Inhibition of Transforming Growth Factor-β Activation Diminishes Tumor Progression and Osteolytic Bone Disease in Mouse Models of Multiple Myeloma

Abstract

Transforming growth factor (TGF)-β supports multiple myeloma progression and associated osteolytic bone disease. Conversion of latent TGF-β to its biologically active form is a major regulatory node controlling its activity. Thrombospondin1 (TSP1) binds and activates TGF-β. TSP1 is increased in myeloma, and TSP1-TGF-β activation inhibits osteoblast differentiation. We hypothesized that TSP1 regulates TGF-β activity in myeloma and that antagonism of the TSP1-TGF-β axis inhibits myeloma progression. Antagonists (LSKL peptide, SRI31277) derived from the LSKL sequence of latent TGF-β that block TSP1-TGF-β activation were used to determine the role of the TSP1-TGF-β pathway in mouse models of myeloma. TSP1 binds to human myeloma cells and activates TGF-β produced by cultured human and mouse myeloma cell lines. Antagonists delivered via osmotic pump in an intratibial severe combined immunodeficiency CAG myeloma model or in a systemic severe combined immunodeficiency CAG-heparanase model of aggressive myeloma reduced TGF-β signaling (phospho-Smad 2) in bone sections, tumor burden, mouse IL-6, and osteoclasts, increased osteoblast number, and inhibited bone destruction as measured by microcomputed tomography. SRI31277 reduced tumor burden in the immune competent 5TGM1 myeloma model. SRI31277 was as effective as dexamethasone or bortezomib, and SRI31277 combined with bortezomib showed greater tumor reduction than either agent alone. These studies validate TSP1-regulated TGF-β activation as a therapeutic strategy for targeted inhibition of TGF-β in myeloma.

Preventing and Repairing Myeloma Bone Disease by Combining Conventional Antiresorptive Treatment With a Bone Anabolic Agent in Murine Models

“…In addition, this effect was not mediated by a reduction in tumor burden, which did not alter after 1D11/combination treatment groups, consistent with other findings in myeloma . However, this lack of effect upon tumor burden is somewhat contradictory to some other studies in myeloma and breast cancer models, which did observe an anti‐tumor effect. To confirm whether 1D11 had a direct anti‐tumor effect on JJN3 or U266 cells, we treated them with 1D11 in vitro and observed no effect on cell viability for either cell line.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…225 In a study exploring novel combinatorial regimens, Lu and colleagues (from University of Alabama, Birmingham, AL, USA) documented that combining an inhibitor of thrombospondin 1 (THBS1; also known as TSP1) and transforming growth factor beta 1 (TFGB1) signaling, i.e., SRI31277, with bortezomib mediates superior antineoplastic effects as compared to either agents alone. 226 In a different combinatorial approach, Hsu and colleagues (from National Yang-Ming University, Taipei, Taiwan) revealed that pre-conditioning with low-dose doxorubicin or paclitaxel before adoptive cell transfer (ACT) significantly improves antitumor immunity upon inhibition of NF-kB-regulated immunosuppressive factors. 227 Similarly, Koo and collaborators (from Catholic University of Korea, Bucheon, Republic of Korea) found that X-shaped double-stranded oligodeoxynucleotide molecules (so called "X-DNA") that bind TLR9 228 greatly enhance the antitumor efficacy of doxorubicin against colitis-associated colorectal carcinoma, via a mechanism that depends on DCs and T cells.…”

TGFβ Inhibition Stimulates Collagen Maturation to Enhance Bone Repair and Fracture Resistance in a Murine Myeloma Model

“…TGFβ stimulates microenvironment expression of genes involved in tumorigenesis and bone disease in myeloma, including Il6 , Vegfa , Mcp1 , Pthlh (encoding PTHrP), and Thbs1 . Thbs1 , Mcp1 , and Il6 expression in bone marrow was comparable between all treatment groups (Supplemental Fig.…”

“…Inhibition of TGFβ has both bone anabolic and anti‐resorptive effects in non‐tumor‐bearing mice, leading to increased bone volume and improved bone quality . Similarly, TGFβ inhibition prevented development of myeloma bone disease, and repaired existing bone lesions if administered with the bisphosphonate zoledronic acid …”

“…(15,16) Inhibition of TGFβ has both bone anabolic and anti-resorptive effects in non-tumorbearing mice, (17,18) leading to increased bone volume and improved bone quality. (19) Similarly, TGFβ inhibition prevented development of myeloma bone disease, (20)(21)(22) and repaired existing bone lesions if administered with the bisphosphonate zoledronic acid. (23) Until recently, healing of lytic lesions in myeloma patients was generally considered to only occur in rare instances.…”