Chris Albanese

Georgetown University, Washington, Washington, D.C., United States

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Publications (134)741.2 Total impact

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    ABSTRACT: Metabotropic glutamate 1 (mGlu) receptor has been proposed as a target for the treatment of metastatic melanoma. Studies have demonstrated that inhibiting the release of glutamate (the natural ligand of mGlu1 receptors), results in a decrease of melanoma tumor growth in mGlu1 receptor-expressing melanomas. Here we demonstrate that mGlu1 receptors, which have been previously characterized as oncogenes, also behave like dependence receptors by creating a dependence on glutamate for sustained cell viability. In the mGlu1 receptor-expressing melanoma cell lines SK-MEL-2 (SK2) and SK-MEL-5 (SK5), we show that glutamate is both necessary and sufficient to maintain cell viability, regardless of underlying genetic mutations. Addition of glutamate increased DNA synthesis, whereas removal of glutamate not only suppressed DNA synthesis but also promoted cell death in SK2 and SK5 melanoma cells. Using genetic and pharmacological inhibitors, we established that this effect of glutamate is mediated by the activation of mGlu1 receptors. The stimulatory potential of mGlu1 receptors was further confirmed in vivo in a melanoma cell xenograft model. In this model, subcutaneous injection of SK5 cells with short hairpin RNA-targeted downregulation of mGlu1 receptors resulted in a decrease in the rate of tumor growth relative to control. We also demonstrate for the first time that a selective mGlu1 receptor antagonist JNJ16259685 ((3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-(cis-4-methoxycyclohexyl)-methanone) slows SK2 and SK5 melanoma tumor growth in vivo. Taken together, these data suggest that pharmacological inhibition of mGlu1 receptors may be a novel approach for the treatment of metastatic melanoma.Oncogene advance online publication, 28 July 2014; doi:10.1038/onc.2014.231.
    Oncogene 07/2014; · 8.56 Impact Factor
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    ABSTRACT: Mutations of the p53 gene hallmark many human cancers. Several p53 mutant proteins acquire the capability to promote cancer progression and metastasis, a phenomenon defined as Gain of Oncogenic Function (GOF). The downstream targets by which GOF p53 mutants perturb cellular programs relevant to oncogenesis are only partially known. We have previously demonstrated that SLC25A1 (CIC) promotes tumorigenesis, while its inhibition blunts tumor growth. We now report that CIC is a direct transcriptional target of several p53 mutants. We identify a novel interaction between mutant p53 (mutp53) and the transcription factor FOXO-1 which is responsible for regulation of CIC expression levels. Tumor cells harboring mutp53 display higher CIC levels relative to p53 null or wild-type tumors, and inhibition of CIC activity blunts mutp53-driven tumor growth, partially overcoming GOF activity. CIC inhibition also enhances the chemotherapeutic potential of platinum-based agents. Finally, we found that elevated CIC levels predict poor survival outcome in tumors hallmarked by high frequency of p53 mutations. Our results identify CIC as a novel target of mutp53 and imply that the employment of CIC inhibitors may improve survival rates and reduce chemo-resistance in tumors harboring these types of mutations, which are among the most intractable forms of cancers.
    Oncotarget 03/2014; · 6.64 Impact Factor
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    ABSTRACT: Metal-oxo clusters have been used as building blocks to form hybrid nanomaterials and evaluated as potential MRI contrast agents. We have synthesized a biocompatible co-polymer based on a water stable, non-toxic, mixed-metal oxo cluster, Mn8Fe4O12(O2CCH3)16(H2O)4 or Mn8Fe4 and styrene. The cluster alone was screened by NMR for relaxivity was found to be a promising T2 contrast agent, with r1 = 2.3 mM-1s-1 and r2 = 29.5 mM-1s-1. Initial cell studies on two human prostate cancer cell lines, DU-145 and LNCap, reveal that the cluster has low cytotoxicity and may be potentially used in vivo. By exchanging the acetate for vinyl benzoic acid, the metal oxo-cluster Mn8Fe4(VBA)16 (VBA = vinyl benzoic acid), can be co-polymerized with styrene. Miniemulsion synthesis of this co-polymer was used to form paramagnetic nanobeads (~80 nm diameter), which were also evaluated as a contrast agent for MRI. These highly monodispersed, hybrid nanoparticles have enhanced properties, with the option for surface functionalization, making them a promising tool for biomedicine. Interestingly, both relaxivity measurements and MRI studies show that embedding the Mn8Fe4 core within a polymer matrix decreases r2 effects with little effect on r1, resulting in a positive T1 contrast enhancement.
    ACS Nano 09/2013; · 12.03 Impact Factor
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    ABSTRACT: Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.
    EMBO Molecular Medicine 09/2013; · 7.80 Impact Factor
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    ABSTRACT: Despite recent epidemiological evidences linking radiation exposure and a number of human ailments including cancer, mechanistic understanding of how radiation inflicts long-term changes in cerebral cortex, which regulates important neuronal functions, remains obscure. The current study dissects molecular events relevant to pathology in cerebral cortex of 6 to 8 weeks old female C57BL/6J mice two and twelve months after exposure to a γ radiation dose (2 Gy) commonly employed in fractionated radiotherapy. For a comparative study, effects of 1.6 Gy heavy ion56Fe radiation on cerebral cortex were also investigated, which has implications for space exploration. Radiation exposure was associated with increased chronic oxidative stress, oxidative DNA damage, lipid peroxidation, and apoptosis. These results when considered with decreased cortical thickness, activation of cell-cycle arrest pathway, and inhibition of DNA double strand break repair factors led us to conclude to our knowledge for the first time that radiation caused aging-like pathology in cerebral cortical cells and changes after heavy ion radiation were more pronounced than γ radiation.
    Aging 08/2013; · 4.70 Impact Factor
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    Cell cycle (Georgetown, Tex.) 04/2013; 12(10). · 5.24 Impact Factor
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    ABSTRACT: One fundamental feature of mutant forms of p53 consists in their accumulation at high levels in tumors. At least in the case of neomorphic p53 mutations, which acquire oncogenic activity, stabilization is a driving force for tumor progression. It is well documented that p53 mutants are resistant to proteasome-dependent degradation compared to wild-type p53, but the exact identity of the pathways that affect mutant p53 stability is still debated. We have recently shown that macroautophagy (autophagy) provides a route for p53 mutant degradation during restriction of glucose. Here we further show that in basal conditions of growth, inhibition of autophagy with chemical inhibitors or by downregulation of the essential autophagic genes ATG1/Ulk1, Beclin-1 or ATG5, results in p53 mutant stabilization. Conversely, overexpression of Beclin-1 or ATG1/Ulk1 leads to p53 mutant depletion. Furthermore, we found that in many cell lines, prolonged inhibition of the proteasome does not stabilize mutant p53 but leads to its autophagic-mediated degradation. Therefore, we conclude that autophagy is a key mechanism for regulating the stability of several p53 mutants. We discuss plausible mechanisms involved in this newly identified degradation pathway as well as the possible role played by autophagy during tumor evolution driven by mutant p53.
    Cell cycle (Georgetown, Tex.) 03/2013; 12(7). · 5.24 Impact Factor
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    ABSTRACT: Chagas disease, caused by Trypanosoma cruzi, is an important cause of morbidity and mortality primarily resulting from cardiac dysfunction, although T. cruzi infection results in inflammation and cell destruction in many organs. We found that T. cruzi (Brazil strain) infection of mice results in pancreatic inflammation and parasitism within pancreatic β-cells with apparent sparing of α cells and leads to the disruption of pancreatic islet architecture, β-cell dysfunction, and surprisingly, hypoglycemia. Blood glucose and insulin levels were reduced in infected mice during acute infection and insulin levels remained low into the chronic phase. In response to the hypoglycemia, glucagon levels 30 days postinfection were elevated, indicating normal α-cell function. Administration of L-arginine and a β-adrenergic receptor agonist (CL316, 243, respectively) resulted in a diminished insulin response during the acute and chronic phases. Insulin granules were docked, but the lack of insulin secretion suggested an inability of granules to fuse at the plasma membrane of pancreatic β-cells. In the liver, there was a concomitant reduced expression of glucose-6-phosphatase mRNA and glucose production from pyruvate (pyruvate tolerance test), demonstrating defective hepatic gluconeogenesis as a cause for the T. cruzi-induced hypoglycemia, despite reduced insulin, but elevated glucagon levels. The data establishes a complex, multi-tissue relationship between T. cruzi infection, Chagas disease, and host glucose homeostasis.
    American Journal Of Pathology 01/2013; · 4.60 Impact Factor
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    ABSTRACT: This Guest Editorial introduces this month's special Imaging Theme Issue, a series of reviews that highlight the use of noninvasive imaging techniques for the advancement of small animal studies.
    American Journal Of Pathology 12/2012; · 4.60 Impact Factor
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    ABSTRACT: Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy.
    American Journal Of Pathology 12/2012; · 4.60 Impact Factor
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    ABSTRACT: The majority of human tumors express mutant forms of p53 at high levels, promoting gain of oncogenic functions and correlating with disease progression, resistance to therapy and unfavorable prognosis. p53 mutant accumulation in tumors is attributed to the ability to evade degradation by the proteasome, the only currently recognized machinery for p53 disruption. We report here that glucose restriction (GR) induces p53 mutant deacetylation, routing it for degradation via autophagy. Depletion of p53 leads, in turn, to robust autophagic activation and to cell death, while expression of degradation-defective mutant p53 blocks autophagy and enables survival to GR. Furthermore, we found that a carbohydrate-free dietetic regimen that lowers the fasting glucose levels blunts p53 mutant expression and oncogenic activity relative to a normal diet in several animal model systems. These findings indicate that the stability of mutant forms of p53 is influenced by the levels of glucose and by dietetic habits. They also unravel the existence of an inhibitory loop between autophagy and mutant p53 that can be exploited therapeutically.
    Cell cycle (Georgetown, Tex.) 11/2012; 11(23). · 5.24 Impact Factor
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    ABSTRACT: Dysregulation of the pathways that preserve mitochondrial integrity hallmarks many human diseases including diabetes, neurodegeration, aging and cancer. The mitochondrial citrate transporter gene, SLC25A1 or CIC, maps on chromosome 22q11.21, a region amplified in some tumors and deleted in developmental disorders known as velo-cardio-facial- and DiGeorge syndromes. We report here that in tumor cells CIC maintains mitochondrial integrity and bioenergetics, protects from mitochondrial damage and circumvents mitochondrial depletion via autophagy, hence promoting proliferation. CIC levels are increased in human cancers and its inhibition has anti-tumor activity, albeit with no toxicity on adult normal tissues. The knock-down of the CIC gene in zebrafish leads to mitochondria depletion and to proliferation defects that recapitulate features of human velo-cardio-facial syndrome, a phenotype rescued by blocking autophagy. Our findings reveal that CIC maintains mitochondrial homeostasis in metabolically active, high proliferating tissues and imply that this protein is a therapeutic target in cancer and likely, in other human diseases.
    Oncotarget 10/2012; · 6.64 Impact Factor
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    ABSTRACT: The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with its enhanced potency previously observed in a variety of human cancer cell lines. More importantly, in vivo MRI and single voxel proton MR-Spectroscopy further established that VMY-1-103 inhibited disease progression and affected key metabolites in a mouse model of hedgehog-driven medulloblastoma.
    Cell cycle (Georgetown, Tex.) 09/2012; 11(20):3801-9. · 5.24 Impact Factor
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    ABSTRACT: Brown adipose tissue (BAT) and white adipose tissue (WAT) and adipocytes are targets of Trypanosoma cruzi infection. Adipose tissue obtained from CD-1 mice 15 days after infection, an early stage of infection revealed a high parasite load. There was a significant increase in macrophages in infected adipose tissue and a reduction in lipid accumulation, adipocyte size, and fat mass and increased expression of lipolytic enzymes. Infection increased levels of Toll-like receptor (TLR) 4 and TLR9 and in the expression of components of the mitogen-activated protein kinase pathway. Protein and messenger RNA (mRNA) levels of peroxisome proliferator-activated receptor γ were increased in WAT, whereas protein and mRNA levels of adiponectin were significantly reduced in BAT and WAT. The mRNA levels of cytokines, chemokines, and their receptors were increased. Nuclear Factor Kappa B levels were increased in BAT, whereas Iκκ-γ levels increased in WAT. Adipose tissue is an early target of T. cruzi infection.
    The Journal of Infectious Diseases 03/2012; 205(5):830-40. · 5.85 Impact Factor
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    ABSTRACT: The role of caveolin and caveolae in the pathogenesis of infection has only recently been appreciated. In this chapter, we have highlighted some important new data on the role of caveolin in infections due to bacteria, viruses and fungi but with particular emphasis on the protozoan parasites Leishmania spp., Trypanosoma cruzi and Toxoplasma gondii. This is a continuing area of research and the final chapter has not been written on this topic.
    Advances in experimental medicine and biology 01/2012; 729:65-82. · 1.83 Impact Factor
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    ABSTRACT: Medulloblastoma is a highly malignant childhood brain tumor and is often characterized by alterations in cell cycle regulatory pathways and genes. Using FDA-approved arsenic trioxide (ATO) treated ND2-SmoAl mouse model, we present an integrated imaging and systems biology approach to assess tumor responses to ATO and to uncover the complexity of therapeutic molecular biology. Kaplan-Meier survival and MRI tumor growth analyses established the effectiveness of ATO treatment. Differential analysis of protein data identified biologically plausible gene markers. Differential dependence network analyses further revealed novel rewiring “hubs” of biological networks triggered by ATO at systems level. Functional analyses on statistically significant networked molecular markers confirmed ATO's role as an effective anti-proliferative and pro-apoptotic drug, in vivo.
    Genomic Signal Processing and Statistics, (GENSIPS), 2012 IEEE International Workshop on; 01/2012
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    ABSTRACT: The blood-brain barrier (BBB) provides natural protection to the central nervous system against noxious substances but also prevents access to therapeutics. Previously-investigated strategies for introducing drugs into the brain have included disruption of the BBB through energy deposition (RF, ultrasound), and diffusion from brain injections (along nonvascular routes) directly into the brain parenchyma. Magnetic gradients can increase transport rates of nanoparticle ferrofluids. As an example, we and others have shown significant increases in transport of drug-coated magnetic nanoparticles across the round window membrane [1]. Transport of chemicals across the cribiform plate (that separates the nasal cavity from the intracranial compartment) and into the brain is used naturally for olfaction, and by drug users (both legal and illicit). In pilot animal studies, we have shown that transport of magnetic nanoparticles can be dramatically increased across the cribiform plate into the brain olfactory bulb, through the application of magnetic gradients on the order of 0.5 T/cm. The increased concentrations of nanoparticles were easily detected with 4.7 T MRI systems. Transport of ferrofluid was observed from the posterior brain to the olfactory bulb under the influence of similar gradients. Such high magnetic gradients could be implemented through custom coils to effect MRI guidance, with minimal bioeffects if ramped up quickly [2]. These levels of gradients are easily realized in either a classic pull magnet configuration or with a Halbach push magnet array, with the push conferring additional flexibility as compared to standard approaches [3]. Additional studies are underway to exploit the use of drug-coated magnetic nanoparticles to gain entry in the central nervous system via natural entry-ways. Potential applications include delivery of drugs for the amelioration of epilepsy, motor and behavior/addictive disorders and to combat infectious diseases.
    Nuclear Science Symposium and Medical Imaging Conference (NSS/MIC), 2012 IEEE; 01/2012
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    ABSTRACT: We demonstrate that a Rho kinase inhibitor (Y-27632), in combination with fibroblast feeder cells, induces normal and tumor epithelial cells from many tissues to proliferate indefinitely in vitro, without transduction of exogenous viral or cellular genes. Primary prostate and mammary cells, for example, are reprogrammed toward a basaloid, stem-like phenotype and form well-organized prostaspheres and mammospheres in Matrigel. However, in contrast to the selection of rare stem-like cells, the described growth conditions can generate 2 × 10(6) cells in 5 to 6 days from needle biopsies, and can generate cultures from cryopreserved tissue and from fewer than four viable cells. Continued cell proliferation is dependent on both feeder cells and Y-27632, and the conditionally reprogrammed cells (CRCs) retain a normal karyotype and remain nontumorigenic. This technique also efficiently establishes cell cultures from human and rodent tumors. For example, CRCs established from human prostate adenocarcinoma displayed instability of chromosome 13, proliferated abnormally in Matrigel, and formed tumors in mice with severe combined immunodeficiency. The ability to rapidly generate many tumor cells from small biopsy specimens and frozen tissue provides significant opportunities for cell-based diagnostics and therapeutics (including chemosensitivity testing) and greatly expands the value of biobanking. In addition, the CRC method allows for the genetic manipulation of epithelial cells ex vivo and their subsequent evaluation in vivo in the same host.
    American Journal Of Pathology 12/2011; 180(2):599-607. · 4.60 Impact Factor
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    ABSTRACT: Commentary to:: Glutamine fuels a vicious cycle of autophagy in the tumor stroma and oxidative mitochondrial metabolism in epithelial cancer cells: Implications for preventing chemotherapy resistance: Ying-Hui Ko, Zhao Lin, Neal Flomenberg, Richard G. Pestell, Anthony Howell, Federica Sotgia, Michael P. Lisanti and Ubaldo E. Martinez-Outschoorn.
    Cancer biology & therapy 12/2011; 12(12). · 3.29 Impact Factor
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    ABSTRACT: Medulloblastoma is the most prevalent of childhood brain malignancies, constituting 25% of childhood brain tumors. Craniospinal radiotherapy is a standard of care, followed by a 12mo regimen of multi-agent chemotherapy. For children less than 3 y of age, irradiation is avoided due to its destructive effects on the developing nervous system. Long-term prognosis is worst for these youngest children and more effective treatment strategies with a better therapeutic index are needed. VMY-1-103, a novel dansylated analog of purvalanol B, was previously shown to inhibit cell cycle progression and proliferation in prostate and breast cancer cells more effectively than purvalanol B. In the current study, we have identified new mechanisms of action by which VMY-1-103 affected cellular proliferation in medulloblastoma cells. VMY-1-103, but not purvalanol B, significantly decreased the proportion of cells in S phase and increased the proportion of cells in G(2)/M. VMY-1-103 increased the sub G(1) fraction of apoptotic cells, induced PARP and caspase-3 cleavage and increased the levels of the Death Receptors DR4 and DR5, Bax and Bad while decreasing the number of viable cells, all supporting apoptosis as a mechanism of cell death. p21(CIP1/WAF1) levels were greatly suppressed. Importantly, we found that while both VMY and flavopiridol inhibited intracellular CDK1 catalytic activity, VMY-1-103 was unique in its ability to severely disrupt the mitotic spindle apparatus significantly delaying metaphase and disrupting mitosis. Our data suggest that VMY-1-103 possesses unique antiproliferative capabilities and that this compound may form the basis of a new candidate drug to treat medulloblastoma.
    Cancer biology & therapy 11/2011; 12(9):818-26. · 3.29 Impact Factor

Publication Stats

9k Citations
741.20 Total Impact Points

Institutions

  • 2003–2014
    • Georgetown University
      • • Department of Pharmacology
      • • Department of Oncology
      • • Lombardi Cancer Center
      Washington, Washington, D.C., United States
  • 1997–2013
    • Albert Einstein College of Medicine
      • • Department of Pathology
      • • Diabetes Research Center
      • • Department of Developmental and Molecular Biology
      • • Albert Einstein Cancer Center
      • • Department of Medicine
      New York City, NY, United States
  • 2012
    • Federal University of Minas Gerais
      Cidade de Minas, Minas Gerais, Brazil
  • 2010
    • University of Texas Southwestern Medical Center
      • Touchstone Center for Diabetes
      Dallas, Texas, United States
    • University of Washington Seattle
      • Division of Oncology
      Seattle, WA, United States
  • 2009
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      Maryland, United States
  • 2007
    • Thomas Jefferson University
      • Kimmel Cancer Center
      Philadelphia, PA, United States
  • 2003–2005
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 2001
    • Albert Einstein Medical Center
      Philadelphia, Pennsylvania, United States
    • University of California, San Francisco
      San Francisco, California, United States
  • 1999–2001
    • University of Western Australia
      Perth City, Western Australia, Australia
  • 2000
    • McMaster University
      Hamilton, Ontario, Canada
  • 1991–1999
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1995–1997
    • Northwestern University
      • Division of Endocrinology, Metabolism and Molecular Medicine
      Evanston, IL, United States