INHIBITION OF S100A9 WITH TASQUINIMOD DEMONSTRATES POTENT ANTI-TUMOR ACTIVITY IN PRE-CLINICAL MODELS OF MULTIPLE MYELOMA
Author(s): ,
Cindy Lin
Affiliations:
The Wistar Institute,Philadelphia,United States
,
Aubrey Leso
Affiliations:
The Wistar Institute,Philadelphia,United States
,
Matthew Rosenwasser
Affiliations:
The Wistar Institute,Philadelphia,United States
,
Marie Torngren
Affiliations:
Active Biotech,Lund,Sweden
,
Helena Eriksson
Affiliations:
Active Biotech,Lund,Sweden
Yulia Nefedova
Affiliations:
The Wistar Institute,Philadelphia,United States
EHA Library. Lin C. 06/12/20; 294813; EP896
Dr. Cindy Lin
Dr. Cindy Lin
Contributions
Abstract

Abstract: EP896

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background

Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal proliferation of plasma cells localized preferentially in the bone marrow (BM). Despite the emergence of novel therapeutics, MM remains a fatal disease. The tumor microenvironment plays a critical role in promoting MM growth and we have recently demonstrated that a population of myeloid-derived suppressor cells in the BM microenvironment is involved in regulation of MM progression. These cells abundantly produce the protein S100A9 which has recently been implicated in the development of cancer.   Tasquinimod (ABR-215050, Active Biotech, Lund, Sweden) is an investigational drug that binds the S100A9 protein and inhibits the interactions with its receptors.

Aims
To investigate the anti-tumor effects of tasquinimod as a single agent and in combination with standard therapeutics in pre-clinical models of MM.

Methods
Syngeneic and xenograft mouse models of MM were used to evaluate anti-tumor effect of tasquinimod. In a syngeneic model, DP42 cells were injected intravenously into wild type and S100A9 knockout (KO) mice and their survival was determined. For xenograft models, MM tumors were established by subcutaneous injection of H929, RPMI-8226 or MM1S human MM cells into NSG mice. Mice were treated with tasquinimod (30mg/kg/day) and lenalidomide (oral gavage, 5mg/kg/day), bortezomib (every 4 days, i.v., 0.5mg/kg), or dexamethasone (i.p., 10mg/kg). Immunohistochemical staining of the bone marrow was performed using anti-CD31 antibodies. Serum levels of angiogenic factors was determined using Mouse Angiogenesis Proteome Profiler Antibody Array (R&D). The in vitro effect of tasquinimod on viability and apoptosis of MM cells was evaluated by MTT assay and by flow cytometry using Annexin V/DAPI staining.

Results

In a syngeneic model, MM-bearing mice treated with tasquinimod demonstrated a significantly superior survival compared to the vehicle-treated group (p<0.005). However, tasquinimod did not improve the survival of MM-bearing S100A9KO mice, indicating that the observed anti-MM effect is indeed mediated through the inhibition of S100A9. Tasquinimod used as a single agent significantly (p<0.0001) reduced the growth of human H929, MM1.S and RPMI-8226 MM tumors established in NSG mice. Tasquinimod did not affect MM cell viability or apoptosis in vitro. This suggests that the in vivo anti-MM effect of tasquinimod was mediated by alteration of the tumor microenvironment. The combination of tasquinimod and lenalidomide or bortezomib significantly reduced tumor growth compared to treatments with the single agents alone (p<0.01 and p<0.0001 respectively). Tasquinimod did not affect the anti-MM effect of dexamethasone.

BM angiogenesis plays a critical role in MM progression. Immunohistochemical staining with anti-CD31 antibody demonstrated increased angiogenesis in the BM of MM-bearing mice compared with control tumor-free mice, and treatment with tasquinimod significantly reduced angiogenesis (p<0.005). A significant decrease in serum levels of pro-angiogenic factors including VEGF, FGF2, tissue factor, and endoglin was detected in tasquinimod-treated mice compared to vehicle control.

Conclusion
Our data demonstrated a significant anti-tumor effect of tasquinimod as a single agent and in combination with standard anti-MM therapies (proteasome inhibitors (bortezomib) and immunomodulating agent (lenalidomide)) in pre-clinical models of MM.  This suggests that tasquinimod combined with standard anti-MM therapies could represent a novel and promising treatment strategy in multiple myeloma.

Session topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research

Keyword(s): Bone Marrow, Microenvironment, Multiple myeloma, Therapy

Abstract: EP896

Type: e-Poster

Presentation during EHA25: All e-Poster presentations will be made available on the on-demand Virtual Congress platform as of Friday, June 12 at 08:30 CEST and will be accessible until October 15, 2020.

Background

Multiple myeloma (MM) is an incurable hematological malignancy characterized by clonal proliferation of plasma cells localized preferentially in the bone marrow (BM). Despite the emergence of novel therapeutics, MM remains a fatal disease. The tumor microenvironment plays a critical role in promoting MM growth and we have recently demonstrated that a population of myeloid-derived suppressor cells in the BM microenvironment is involved in regulation of MM progression. These cells abundantly produce the protein S100A9 which has recently been implicated in the development of cancer.   Tasquinimod (ABR-215050, Active Biotech, Lund, Sweden) is an investigational drug that binds the S100A9 protein and inhibits the interactions with its receptors.

Aims
To investigate the anti-tumor effects of tasquinimod as a single agent and in combination with standard therapeutics in pre-clinical models of MM.

Methods
Syngeneic and xenograft mouse models of MM were used to evaluate anti-tumor effect of tasquinimod. In a syngeneic model, DP42 cells were injected intravenously into wild type and S100A9 knockout (KO) mice and their survival was determined. For xenograft models, MM tumors were established by subcutaneous injection of H929, RPMI-8226 or MM1S human MM cells into NSG mice. Mice were treated with tasquinimod (30mg/kg/day) and lenalidomide (oral gavage, 5mg/kg/day), bortezomib (every 4 days, i.v., 0.5mg/kg), or dexamethasone (i.p., 10mg/kg). Immunohistochemical staining of the bone marrow was performed using anti-CD31 antibodies. Serum levels of angiogenic factors was determined using Mouse Angiogenesis Proteome Profiler Antibody Array (R&D). The in vitro effect of tasquinimod on viability and apoptosis of MM cells was evaluated by MTT assay and by flow cytometry using Annexin V/DAPI staining.

Results

In a syngeneic model, MM-bearing mice treated with tasquinimod demonstrated a significantly superior survival compared to the vehicle-treated group (p<0.005). However, tasquinimod did not improve the survival of MM-bearing S100A9KO mice, indicating that the observed anti-MM effect is indeed mediated through the inhibition of S100A9. Tasquinimod used as a single agent significantly (p<0.0001) reduced the growth of human H929, MM1.S and RPMI-8226 MM tumors established in NSG mice. Tasquinimod did not affect MM cell viability or apoptosis in vitro. This suggests that the in vivo anti-MM effect of tasquinimod was mediated by alteration of the tumor microenvironment. The combination of tasquinimod and lenalidomide or bortezomib significantly reduced tumor growth compared to treatments with the single agents alone (p<0.01 and p<0.0001 respectively). Tasquinimod did not affect the anti-MM effect of dexamethasone.

BM angiogenesis plays a critical role in MM progression. Immunohistochemical staining with anti-CD31 antibody demonstrated increased angiogenesis in the BM of MM-bearing mice compared with control tumor-free mice, and treatment with tasquinimod significantly reduced angiogenesis (p<0.005). A significant decrease in serum levels of pro-angiogenic factors including VEGF, FGF2, tissue factor, and endoglin was detected in tasquinimod-treated mice compared to vehicle control.

Conclusion
Our data demonstrated a significant anti-tumor effect of tasquinimod as a single agent and in combination with standard anti-MM therapies (proteasome inhibitors (bortezomib) and immunomodulating agent (lenalidomide)) in pre-clinical models of MM.  This suggests that tasquinimod combined with standard anti-MM therapies could represent a novel and promising treatment strategy in multiple myeloma.

Session topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research

Keyword(s): Bone Marrow, Microenvironment, Multiple myeloma, Therapy

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