Greenebaum Cancer Center

Dunkirk Town Center, MD, United States

Greenebaum Cancer Center

Dunkirk Town Center, MD, United States
SEARCH FILTERS
Time filter
Source Type

Zhou H.,University of Maryland, Baltimore | Binmadi N.O.,University of Maryland, Baltimore | Binmadi N.O.,King Abdulaziz University | Yang Y.-H.,University of Maryland, Baltimore | And 4 more authors.
Angiogenesis | Year: 2012

The semaphorins and plexins comprise a family of cysteine-rich proteins implicated in control of nerve growth and development and regulation of the immune response. Our group and others have found that Semaphorin 4D (SEMA4D) and its receptor, Plexin-B1, play an important role in tumor-induced angiogenesis, with some neoplasms producing SEMA4D in a manner analogous to vascular endothelial growth factor (VEGF) in order to attract Plexin-B1-expressing endothelial cells into the tumor for the purpose of promoting growth and vascularity. While anti-VEGF strategies have been the focus of most angiogenesis inhibition research, such treatment can lead to upregulation of pro-angiogenic factors that can compensate for the loss of VEGF, eventually leading to failure of therapy. Here, we demonstrate that SEMA4D cooperates with VEGF to promote angiogenesis in malignancies and can perform the same function in a setting of VEGF blockade. We also show the potential value of inhibiting SEMA4D/Plexin-B1 signaling as a complementary mechanism to anti-VEGF treatment, particularly in VEGF inhibitor-resistant tumors, suggesting that this may represent a novel treatment for some cancers. © 2012 Springer Science+Business Media B.V.


Zhou H.,University of Maryland, Baltimore | Yang Y.-H.,University of Maryland, Baltimore | Binmadi N.O.,University of Maryland, Baltimore | Binmadi N.O.,King Abdulaziz University | And 4 more authors.
Experimental Cell Research | Year: 2012

Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, . in vitro and . in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. © 2012 Elsevier Inc.


Yang Y.-H.,University of Maryland, Baltimore | Buhamrah A.,University of Maryland, Baltimore | Schneider A.,University of Maryland, Baltimore | Schneider A.,Greenebaum Cancer Center | And 5 more authors.
PLoS ONE | Year: 2016

Bone density is controlled by interactions between osteoclasts, which resorb bone, and osteoblasts, which deposit it. The semaphorins and their receptors, the plexins, originally shown to function in the immune system and to provide chemotactic cues for axon guidance, are now known to play a role in this process as well. Emerging data have identified Semaphorin 4D (Sema4D) as a product of osteoclasts acting through its receptor Plexin-B1 on osteoblasts to inhibit their function, tipping the balance of bone homeostasis in favor of resorption. Breast cancers and other epithelial malignancies overexpress Sema4D, so we theorized that tumor cells could be exploiting this pathway to establish lytic skeletal metastases. Here, we use measurements of osteoblast and osteoclast differentiation and function in vitro and a mouse model of skeletal metastasis to demonstrate that both soluble Sema4D and protein produced by the breast cancer cell line MDA-MB-231 inhibits differentiation of MC3T3 cells, an osteoblast cell line, and their ability to form mineralized tissues, while Sema4D-mediated induction of IL-8 and LIX/CXCL5, the murine homologue of IL-8, increases osteoclast numbers and activity. We also observe a decrease in the number of bone metastases in mice injected with MDA-MB-231 cells when Sema4D is silenced by RNA interference. These results are significant because treatments directed at suppression of skeletal metastases in bone-homing malignancies usually work by arresting bone remodeling, potentially leading to skeletal fragility, a significant problem in patient management. Targeting Sema4D in these cancers would not affect bone remodeling and therefore could elicit an improved therapeutic result without the debilitating side effects. © 2016 Yang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Zhou H.,University of Maryland, Baltimore | Yang Y.-H.,University of Maryland, Baltimore | Basile J.R.,University of Maryland, Baltimore | Basile J.R.,Greenebaum Cancer Center
Angiogenesis | Year: 2014

Semaphorin 4D (SEMA4D) is a member of a family of transmembrane and secreted proteins that have been shown to act through its receptor Plexin-B1 to regulate axon growth cone guidance, lymphocyte activation, and bone density. SEMA4D is also overexpressed by some malignancies and plays a role in tumor-induced angiogenesis similar to vascular endothelial growth factor (VEGF), a protein that has been targeted as part of some cancer therapies. In an attempt to examine the different effects on tumor growth and vascularity for these two pro-angiogenic factors, we previously noted that while inhibition of both VEGF and SEMA4D restricted tumor vascularity and size, vessels forming under conditions of VEGF blockade retained their association with pericytes while those arising in a background of SEMA4D/Plexin-B1 deficiency did not, an intriguing finding considering that alteration in pericyte association with endothelial cells is an emerging aspect of anti-angiogenic intervention in the treatment of cancer. Here we show through array analysis, immunoblots, migration and co-culture assays and VE-cadherin immunohistochemistry that SEMA4D production by head and neck carcinoma tumor cells induces expression of platelet-derived growth factor-B and angiopoietin-like protein 4 from endothelial cells in a Plexin-B1/Rho-dependent manner, thereby influencing proliferation and differentiation of pericytes and vascular permeability, whereas VEGF lacks these effects. These results partly explain the differences observed between SEMA4D and VEGF in pathological angiogenesis and suggest that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of solid tumors. © 2013 Springer Science+Business Media Dordrecht.


McKay R.R.,Dana-Farber Cancer Institute | Gray K.P.,Dana-Farber Cancer Institute | Hayes J.H.,Dana-Farber Cancer Institute | Bubley G.J.,Beth Israel Deaconess Medical Center | And 4 more authors.
Cancer | Year: 2015

BACKGROUND Patients with biochemical disease recurrence (BCR) after definitive treatment for prostate cancer comprise a heterogeneous population for whom standard therapy options are lacking. The purpose of the current trial was to evaluate the feasibility, toxicity, and efficacy of early multimodality systemic therapy in men with BCR. METHODS Eligible patients had an increasing prostate-specific antigen (PSA) level, a PSA doubling time ≤10 months, and no evidence of metastases after radical prostatectomy (RP) and/or radiotherapy (RT) for localized disease. Treatment consisted of docetaxel at a dose of 75 mg/m2 every 3 weeks for 4 cycles, bevacizumab at a dose of 15 mg/kg every 3 weeks for 8 cycles, and androgen deprivation therapy (ADT) for 18 months. The primary endpoint was the percentage of patients who were free from PSA progression 1 year after the completion of therapy. RESULTS A total of 41 patients were included in the analysis. At 1 year after the completion of ADT, 45% of patients (13 of 29 patients) and 29% of patients (5 of 17 patients) with a testosterone level ≥100 ng/dL and ≥240 ng/dL, respectively, had a PSA <0.2 ng/mL. The median follow-up was 27.5 months (interquartile range, 21.8-38.1 months). Eight patients (20%) were free from PSA progression, 19 patients (46%) did not reinitiate ADT, and 34 patients (83%) were free from metastasis. Sixteen patients (39%) experienced grade 3 and 5 patients (12%) experienced grade 4 toxicities (toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]). CONCLUSIONS Multimodality systemic therapy with docetaxel, bevacizumab, and ADT is feasible and produces PSA responses in men with BCR. Long-term follow-up is needed to determine the percentage of patients with a durable PSA response who are able to avoid having to reinitiate prostate cancer therapy. Cancer 2015;121:2603-2611. © 2015 American Cancer Society.


Jain A.,Albany State University | Kaczanowska S.,University of Maryland Baltimore County | Davila E.,University of Maryland Baltimore County | Davila E.,Greenebaum Cancer Center | Davila E.,Bressler Research Building
Frontiers in Immunology | Year: 2014

Chronic inflammation has long been associated with the development of cancer. Among the various signaling pathways within cancer cells that can incite the expression of inflammatory molecules are those that activate IL-1 receptor-associated kinases (IRAK). The IRAK family is comprised of four family members, IRAK-1, IRAK-2, IRAK-3 (also known as IRAK-M), and IRAK-4, which play important roles in both positively and negatively regulating the expression of inflammatory molecules. The wide array of inflammatory molecules that are expressed in response to IRAK signaling within the tumor microenvironment regulate the production of factors which promote tumor growth, metastasis, immune suppression, and chemotherapy resistance. Based on published reports we propose that dysregulated activation of the IRAK signaling pathway in cancer cells contributes to disease progression by creating a highly inflammatory tumor environment. In this article, we present both theoretical arguments and reference experimental data in support of this hypothesis. © 2014 Jain, Kaczanowska and Davila.


Tseng I.-C.,Greenebaum Cancer Center | Xu H.,Greenebaum Cancer Center | Chou F.-P.,Greenebaum Cancer Center | Li G.,University of Maryland, Baltimore | And 4 more authors.
Journal of Biological Chemistry | Year: 2010

Extracellular acidosis often rapidly causes intracellular acidification, alters ion channel activities, and activates G protein-coupled receptors. In this report, we demonstrated a novel cellular response to acidosis: induction of the zymogen activation of matriptase. Acid-induced matriptase activation is ubiquitous among epithelial and carcinoma cells and is characterized by rapid onset, fast kinetics, and the magnitude of activation seen. Trace amounts of activated matriptase can be detected 1 min after cells are exposed to pH 6.0 buffer, and the vast majority of latent matriptase within the cells is converted to activated matriptase within 20 min. Matriptase activation may be a direct response to proton exposure because acid-induced matriptase activation also occurs in an in vitro, cell-free setting in which intracellular signaling molecules and ion channel activities are largely absent. Acid-induced matriptase activation takes place both on the cell surface and inside the cells, likely due to the parallel intracellular acidification that activates intracellular matriptase. Following matriptase activation, the active enzyme is immediately inhibited by binding to hepatocyte growth factor activator inhibitor 1, resulting in stable matriptase-hepatocyte growth factor activator inhibitor 1 complexes that are rapidly secreted. As an early response to acidosis, matriptase activation can also be induced by perturbation of intracellular pH homeostasis by 5-(N-methyl-N-isobutyl)-amiloride and 5-(N-ethyl-Nisopropyl)- amiloride, both of which inhibit Na+/H+ exchangers, and diisothiocyanostilbene-2,2′-disulfonic acid, which can inhibit other acid-base ion channels. This study uncovers a novel mechanism regulating proteolysis in epithelial and carcinoma cells, and also demonstrates that a likely function of matriptase is as an early response to acidosis. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Shum J.W.,University of Texas Health Science Center at Houston | Emmerling M.,University of Maryland, Baltimore | Lubek J.E.,Greenebaum Cancer Center | Lubek J.E.,University of Maryland, Baltimore | Ord R.A.,University of Maryland, Baltimore
Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology | Year: 2014

Lymphoma of the parotid gland is a relatively rare occurrence among head and neck tumors. Presentation is indistinguishable from other swellings of the parotid gland; therefore, it is important to consider lymphoma in the differential diagnosis when examining parotid swellings. Parotid lymphomas are most likely to be B-cell non-Hodgkin lymphoma of 1 of 3 types, which include follicular, marginal zone, and diffuse large B cell, although other histologic patterns have been described. We present a review of 3 patients with parotid lymphoma who presented to the University of Maryland Medical Center's Department of Oral and Maxillofacial Surgery with facial swelling. Two patients were diagnosed with follicular lymphoma, whereas the third was diagnosed with marginal zone lymphoma. © 2014 Elsevier Inc. All rights reserved.


PubMed | Sloan Kettering Cancer Center, Greenebaum Cancer Center, Beth Israel Deaconess Medical Center and Dana-Farber Cancer Institute
Type: Clinical Trial, Phase II | Journal: Cancer | Year: 2015

Patients with biochemical disease recurrence (BCR) after definitive treatment for prostate cancer comprise a heterogeneous population for whom standard therapy options are lacking. The purpose of the current trial was to evaluate the feasibility, toxicity, and efficacy of early multimodality systemic therapy in men with BCR.Eligible patients had an increasing prostate-specific antigen (PSA) level, a PSA doubling time 10 months, and no evidence of metastases after radical prostatectomy (RP) and/or radiotherapy (RT) for localized disease. Treatment consisted of docetaxel at a dose of 75 mg/m(2) every 3 weeks for 4 cycles, bevacizumab at a dose of 15 mg/kg every 3 weeks for 8 cycles, and androgen deprivation therapy (ADT) for 18 months. The primary endpoint was the percentage of patients who were free from PSA progression 1 year after the completion of therapy.A total of 41 patients were included in the analysis. At 1 year after the completion of ADT, 45% of patients (13 of 29 patients) and 29% of patients (5 of 17 patients) with a testosterone level 100 ng/dL and 240 ng/dL, respectively, had a PSA <0.2 ng/mL. The median follow-up was 27.5 months (interquartile range, 21.8-38.1 months). Eight patients (20%) were free from PSA progression, 19 patients (46%) did not reinitiate ADT, and 34 patients (83%) were free from metastasis. Sixteen patients (39%) experienced grade 3 and 5 patients (12%) experienced grade 4 toxicities (toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 3.0]).Multimodality systemic therapy with docetaxel, bevacizumab, and ADT is feasible and produces PSA responses in men with BCR. Long-term follow-up is needed to determine the percentage of patients with a durable PSA response who are able to avoid having to reinitiate prostate cancer therapy.


PubMed | Greenebaum Cancer Center
Type: Journal Article | Journal: Leukemia & lymphoma | Year: 2015

Patients with acute leukemia develop venous thrombosis (VT) related to central venous catheters (CVCs). Anticoagulation (AC) in these patients who are thrombocytopenic and often coagulopathic is challenging. To evaluate the safety and efficacy of AC in treating CVC-related VT, we retrospectively compared outcomes of patients with acute leukemia who were treated or not with AC during induction chemotherapy and post-discharge. Twenty-one patients with CVC-related VT received AC, 14 did not. VT resolved in 80% of patients in the AC group (similarly with low-dose and high-dose enoxaparin) and 45% in the non-AC group (p = 0.11). Fourteen (67%) patients in the AC group are alive (median survival not reached), compared to four patients (29%) in the non-AC group (median survival 9 months) (p = 0.015) with a hazard ratio (HR) of 0.32 (95% confidence interval: 0.12-0.85) in favor of AC. HR remained < 1 after adjustments for leukemia type and cytogenetics. Bleeding (< grade 4) occurred in five and one patients in the AC vs. non-AC groups, respectively (p = 0.37).

Loading Greenebaum Cancer Center collaborators
Loading Greenebaum Cancer Center collaborators