title: SDF-1 inhibition targets the bone marrow niche for cancer therapy.
abstract: Bone marrow (BM) metastasis remains one of the main causes of death associated with solid tumors as well as multiple myeloma (MM). Targeting the BM niche to prevent or modulate metastasis has not been successful to date. Here, we show that stromal cell-derived factor-1 (SDF-1/CXCL12) is highly expressed in active MM, as well as in BM sites of tumor metastasis and report on the discovery of the high-affinity anti-SDF-1 PEGylated mirror-image l-oligonucleotide (olaptesed-pegol). In vivo confocal imaging showed that SDF-1 levels are increased within MM cell-colonized BM areas. Using in vivo murine and xenograft mouse models, we document that in vivo SDF-1 neutralization within BM niches leads to a microenvironment that is less receptive for MM cells and reduces MM cell homing and growth, thereby inhibiting MM disease progression. Targeting of SDF-1 represents a valid strategy for preventing or disrupting colonization of the BM by MM cells.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Roccaro
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Sacco
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Werner G
authors.initials: WG
authors.lastname: Purschke
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Buchner
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Maasch
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Zboralski
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zöllner
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Vonhoff
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishima
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Maiso
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Michaela R
authors.initials: MR
authors.lastname: Reagan
authors.affiliation: Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Lonardi
authors.affiliation: Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Ungari
authors.affiliation: Department of Pathology, University of Brescia Medical School, Spedali Civili di Brescia, 25123 Brescia, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Eulberg
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Kruschinski
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Vater
authors.affiliation: Spedali Civili di Brescia, Department of Hematology, Centro per la Ricerca Onco-ematologica AIL, (CREA), 25123 Brescia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rossi
authors.affiliation: NOXXON Pharma AG, 10589 Berlin, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: irene_ghobrial@dfci.harvard.edu.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Ghobrial
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D019046:Bone Marrow Neoplasms / Q000378:metabolism / Q000556:secondary; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009362:Neoplasm Metastasis; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000737:chemistry; D011719:Pyrazines / Q000494:pharmacology
chemical_list: D001897:Boronic Acids; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D009841:Oligonucleotides; D011719:Pyrazines; D011092:Polyethylene Glycols; D000069286:Bortezomib