Doxycycline-Induced Changes in Circulating MMP or TIMP2 Levels Are Not Associated with Skeletal-Related Event-Free or Overall Survival in Patients with Bone Metastases from Breast Cancer.

Doxycycline is often used as a promoter of inducible gene expression in preclinical models; however, it can also have direct effects on tumor growth and survival. This is due in part to its ability to inhibit cell invasion and regulate matrix metalloproteinase (MMP) expression. Given that doxycycline is also osteotropic, a clinical study to assess its effects on modulation of tumor progression or prevention of skeletal-related events (SRE) in patients with bone metastases from breast cancer (the Achilles trial) was undertaken.

Focal adhesion kinase inhibitors prevent osteoblast mineralization in part due to suppression of Akt-mediated stabilization of osterix.

Focal Adhesion Kinase (FAK) is an important regulator of tumor cell proliferation, survival and metastasis. As such it has become a therapeutic target of interest in cancer. Previous studies suggested that use of FAK tyrosine kinase inhibitors (TKIs) blocks osteolysis in models of bone metastasis.

VIVA1: a more invasive subclone of MDA-MB-134VI invasive lobular carcinoma cells with increased metastatic potential in xenograft models.

Background: Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. As few tools exist to study ILC metastasis, we isolated ILC cells with increased invasive properties to establish a spontaneously metastasising xenograft model.

Methods: MDA-MB-134VI ILC cells were placed in transwells for 7 days.

Mapping vitamin B metabolism by hydrazoCEST magnetic resonance imaging.

A new CEST-MRI contrast agent, 2-HYNIC, capable of sensing aromatic aldehydes is reported. Pyridoxal 5'-phosphate, a key Vitamin B metabolite necessary for >140 biotransformations was mapped by CEST-MRI and in lung cancer. 2-HYNIC provided access to this key biomarker associated with a variety of human diseases.

Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth.

Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth.

MicroRNA-30b controls endothelial cell capillary morphogenesis through regulation of transforming growth factor beta 2.

The importance of microRNA (miRNA) to vascular biology is becoming increasingly evident; however, the function of a significant number of miRNA remains to be determined. In particular, the effect of growth factor regulation of miRNAs on endothelial cell morphogenesis is incomplete. Thus, we aimed to identify miRNAs regulated by pro-angiogenic vascular endothelial growth factor (VEGF) and determine the effects of VEGF-regulated miRNAs and their targets on processes important for angiogenesis.

A phase II trial of dovitinib in previously-treated advanced pleural mesothelioma: The Ontario Clinical Oncology Group.

Objectives: Following failure of a platinum-antifolate combination regimen, there is no standard therapy for advanced malignant pleural mesothelioma (MPM). The fibroblast growth factor receptor (FGFR) signaling pathways may be a relevant target in MPM. Dovitinib inhibits multiple tyrosine receptor kinases, predominantly the vascular endothelial growth factor receptors (VEGFR), but also FGFRs, and could be active in MPM.

Focal Adhesion Kinase Inhibitors in Combination with Erlotinib Demonstrate Enhanced Anti-Tumor Activity in Non-Small Cell Lung Cancer.

Blockade of epidermal growth factor receptor (EGFR) activity has been a primary therapeutic target for non-small cell lung cancers (NSCLC). As patients with wild-type EGFR have demonstrated only modest benefit from EGFR tyrosine kinase inhibitors (TKIs), there is a need for additional therapeutic approaches in patients with wild-type EGFR. As a key component of downstream integrin signalling and known receptor cross-talk with EGFR, we hypothesized that targeting focal adhesion kinase (FAK) activity, which has also been shown to correlate with aggressive stage in NSCLC, would lead to enhanced activity of EGFR TKIs.

Correlation of baseline biomarkers with clinical outcomes and response to fulvestrant with vandetanib or placebo in patients with bone predominant metastatic breast cancer: An OCOG ZAMBONEY sub-study.

Background: Bone metastases are common in women with breast cancer and often result in skeletal related events (SREs). As the angiogenic factor vascular endothelial growth factor (VEGF) regulates osteoclast activity and is associated with more extensive bone metastases and SRE risk in metastatic breast cancer, we hypothesized that blockade of VEGF signaling could be a therapeutic strategy for inhibiting bone metastases progression and possibly prolonging overall (OS) or progression-free survival (PFS). The Zamboney trial was a randomized placebo-controlled study designed to assess whether patients with bone predominant metastatic breast cancer benefited from addition of the VEGF receptor (VEGFR) targeting agent, vandetanib, to endocrine therapy with fulvestrant.

Cardamonin reduces chemotherapy-enriched breast cancer stem-like cells in vitro and in vivo.

The failure of cytotoxic chemotherapy in breast cancers has been closely associated with the presence of drug resistant cancer stem cells (CSCs). Thus, screening for small molecules that selectively inhibit growth of CSCs may offer great promise for cancer control, particularly in combination with chemotherapy. In this report, we provide the first demonstration that cardamonin, a small molecule, selectively inhibits breast CSCs that have been enriched by chemotherapeutic drugs.

Analysis of serum protein levels of angiogenic factors and their soluble receptors as markers of response to cediranib in the NCIC CTG BR.24 clinical trial.

Objectives: Prognostic and predictive ability of circulating vascular endothelial growth factor (VEGF), stromal derived factor (SDF)-1α and soluble VEGF receptors (sVEGFR) 2 and 3, were evaluated in non-small cell lung cancer (NSCLC) patients enrolled in NCIC Clinical Trials Group BR. 24 comparing chemotherapy with or without cediranib.

Materials And Methods: Biomarker levels were assessed by ELISA in serum from 149/296 enrolled patients at baseline and 146/149 patients after one treatment cycle.

VEGF-Mediated Induction of PRD1-BF1/Blimp1 Expression Sensitizes Tumor Vasculature to Oncolytic Virus Infection.

Oncolytic viruses designed to attack malignant cells can in addition infect and destroy tumor vascular endothelial cells. We show here that this expanded tropism of oncolytic vaccinia virus to the endothelial compartment is a consequence of VEGF-mediated suppression of the intrinsic antiviral response. VEGF/VEGFR2 signaling through Erk1/2 and Stat3 leads to upregulation, nuclear localization, and activation of the transcription repressor PRD1-BF1/Blimp1.

Angiotensin-Converting Enzyme and Aldosterone Serum Levels as Prognostic and Predictive Biomarkers for Cediranib in NCIC Clinical Trials Group Study BR.24.

Unlabelled: Predictive biomarkers of benefit from angiogenesis inhibition are lacking. Serum angiotensin-converting enzyme (ACE) and aldosterone levels of non-small-cell lung cancer patients treated with chemotherapy with or without cediranib were evaluated. Low baseline ACE serum levels were prognostic of poor chemotherapy outcome and predictive of benefit from cediranib.

Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity.

Tumors are complex ecosystems composed of networks of interacting 'normal' and malignant cells. It is well recognized that cytokine-mediated cross-talk between normal stromal cells, including cancer-associated fibroblasts (CAFs), vascular endothelial cells, immune cells, and cancer cells, influences all aspects of tumor biology. Here we demonstrate that the cross-talk between CAFs and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics.

Evaluating the feasibility of performing window of opportunity trials in breast cancer.

Background: The waiting period to surgery represents a valuable "window of opportunity" to evaluate novel therapeutic strategies. Interventional studies performed during this period require significant multidisciplinary collaboration to overcome logistical hurdles. We undertook a one-year prospective window of opportunity study to assess feasibility.

Effects of de-escalated bisphosphonate therapy on bone turnover biomarkers in breast cancer patients with bone metastases.

While de-escalation of bisphosphonates from 4 to 12-weekly dosing has been shown to be clinically non-inferior to standard dosing, there is evidence the de-escalation is associated with increased bone turnover biomarkers. Here we evaluated the effect of de-escalated dosing on a panel of biomarkers and determined their association with incidence of skeletal related events (SREs) in breast cancer patients with 'low risk' bone metastases. As part of a pilot randomized trial, women with baseline C-telopeptide levels <600 ng/L after >3 months of 3-4 weekly pamidronate were randomized to continue pamidronate every 4 weeks or de-escalation to 12-weekly treatment.

Essential role for the SLK protein kinase in embryogenesis and placental tissue development.

Background: Over the past decade, the Ste20-like kinase SLK, has been implicated in several signaling processes. SLK repression has been shown to impair cell cycle kinetics and inhibit FAK-mediated cell migration. Here, using a gene trapped allele, we have generated mice expressing a truncated form of the SLK kinase.

A phase II, multicentre trial evaluating the efficacy of de-escalated bisphosphonate therapy in metastatic breast cancer patients at low-risk of skeletal-related events.

The optimal frequency of intravenous (IV) bisphosphonate administration is unclear. We thus performed a study evaluating the effects of switching from 3-4 to 12 weekly therapy in patients with biochemically defined low-risk bone metastases. Patients with serum C-telopeptide (CTx) levels ≤600 ng/L after ≥3 months of 3-4 weekly IV pamidronate were switched to 12 weekly therapy for 48 weeks.

Effects of de-escalated bisphosphonate therapy on the Functional Assessment of Cancer Therapy-Bone Pain, Brief Pain Inventory and bone biomarkers.

Background: The Brief Pain Inventory (BPI) and Functional Assessment of Cancer Therapy-Bone Pain (FACT-BP) are commonly used measures of patient reported pain outcomes. We report on the performance of the FACT-BP in comparison to the BPI within a small, randomized trial.

Methods: Patients with biochemically defined low risk bone metastases were randomized to 4 weekly (control arm) or 12 weekly (de-escalating arm) pamidronate for 1 year.

A systematic review of dosing frequency with bone-targeted agents for patients with bone metastases from breast cancer.

Background: Bone-targeted agents are usually administered to breast cancer patients with bone metastases every 3-4 weeks. Less frequent ('de-escalated') treatment may provide similar benefits with improved safety and reduced cost.

Methods: To systematically review randomised trials comparing de-escalated treatment with bone-targeted agents (i.

Bone-targeted agent use for bone metastases from breast cancer and prostate cancer: A patient survey.

Background: In order to design studies assessing the optimal use of bone-targeted agents (BTAs) patient input is clearly desirable.

Methods: Patients who were receiving a BTA for metastatic prostate or breast cancer were surveyed at two Canadian cancer centres. Statistical analysis of respondent data was performed to establish relevant proportions of patient responses.

miR-105 inhibits prostate tumour growth by suppressing CDK6 levels.

A significant role for micro (mi)RNA in the regulation of gene expression in tumours has been recently established. In order to further understand how miRNA expression may contribute to prostate tumour growth and progression, we evaluated expression of miRNA in two invasive prostate tumour lines, PC3 and DU145, and compared it to that in normal prostate epithelial cells. Although a number of miRNAs were differentially expressed, we focused our analysis on miR-105, a novel miRNA not previously linked to prostate cancer.

Oral care and the use of bone-targeted agents in patients with metastatic cancers: A practical guide for dental surgeons and oncologists.

Background: Bone-targeted agents such as bisphosphonates and the RANKL antibody have revolutionised the care of patients with bone metastases. There has, however been increasing concern about the oral health of these patients and in particular osteonecrosis of the jaw (ONJ), especially with the increasing use of these agents at higher potencies for greater periods of time.

Methods: A review of the published data in PubMed and meeting abstracts was performed to examine incidence, risk factors, pathogenesis, clinical course and management of osteonecrosis of the jaw with focus on cancer patients treated with bone-targeted agents (BTA) for bone metastases.