.0.
PMID: 24839931
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MicroRNAs in personalized cancer therapy.
Authors: Sethi S. , Ali S. , Sethi S. , Sarkar F.H. .
Source: Clinical Genetics, 2014 Jul; 86(1), p. 68-73.
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Targeting CSCs in tumor microenvironment: the potential role of ROS-associated miRNAs in tumor aggressiveness.
Authors: Bao B. , Azmi A.S. , Li Y. , Ahmad A. , Ali S. , Banerjee S. , Kong D. , Sarkar F.H. .
Source: Current Stem Cell Research & Therapy, 2014 Jan; 9(1), p. 22-35.
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Emerging roles of PDGF-D in EMT progression during tumorigenesis.
Authors: Wu Q. , Hou X. , Xia J. , Qian X. , Miele L. , Sarkar F.H. , Wang Z. .
Source: Cancer Treatment Reviews, 2013 Oct; 39(6), p. 640-6.
EPub date: 2012-12-20 00:00:00.0.
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Pancreatic cancer stem cells: emerging target for designing novel therapy.
Authors: Li Y. , Kong D. , Ahmad A. , Bao B. , Sarkar F.H. .
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EPub date: 2012-03-20 00:00:00.0.
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Regulating miRNA by natural agents as a new strategy for cancer treatment.
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Systems biology approaches in identifying the targets of natural compounds for cancer therapy.
Authors: Tan Y. , Wu Q. , Xia J. , Miele L. , Sarkar F.H. , Wang Z. .
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Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy.
Authors: Bao B. , Ahmad A. , Azmi A.S. , Ali S. , Sarkar F.H. .
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Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype.
Authors: Wang Z. , Ali S. , Banerjee S. , Bao B. , Li Y. , Azmi A.S. , Korc M. , Sarkar F.H. .
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The role of cancer stem cells and miRNAs in defining the complexities of brain metastasis.
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Down-regulation of miR-221 inhibits proliferation of pancreatic cancer cells through up-regulation of PTEN, p27(kip1), p57(kip2), and PUMA.
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The biological kinship of hypoxia with CSC and EMT and their relationship with deregulated expression of miRNAs and tumor aggressiveness.
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MicroRNA profiling of diagnostic needle aspirates from patients with pancreatic cancer.
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Source: Journal Of Cellular Physiology, 2012 Oct; 227(10), p. 3373-80.
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Proof Of Concept: Network And Systems Biology Approaches Aid In The Discovery Of Potent Anticancer Drug Combinations
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Notch Signaling Proteins: Legitimate Targets For Cancer Therapy
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