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Growth factor receptors as target for melanoma treatment
Universita degli Studi di Roma 'Tor Vergata'
DEPARTMENT OF SYSTEMS MEDICINE, University of Rome Tor Vergata, Via Montpellier, 1, 00133 Rome Italy
English, Italian, Spanish
Type of Research Project
- Basic science
What is the background of the project?
Cutaneous melanoma is an aggressive cancer with high metastatic potential and low survival rates. In the search of new molecularly targeted therapies, identification of signaling molecules involved in acquisition of a metastatic phenotype by melanoma cells is of primary importance. We recently generated a murine anti-Vascular endothelial growth factor receptor-1 (VEGFR-1) monoclonal antibody (D16F7 mAb), having a novel non-competitive mechanism of action: it down-modulates membrane receptor signaling without interfering with Vascular endothelial growth factor A (VEGF-A) or Placental growth factor (PlGF) binding. Thus, this mAb doesn’t interfere with the decoy function of the soluble VEGFR-1. D16F7 has activity against melanoma through: a) inhibition of tumor-associated angiogenesis; b) reduction of myeloid progenitor mobilization and tumor infiltration by myelomonocytic cells contributing to disease progression; c) direct inhibition of chemotaxis and vasculogenic mimicry of VEGFR-1 positive melanoma cells. Our preliminary results indicate that Platelet Derived Growth Factor (PDGF)-C is able to stimulate neuropilin-1 (NRP-1) favoring melanoma switch from proliferative to invasive phenotypes. Interestingly, both NRP-1 and PDGF-C are expressed by melanoma and tumor stromal cells. We recently identified an amino acid PDGF-C sequence potentially involved in its interaction with NRP-1.
What is the aim of the project?
The aims of the projects are: a) to validate the efficacy of targeting VEGFR-1 signaling, as monotherapy or combined with immune checkpoint and kinase inhibitors, for melanoma treatment and to generate a humanized antibody that recapitulates D16F7 properties as a prototype for future clinical development. b) to use the identified PDGF-C peptide to generate a mAbs that abrogates PDGF-C/NRP-1 interaction and inhibits melanoma invasiveness.
What techniques and methods are used?
1) Tumor cell chemotaxis assay; 2) Invasion assay; 3) Cell proliferation assays 4) Western blot analysis of proteins; 5) Mice immunization to generate mAbs; 6) mAb screning by ELISA (enzyme-linked immunosorbent assay).
What is the role of the student?
- The student will mainly observe
- The student will observe the practical experiments but will be highly involved in the analysis of the results
- The tasks will be done under supervision
What are the tasks expected to be accomplished by the student?
Students are expected to: a) to spend at least 40 hours/week in the laboratory; b) to critically report the content of scientific articles related to the topics of the project; c) to participate to lab meeting aimed at planning experimental activities performed in the laboratory related to the ongoing projects; d) keep record on a daily basis of the laboratory activities in a paper notebook as well as in a pc; d) to analyse the experimental results and to make hypothesis for planning next experiments; e) to learn how to write a scientific protocol.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a scientific report
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
Basic skills of working in a research laboratory. Subjects passed: Biochemistry, General pathology; Pharmacology
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Graduated students (less than 6 months)
- Lacal PM; Graziani G.Therapeutic implication of vascular endothelial growth factor receptor-1 (VEGFR-1) targeting in cancer cells and tumor microenvironment by competitive and non-competitive inhibitors. Pharmacol Res. 2018;136:97-107.doi: 10.1016/j.phrs.2018.08.023
- Atzori MG; Tentori L; Ruffini F; Ceci C; Bonanno E; Scimeca M; Lacal PM; Graziani G. The Anti-Vascular Endothelial Growth Factor Receptor-1 Monoclonal Antibody D16F7 Inhibits Glioma Growth and Angiogenesis In Vivo. J Pharmacol Exp Ther. 2018;364(1):77-86. doi: 10.1124/jpet.117.244434.
- Atzori MG; Tentori L; Ruffini F; Ceci C; Lisi L; Bonanno E; Scimeca M; Eskilsson E; Daubon T; Miletic H; Ricci Vitiani L; Pallini R; Navarra P; Bjerkvig R; D'Atri S; Lacal PM; Graziani G. The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells. J Exp Clin Cancer Res. 2017;36(1):106. doi: 10.1186/s13046-017-0577-2.
- Ruffini F; Levati L; Graziani G; Caporali S; Atzori MG; D'Atri S; Lacal PM.Platelet-derived growth factor-C promotes human melanoma aggressiveness through activation of neuropilin-1. Oncotarget. 2017;8(40):66833-66848. doi: 10.18632/oncotarget.18706
- Graziani G; Ruffini F; Tentori L; Scimeca M; Dorio AS; Atzori MG; Failla CM; Morea V; Bonanno E; D'Atri S; Lacal PM. Antitumor activity of a novel anti-vascular endothelial growth factor receptor-1 monoclonal antibody that does not interfere with ligand binding. Oncotarget. 2016;7(45):72868-72885. doi: 10.18632/oncotarget.12108.
- Graziani G; Lacal PM. Neuropilin-1 as Therapeutic Target for Malignant Melanoma. Front Oncol. 2015 Jun 3;5:125. doi: 10.3389/fonc.2015.00125.
- Ruffini F; Graziani G; Levati L; Tentori L; D'Atri S; Lacal PM. Cilengitide downmodulates invasiveness and vasculogenic mimicry of neuropilin 1 expressing melanoma cells through the inhibition of αvβ5 integrin. Int J Cancer. 2015;136(6):E545-58. doi: 10.1002/ijc.29252.
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