Fournier, P. et al. Cancer Cell, 2015

Fournier, P. et al. Cancer Cell, 2015

Treatment with the small molecule inhibitor SD-208 decreases bone destruction caused by PC-3 prostate cancer cells in mice. Arrows indicate osteolytic lesions

Treatment with the small molecule inhibitor SD-208 decreases bone destruction caused by PC-3 prostate cancer cells in mice. Arrows indicate osteolytic lesions

The TGF-b signaling regulator PMEPA1 suppresses prostate cancer metastases to bone

Transforming growth factor-beta (TGF-beta) is the main factor released from the bone mineral matrix that drives the growth of cancer cells in bone. Therefore TGF-beta represents an attractive therapeutic target and we have shown that small molecule inhibitors of TGF-beta signaling are efficient for the treatment of bone metastases. We applied whole transcriptome analysis to identify multiple target genes that could be used as new targets for the treatment of bone metastases or that could be used as predictive markers. Among those, we identified a new gene called PMEPA1 that inhibits TGF-beta signaling in cancer cells. We determined that loss of expression of PMEPA1 in cancer cells increases bone metastases in mice. We also determined that low expression of PMEPA1 in the primary tumor of breast cancer patients is associated with a decreased survival as well as a decreased time to the occurrence of metastases. We are now investigating how PMEPA1 is affecting tumor initiation whether PMEPA1 expression could be used for diagnostic purposes in cancer patients.


 
Dichroa febrifuga is the herb from which Halofuginone is derrived

Dichroa febrifuga is the herb from which Halofuginone is derrived

To decrease breast cancer bone metastases combined treatment of Halofuginone (Hfg) and Zoledronic Acid (ZA) is more efficient than either drug individually.

To decrease breast cancer bone metastases combined treatment of Halofuginone (Hfg) and Zoledronic Acid (ZA) is more efficient than either drug individually.

Development of new therapies for the treatment of bone metastases

Breast cancer frequently metastasizes to the skeleton causing bone destruction. We have shown that Halofuginone (Hfg), a plant alkaloid derivate, 1) reduces osteolytic bone metastasis through inhibition of TGF-beta and BMP signaling; and 2) induces bone loss by increasing bone resorption and decreasing bone formation. To further evaluate the mechanism for Hfg-induced bone loss, we tested a combined treatement of Hfg with zoledronic acid (ZOL) to determine if we could prevent Hfg-induced bone loss in normal mice and the combination therapy could be beneficial in our model of breast cancer bone metastases using MDA-MB-231 cells. Our results showed that Hfg reduced breast cancer bone metastases and this effect is enhanced with Hfg-ZOL combined therapy. Further, ZOL prevented Hfg-induced bone loss in mice. Hfg has completed Phase II trials for use in sarcoma and could rapidly be brought to the clinic for the treatment of patients with breast cancer bone metastases.


A: X-ray images of mice with MDA-MB-231 bone metastases; B: Osteolytic lesion area measurements (mm2); C: Tumor burden measured by optical imaging; D: Survival curve

A: X-ray images of mice with MDA-MB-231 bone metastases; B: Osteolytic lesion area measurements (mm2); C: Tumor burden measured by optical imaging; D: Survival curve

Role of c-Met and VEGFR2 in breast cancer bone metastases

Breast cancer commonly metastasizes to bone, causing pain and fracture. During tumor development, cells within the expanding tumor are deprived of oxygen which results in induction of mediators of angiogenesis including VEGF, MET and VEGFR2. Both osteoblasts and osteoclasts express MET and VEGFRs. Cabozantinib (cabo, XL184) is a balanced inhibitor of MET and VEGFR2. Cabo treatment in preclinical models results in tumor regression and blockade of tumor invasiveness and metastasis. To elucidate the mechanisms of cabo activity we are studying a human breast cancer bone xenograft model. Female nude mice are inoculated with MDA-MB-231 cells via the left cardiac ventricle and treated with cabozantinib after detection of osteolytic lesions on x-ray (approx. 13 days). Mice treated with cabo exhibited less weight loss as vehicle-treated mice and a reduction in osteolytic lesion area. Cabo treatment also reduced the intensity of photon emission from tumors as measured by optical imaging using a Cathepsin K-linked fluorescent probe. Finally, mice treated with cabo had significantly improved survival. Studies to further characterize the molecular mechanisms underlying these effects are ongoing.


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Estrogen deprivation causes muscle weakness in mice and is associated with the dissociation of RyR1 from its stabilizing subunit Calstabin1.

Estrogen deprivation causes muscle weakness in mice and is associated with the dissociation of RyR1 from its stabilizing subunit Calstabin1.

Musculoskeletal complications with sex steroid deprivation

Adjuvant hormone therapy commonly causes musculoskeletal complications in cancer patients. The mechanism(s) of androgen and estrogen deprivation-induced muscle dysfunction has not been identified, although both have been associated with increased inflammation and oxidative stress. The ryanodine receptor (RyR1)/calcium release channel on the sarcoplasmic reticulum is required for muscle excitation-contraction coupling. Pathological oxidation-dependent depletion of the stabilizing subunit calstabin from RyR1 results in leaky channels and impaired muscle function. We are interested in the effects of sex steroid deprivation on calcium handling, RyR1-calstabin stability and skeletal muscle contractility. Our aim is to determine whether pharmacological stabilization of the RyR1 channel might ameliorate muscle weakness in patients treated with adjuvant hormone therapy.


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Muscle function is impaired in mice with breast cancer bone metastases (MDA-MB-231 cells). Ex vivo contractility of the extensor digitorum longus (EDL) muscle (L) and forelimb grip strength at four weeks post inoculation (R).

Muscle function is impaired in mice with breast cancer bone metastases (MDA-MB-231 cells). Ex vivo contractility of the extensor digitorum longus (EDL) muscle (L) and forelimb grip strength at four weeks post inoculation (R).

Ryanodine receptor 1 remodeling in cancer-associated muscle dysfunction

Muscle weakness is common in advanced cancers and is a cause of significant cancer-related morbidity and mortality. The mechanisms of cancer-associated muscle dysfunction are unknown and no effective treatment exists. Ryanodine receptor 1 (RyR1) is the skeletal muscle sarcoplasmic reticulum Ca2+ release channel required for excitation-contraction coupling. RyR1 remodeling via oxidative stress results in leaky channels and poor muscle function. We have found that mice with breast cancer bone metastases exhibit significant muscle dysfunction due to leaky RyR1 channels. Targeted therapy against leaky RyR1 channels (Rycals) improve muscle function and may be an effective therapy for cancer-associated muscle weakness


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Radiation exposure (2Gy) leads to loss in trabecular bone volume and an increase in the number of bone-resorbing osteoclasts in mice.

Radiation exposure (2Gy) leads to loss in trabecular bone volume and an increase in the number of bone-resorbing osteoclasts in mice.

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Radiation-induced bone loss

Patients undergoing radiation therapy for cancer are at increased risk of musculoskeletal complications including bone loss and fracture. This project’s overarching goal is to evaluate the cellular mechanisms of radiation-induced bone loss and determine the effect of radiation exposure on development and progression of prostate cancer bone metastases. Our findings indicate radiation exposure may have direct effect on multiple bone cells (osteoclasts, osteoblasts and osteocytes) and that radiation-induced bone loss may be partially driven by systemic factors, including osteoclastogenic cytokines. Further studies will determine the relative contribution of inflammatory cytokines on short- and long-term radiation-induced bone loss as well as the role radiation-induced bone loss may play in the progression of prostate cancer bone metastases. These studies emphasize the sensitivity of the musculoskeletal system to radiation, and may be useful in developing therapeutics that can prevent musculoskeletal weakness following radiation exposure


Regulation of ceramide/sphingosine-1-phosphate rheostat

Regulation of ceramide/sphingosine-1-phosphate rheostat

Impact of sphingosine-1-phosphate in osteolytic bone metastasis

Recent evidence has revealed the direct regulatory activities between TGF-beta/Smad signaling and alterations of sphingosine metabolism including the activation of sphingosine kinase-1 (SphK1) and subsequent production of sphingosine-1-phosphate (S1P). S1P signaling is important in the migratory behavior of monocytic-osteoclast precursor cells to and from the bone surface. TGF-beta-mediated upregulation of sphingosine kinase-1/S1P3 activity drives cellular trans-differentiation to a fibroblastic phenotype. Our hypothesis is that TGF-beta stimulates S1P production via increased sphingosine kinase activity in osteolytic human tumor cells and S1P production/secretion within the bone-tumor microenvironment is a potential key determinant in tumor-induced osteolytic bone destruction. A combined therapy targeting S1P signaling pathways with bisphosphonates(s)/anti-RANKL antibody treatments may be superior in the prevention and/or management of osteolytic bone metastases.