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43
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Introduction
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April 2009 - present
Publications
Publications (43)
Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantin...
We performed parallel investigations in cabozantinib-treated patients in a Phase 2 trial and simultaneously in Patient-derived Xenograft (PDX) models to better understand the roles of MET and VEGFR-2 as targets for prostate cancer therapy.
In the clinical trial, radiographic imaging and serum markers were examined, as well as molecular markers in t...
While several new therapies are FDA-approved for bone-metastatic prostate cancer (PCa), patient survival has only improved marginally. Here, we report that chitosan nanoparticle-mediated delivery of miR-34a, a tumor suppressive microRNA that downregulates multiple gene products involved in PCa progression and metastasis, inhibited prostate tumor gr...
Background:
Src has a critical role in tumor cell migration and invasion. Increased Src activity has been shown to correlate with disease progression and poor prognosis, suggesting Src could serve as a therapeutic target for kinase inhibition. Saracatinib (AZD0530) is a novel selective oral Src kinase inhibitor.
Methods:
Metastatic colorectal ca...
To study the role of FAK signaling complexes in promoting metastatic properties of prostate cancer (PCa) cells, we selected stable, highly migratory variants, termed PC3 Mig-3 and DU145 Mig-3, from two well-characterized PCa cell lines, PC3 and DU145. These variants were not only increased migration and invasion in vitro, but were also more metasta...
Metastatic Prostate Cancer (PCa) is the second leading cause of cancer related-deaths in men in the United States. Understanding the molecular events critical to PCa metastasis should lead to novel therapies for treatment of metastatic disease. To assess molecular alterations required for increased PCa cell migration, a critical step in metastasis,...
The nonreceptor tyrosine kinase Src regulates multiple pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. It is robustly activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance in vitro and in vivo, but not after 5-fluorouracil (5-FU) alone. However, activation of Src and i...
Background: Ligand independent receptor tyrosine kinase activation can be mediated by activation through other growth factor receptors. Understanding this cross-talk has implications in the use of combination therapies, as growth factor receptors often stimulate overlapping signaling pathways.
Purpose: To examine crosstalk between IGF-R1 and MET i...
The receptor tyrosine kinase, MET, has been implicated in tumorigenesis and metastasis of many solid tumors, by multiple mechanisms, including cross talk with Epidermal Growth Factor Receptor. In this study, we examined the role of Insulin Like Growth Factor Receptor-1 (IGF-1R) signaling in MET activation, focusing on prostate cancer cells. Stimula...
Background: Cancer stem cells have tumor-initiation and tumor-maintenance capabilities. Stem-like cells are present in colorectal adenomas, but their relationship to adenoma pathology and patient characteristics, including metachronous development of an additional adenoma ("recurrence"), have not been studied extensively. We evaluated the expressio...
Background: Prostate cancer (PCa) is the second leading cause of cancer deaths. Deaths invariably result from metastasis, most commonly to the bone. Tumor-microenvironment interactions of metastatic PCa in the bone are critical for growth at the metastatic site. These interactions suggest that therapies will need to target both tumor cells and the...
Treatment of metastatic prostate cancer (PCa) with single agents has shown only modest efficacy. We hypothesized dual inhibition of different pathways in PCa results in improved tumor inhibition. The Src family kinases (SFK) and insulin-like growth factor-1 (IGF-1) signaling axes are aberrantly activated in both primary PCa and bone metastases and...
(A) Expression of SFK proteins Src, Yes, Fyn, and Lyn was demonstrated by Western Blot in AR-negative PC-3 cells, AR-positive LNCaP cells, and in the primary human AR-expressing CRPC xenograft MDA PCa 133. (B) Knockdown of Src and IGF-1R in PC-3 and LNCaP cells. (C) PC-3–shIGF-1R or control cells were incubated for up to 72 hours with and without d...
Dasatinib and BMS-754807 (BMS-807) do not modulate Erk1/2 phosphorylation. PC-3 cells were serum starved for 72 hours and then pre-incubated for 2 hours with BMS-754807 at either 2 µM or 5 µM, with dasatinib at 100 nM, or with both. After 2 hours, the cells were stimulated with 50 ng/mL rhIGF-1 for 3 minutes. Then protein was harvested and the (pho...
Dasatinib (DSA) and BMS-754807 (BMS-807) inhibit tumor growth after orthotopic injection of PC3-LG cells into the prostates of nude mice. The mice (n = 8 per group) were treated with dasatinib and BMS-754807 alone and in combination at the doses described in Methods starting 10 days after injection of the tumor cells. (A) The prostates were removed...
3561
Background: The nonreceptor tyrosine kinase Src regulates pathways critical to tumor proliferation, chemoresistance, and epithelial-to-mesenchymal transition. In vitro, Src is activated after acute oxaliplatin exposure and in acquired oxaliplatin resistance, but not after 5-FU alone. Activation of Src and its substrate FAK in metastatic colore...
61
Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases (SFK) and IR/IGF-1R, respectively. Based on a phase I/II clinical trial in which 9/19 pts treated with docet...
21
Background: The Src and IGF-1R axes are aberrantly activated in both PCa and the microenvironment of bone metastases. Dasatinib and BMS-754807 are clinically promising small molecule inhibitors with high potency against Src family kinases and IGF-1R, respectively. The aim of this study was to establish antitumor co-operativity by combining IGF-1...
Therapies to target prostate cancer bone metastases have only limited effects. New treatments are focused on the interaction between cancer cells, bone marrow cells and the bone matrix. Osteoclasts play an important role in the development of bone tumors caused by prostate cancer. Since Src kinase has been shown to be necessary for osteoclast funct...
Chemotherapeutic regimens for the treatment of colorectal cancer generally include oxaliplatin, although inherent and acquired resistance is common. One potential mediator of oxaliplatin sensitivity is the nonreceptor protein tyrosine kinase, Src, the activity of which correlates with disease stage and patient survival. Therefore, we investigated t...
Locoregional and distant recurrence remains common and usually fatal for patients with advanced head and neck squamous cell carcinoma (HNSCC). One promising molecular target in HNSCC is the Src family kinases (SFK). SFKs can affect cellular proliferation and survival by activating the signal transducer and activator of transcription (STAT) family o...
Pancreatic cancer is an exceptionally lethal disease with an annual mortality nearly equivalent to its annual incidence. This dismal rate of survival is due to several factors including late presentation with locally advanced, unresectable tumors, early metastatic disease, and rapidly arising chemoresistance. To study the mechanisms of chemoresista...
14032
Background: Colorectal cancer is the leading cause of cancer deaths in the USA, largely due to metastatic disease in the liver. The specific activity of the non-receptor protein tyrosine kinase, Src, is increased during colon tumor progression and contributes to metastasis; thus, Src inhibitors may have efficacy in the treatment of advanced-s...
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Overexpression and/or activation of c-Met, the protein tyrosine kinase receptor for the hepatocyte growth factor/scatter factor (HGF/SF), and the protein tyrosine kinase, Src, have been implicated in the progression and metastasis of human colorectal carcinoma (CRC). Previously, through ribozyme-mediated c-Met downregulation, we demonstrated a caus...
EphA2 is an oncoprotein and tyrosine kinase receptor that is overexpressed in ovarian and many other cancers. We investigated the effects of reduced EphA2 levels on tumor growth and the tumor microenvironment in an orthotopic ovarian cancer model.
The effect of the EphA2-agonistic monoclonal antibody EA5, alone or in combination with paclitaxel, on...
Vascular endothelial growth factor (VEGF) is the predominant pro-angiogenic cytokine in human malignancy, and its expression correlates with disease recurrence and poor outcomes in patients with colorectal cancer. Recently, expression of vascular endothelial growth factor receptors (VEGFRs) has been observed on tumours of epithelial origin, includi...
The nonreceptor protein tyrosine kinase Src is overexpressed in 70% of pancreatic adenocarcinomas. Here, we describe the effect of molecular and pharmacological down-regulation of Src on incidence, growth, and metastasis of pancreatic tumor cells in an orthotopic model. Src expression in L3.6pl human pancreatic tumor cells was reduced by stable exp...
Experimental evidence suggests that CXCR4, a Gi protein-coupled receptor for the ligand CXCL12/stromal cell-derived factor-1alpha (SDF-1alpha), plays a role in breast cancer metastasis. Transactivation of HER2-neu by G protein-coupled receptor activation has been reported as a ligand-independent mechanism of activating tyrosine kinase receptors. We...
To determine whether insulinlike growth factor-I (IGF-I) and hepatocyte growth factor (HGF) cooperate to induce migration and invasion of human colorectal carcinoma (CRC) cells and whether the effects of IGF-I and/or HGF are mediated through activation of the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system, a central mediator of tu...
The urokinase-type plasminogen activator receptor (u-PAR) contributes to colon cancer invasion and metastases. We have shown previously that u-PAR expression in colon cancer is driven by the Src tyrosine kinase. In the current study, we determined the ability of PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine), a Src kinase inh...
Overexpression of c-Met, the protein tyrosine kinase receptor for the hepatocyte growth factor/scatter factor, has been implicated in the progression and metastasis of human colorectal carcinoma. To examine the role of c-Met on in vitro and in vivo growth of human colon tumor cell lines, stable subclones of the high metastatic human colorectal carc...
The objective of this study was to determine if the Src tyrosine kinase is overexpressed and activated in late-stage human ovarian cancers.
Western analysis and immune complex kinase assays were performed on a panel of human ovarian cancer cell lines and normal ovarian epithelial cell cultures, and immunohistochemical analysis for Src and activated...
Src is a non-receptor protein tyrosine kinase, the expression and activity of which is increased in >80% of human colon cancers with respect to normal colonic epithelium. Previous studies from this and other laboratories have demonstrated that Src activity contributes to tumorigenicity of established colon adenocarcinoma cell lines. Src participate...
The purpose of this study was to determine the effects of adenoviral transgene expression of MMAC/PTEN on the in vitro and in vivo growth and survival of PC3 human prostate cancer cells.
Adenoviruses expressing MMAC/PTEN or green fluorescent protein as a control were introduced into PC3 cells, and effects on signal transduction pathways and growth...
The c-Yes proto-oncogene (pp62c-Yes) encodes a non-receptor-type protein tyrosine kinase (NRPTK) of the Src family. c-Yes activities and protein levels are elevated in human melanoma and melanocyte cell lines. Because the neurotrophins (NT) are important in the progression of melanoma to the brain-metastatic phenotype, we determined whether NT stim...
Vascular endothelial growth factor (VEGF) is implicated in the angiogenesis of human colon cancer. Recent evidence suggests
that factors that regulate VEGF expression may partially depend on c-src-mediated signal transduction pathways. The tyrosine kinase activity of Src is activated in most colon tumors and cell lines.
We established stable subclo...
The c-src protooncogene encodes a protein tyrosine kinase, pp60c-src, that is a mediator in many signal transduction pathways. One pathway in which pp60c-src protein tyrosine kinase activity is implicated involves regulation of vascular endothelial growth factor (VEGF), an angiogenic factor important to neovascularization of growing tumors. Recentl...
In greater than 80% of colon tumors and established cell lines, the specific activities of the protein tyrosine kinases pp60(c-src) and pp62(c-yes) are increased with respect to normal colonic epithelial cells. However, no mutations in either gene have been identified in colon tumors. Therefore, the possible biological consequences of activations o...
The effect of herbimycin A, an ansamycin antibiotic which inhibits cellular transformation by retroviral tyrosine kinases, on the monolayer growth of seven colon tumor cell lines and one cell line established from normal colonic mucosa, CCL239, was examined. Each colon tumor cell line tested showed dose-dependent growth inhibition in response to he...
