Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

Tauro, Marilena; Shay, Gemma; Sansil, Samer S.; Laghezza, Antonio; Tortorella, Paolo; Neuger, Anthony; Soliman, Hatem; Lynch, Conor C.

doi:10.1158/1535-7163.mct-16-0315-t

Cited by 29 publications

(38 citation statements)

References 62 publications

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“…We hypothesized that the bisphosphonic nature of the inhibitors would ensure specific targeting to the skeleton, thereby avoiding potential dose limiting systemic toxicities noted in prior MMP inhibitor clinical trials [34]. As we reported, two BMMPIs, ML104 and ML115 had IC 50 s for MMP-2 in the nM range (37 and 140nM respectively) but importantly spare the activity of other MMPs including the closely related MMP-2 family member, MMP-9 [26, 35]. For these studies we also included another BMMPI, ML111 that did not show a high degree MMP-2 selectivity (IC 50 = 4.9μM).…”

Section: Resultsmentioning

confidence: 99%

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

et al. 2017

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Multiple myeloma is a plasma cell malignancy that homes aberrantly to bone causing extensive skeletal destruction. Despite the development of novel therapeutic agents that have significantly improved overall survival, multiple myeloma remains an incurable disease. Matrix metalloproteinase-2 (MMP-2) is associated with cancer and is significantly overexpressed in the bone marrow of myeloma patients. These data provide rationale for selectively inhibiting MMP-2 activity as a multiple myeloma treatment strategy. Given that MMP-2 is systemically expressed, we used novel “bone-seeking” bisphosphonate based MMP-2 specific inhibitors (BMMPIs) to target the skeletal tissue thereby circumventing potential off-target effects of MMP-2 inhibition outside the bone marrow-tumor microenvironment. Using in vivo models of multiple myeloma (5TGM1, U266), we examined the impact of MMP-2 inhibition on disease progression using BMMPIs. Our data demonstrate that BMMPIs can decrease multiple myeloma burden and protect against cancer-induced osteolysis. Additionally, we have shown that MMP-2 can be specifically inhibited in the multiple myeloma-bone microenvironment, underscoring the feasibility of developing targeted and tissue selective MMP inhibitors. Given the well-tolerated nature of bisphosphonates in humans, we anticipate that BMMPIs could be rapidly translated to the clinical setting for the treatment of multiple myeloma.

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Section: Resultsmentioning

confidence: 99%

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

et al. 2017

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“…Our mean-field equations take the form of two coupled hierarchies of integro-partial differential equations [see equations (23)- (24)]. These equations can be solved to indicate how many particles one could expect to find within a small region of space are connected to k other cells (referred to as degree k) at time t. We denote by v k the surface density of osteoblasts (number per unit area, [v k ] = mm −2 ) connected to k osteocytes on the bone surface; and w k the number density osteocytes (number per unit volume, [w k ] = mm −3 ) connected to k osteocytes or osteoblasts with position x at time t within the bone.…”

Section: Simulation and Analysismentioning

confidence: 99%

“…In the steady-state travelling wave regime, one can show that the node degrees of the osteocyte network are geometrically distributed when using either the null model (see Section 2.1.1), or the switch-like proposed mechanism (see Section 2.1.3). This effect comes from the difference equation structure shown in (23)- (24) in Appendix C.1.…”

Section: Osteocyte Degree Distributionmentioning

confidence: 99%

“…In particular, we investigate how stimulatory or inhibitory network dependent signals influence osteoblast-to-osteocyte differentiation and lead to different osteocyte network properties in newly formed bone. Specimens for analysis were derived from mice that were intratibially inoculated with either saline (Control) or breast cancer (BCa, PyMT cell line) as described previously under University of South Florida IACUC approved protocols (R2238 and R1762-CCL) [23,24]. Mice were harvested for analysis prior to breach of the cortical bone (day 21).…”

Section: Introductionmentioning

confidence: 99%

“…Mice were harvested for analysis prior to breach of the cortical bone (day 21). Separately, BCa-PyMT inoculated mice were treated with a bisphosphonate (zoledronate) over the course of the study period (1mg/Kg, subcutaneously thrice weekly) [23,24]. Subsequent to tissue collection and isolation, bones were decalcified, processed and paraffin embedded.…”

Section: Introductionmentioning

confidence: 99%

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Modelling Osteocyte Network Formation: Healthy and Cancerous Environments

Taylor-King

Buenzli

Chapman

et al. 2019

Preprint

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Advanced cancers, such as prostate and breast cancers, commonly metastasize to bone. In the bone matrix, dendritic osteocytes form a spatial network allowing communication between osteocytes and the osteoblasts located on the bone surface. This communication network facilitates coordinated bone remodelling. In the presence of a cancerous microenvironment, the morphology of this network changes. Commonly osteocytes appear to be either overdifferentiated (i.e., there are more dendrites than healthy bone) or underdeveloped (i.e., dendrites do not fully form). In addition to structural changes, histological sections from metastatic breast cancer xenografted mice show that number of osteocytes per unit area is different between healthy bone and cancerous bone. We present a stochastic agent-based model for bone formation incorporating osteoblasts and osteocytes that allows us to probe both network structure and density of osteocytes in bone. Our model both allows for the simulation of our spatial network model and analysis of mean-field equations in the form of integro-partial differential equations. We considered variations of our model to study specific physiological hypotheses related to osteoblast differentiation; for example predicting how changing biological parameters, such as rates of bone secretion, rates of cancer formation and rates of osteoblast differentiation can allow for qualitatively different network morphologies. We then used our model to explore how commonly applied therapies such as bisphosphonates (e.g. zoledronic acid) impact osteocyte network formation. 2/36

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Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice

Arellano

Juàrez

Verdugo‐Meza

et al. 2020

Journal of Bone and Mineral Research

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Immunotherapies use components of the immune system, such as T cells, to fight cancer cells, and are changing cancer treatment, causing durable responses in some patients. Bone metastases are a debilitating complication in advanced breast and prostate cancer patients. Approved treatments fail to cure bone metastases or increase patient survival and it remains unclear whether immunotherapy could benefit patients. The bone microenvironment combines various immunosuppressive factors, and combined with T cell products could increase bone resorption fueling the vicious cycle of bone metastases. Using syngeneic mouse models, our study revealed that bone metastases from 4T1 breast cancer contain tumor-infiltrating lymphocyte (TILs) and their development is increased in normal mice compared to immunodeficient and T-cell depleted mice. This effect seemed caused by the TILs specifically in bone, because T-cell depletion increased 4T1 orthotopic tumors and did not affect bone metastases from RM-1 prostate cancer cells, which lack TILs. T cells increased osteoclast formation ex vivo and in vivo contributing to bone metastasis vicious cycle. This pro-osteoclastic effect is specific to unactivated T cells, because activated T cells, secreting interferon γ (IFNγ) and interleukin 4 (IL-4), actually suppressed osteoclastogenesis, which could benefit patients. However, non-activated T cells from bone metastases could not be activated in ex vivo cultures. 4T1 bone metastases were associated with an increase of functional polymorphonuclear and monocytic myeloid-derived suppressor cells (MDSCs), potent T-cell suppressors. Although effective in other models, sildenafil and zoledronic acid did not affect MDSCs in bone metastases. Seeking other therapeutic targets, we found that monocytic MDSCs are more potent suppressors than polymorphonuclear MDSCs, expressing programmed cell death receptor-1 ligand (PD-L1) + in bone, which could trigger T-cell suppression because 70% express its receptor, programmed cell death receptor-1 (PD-1). Collectively, our findings identified a new mechanism by which suppressed T cells increase osteoclastogenesis and bone metastases. Our results also provide a rationale for using immunotherapy because T-cell activation would increase their anti-cancer and their anti-osteoclastic properties.

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Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth

Cited by 29 publications

References 62 publications

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

Selective inhibition of matrix metalloproteinase-2 in the multiple myeloma-bone microenvironment

Modelling Osteocyte Network Formation: Healthy and Cancerous Environments

Bone Microenvironment-Suppressed T Cells Increase Osteoclast Formation and Osteolytic Bone Metastases in Mice

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