title: Suppression of SRC Signaling Is Effective in Reducing Synergy between Glioblastoma and Stromal Cells.
abstract: Glioblastoma cells efficiently interact with and infiltrate the surrounding normal tissue, rendering surgical resection and adjuvant chemo/radiotherapy ineffective. New therapeutic targets, able to interfere with glioblastoma's capacity to synergize with normal brain tissue, are currently under investigation. The compound Si306, a pyrazolo[3,4-d]pyrimidine derivative, selected for its favorable activity against SRC, was tested in vitro and in vivo on glioblastoma cell lines. In vivo, combination treatment with Si306 and radiotherapy was strongly active in reducing U-87 xenograft growth with respect to control and single treatments. The histology revealed a significant difference in the stromal compartment of tumoral tissue derived from control or radiotherapy-treated samples with respect to Si306-treated samples, showing in the latter a reduced presence of collagen and α-SMA-positive cells. This effect was paralleled in vitro by the capacity of Si306 to interfere with myofibroblastic differentiation of normal fibroblasts induced by U-87 cells. In the presence of Si306, TGF-β released by U-87 cells, mainly in hypoxia, was ineffective in upregulating α-SMA and β-PDGFR in fibroblasts. Si306 efficiently reached the brain and significantly prolonged the survival of mice orthotopically injected with U-87 cells. Drugs that target SRC could represent an effective therapeutic strategy in glioblastoma, able to block positive paracrine loop with stromal cells based on the β-PDGFR axis and the formation of a tumor-promoting microenvironment. This approach could be important in combination with conventional treatments in the effort to reduce tumor resistance to therapy. Mol Cancer Ther; 15(7); 1535-44. ©2016 AACR.
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, L'Aquila, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Calgani
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy. Lead Discovery Siena S.r.l., Castelnuovo Berardenga, Siena, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vignaroli
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy. Lead Discovery Siena S.r.l., Castelnuovo Berardenga, Siena, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Zamperini
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy. Lead Discovery Siena S.r.l., Castelnuovo Berardenga, Siena, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Coniglio
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, L'Aquila, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, L'Aquila, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Di Cesare
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, L'Aquila, Italy.
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, L'Aquila, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Mattei
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, L'Aquila, Italy.
authors.forename: Flora
authors.initials: F
authors.lastname: Vitale
authors.affiliation: Dipartimento di Farmacia, Università di Genova, Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Dipartimento Biotecnologie, Chimica e Farmacia, Università degli Studi di Siena, Siena, Italy. Lead Discovery Siena S.r.l., Castelnuovo Berardenga, Siena, Italy. Biotechnology College of Science and Technology, Temple University, Philadelphia, Pennsylvania.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
authors.affiliation: Dipartimento di Scienze Cliniche Applicate e Biotecnologiche, Università dell'Aquila, L'Aquila, Italy. adriano.angelucci@univaq.it.
authors.forename: Adriano
authors.initials: A
authors.lastname: Angelucci
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002450:Cell Communication / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D019061:src-Family Kinases