A phase 2 trial exploring the clinical and correlative effects of combining doxycycline with bone-targeted therapy in patients with metastatic breast cancer

Abstract

BackgroundBone-targeting agents (BTAs), such as bisphosphonates and denosumab, have demonstrated no discernable effects on tumour response or disease free/overall survival in patients with bone metastases from breast cancer. Doxycycline is both osteotropic and has anti-cancer effects. When combined with zoledronate in animal models, doxycycline showed significantly increased inhibition of tumour burden and increased bone formation. We evaluated the effects of adding doxycycline to ongoing anti-cancer therapy in patients with metastatic breast cancer.MethodsBreast cancer patients with bone metastases and ≥3 months of BTA use, entered this single-arm study. Patients received doxycycline 100 mg orally, twice a day for 12 weeks. The co-primary endpoints were; effect on validated pain scores (FACT-Bone pain and Brief Pain Inventory) and bone resorption markers (serum C-telopeptide, [sCTx]). All endpoints (pain scores, sCTx, bone-specific alkaline phosphatase, skeletal-related events, toxicity) were evaluated at baseline, 4, 8 and 12 weeks. Bone marrow was sampled at baseline and week 12 for exploratory biomarker analysis.ResultsOut of 37 enroled patients, 27 (73%) completed 12 weeks of therapy. No significant changes were seen in pain scores or bone turnover markers. Failure to complete treatment: drug toxicity (70%) and disease progression (30%). Sixteen (43%) patients had GI adverse events.ConclusionsDoxycycline 100 mg twice daily for 12 weeks had no significant effects on either bone pain or bone turnover markers. Its toxicity profile in this patient population would make further evaluation challenging.

Long Non-Coding RNA (LncRNA) HOXA11-AS Promotes Breast Cancer Invasion and Metastasis by Regulating Epithelial-Mesenchymal Transition

“…Recent research has reported that epithelial-mesenchymal transition is closely related to tumor invasion and metastasis. Chen et al [ 24 ] found that lncRNA HOTTIP could promote esophageal cancer invasion and metastasis by inducing EMT. We conducted Western blot analysis and found that after HOXA11-AS was interfered, EMT-related molecular markers and E-cadherin expression were up-regulated, and the expressions of N-cadherin and Vimentin were down-regulated compared with those in the control group ( Figure 6A ).…”

“…EMT plays an important role in the biological behavior of tumor migration and metastasis, and epithelial cells lose cell polarity via EMT and lose epithelial phenotype such as the connection with basement membrane, and then obtains higher migration and invasion ability. Recent research has reported that EMT mediated by lncRNA exists in diverse tumors [ 21 , 24 ]. In combination with the latest achievements in scientific research, we conducted Western blot and immunofluorescence analysis and found that the knockdown of HOXA11-AS expression in breast cancer cell increased the expression of E-cadherin (the EMT molecular marker) and inhibited the expressions of N-cadherin and Vimentin.…”

The Impact of Matrix Metalloproteinase-9 on the Sequential Steps of the Metastatic Process

“…In particular, broad-spectrum MMP inhibitors have failed in clinical trials due to their lack of selectivity and dose-limiting, severe side effects [ 138 ]. For their part, compounds directed at reducing MMP-9 activity have not reached the required efficacy [ 139 , 140 , 141 , 142 , 151 ].…”

“…In contrast, a cyclic peptide (CILINGITIDE) selectively antagonizing αv integrins did not inhibit glioblastoma progression [ 152 ], despite αvβ3 actively cooperating with MMP-9 to promote tumor cell dissemination [ 68 , 69 , 70 , 71 ]. Similarly, the antibiotic DOXYCYCLINE has not been of significant benefit in patients affected by metastatic breast carcinoma ( Table 2 ) [ 142 ]—even though the drug is effective against breast carcinoma in animal models [ 153 , 154 ]—or it increases TIMP-1 levels in treated patients [ 155 ].…”

Avaliação do tratamento quimioterápico paliativo com o esquema LDE- paclitaxel em pacientes portadores de metástases ósseas por neoplasia maligna

“…. E consequentemente, pouco se conhece sobre o impacto no prognóstico de pacientes tratados com várias modalidades de tratamento.Na prática clínica o principal mecanismo de ação dos agentes direcionados à lesão óssea é através da inibição osteoclástica, resultando na redução de eventos relacionados ao esqueleto(ADDISON et al, 2016(ADDISON et al, ). 2019LOYSON et al, 2018).…”