A novel network-based method identifies a cuproplasia-related pan-cancer gene signature to predict patient outcome.

Copper is a vital micronutrient involved in many biological processes and is an essential component of tumour cell growth and migration. Copper influences tumour growth through a process called cuproplasia, defined as abnormal copper-dependent cell-growth and proliferation. Copper-chelation therapy targeting this process has demonstrated efficacy in several clinical trials against cancer. While the molecular pathways associated with cuproplasia are partially known, genetic heterogeneity across different cancer types has limited the understanding of how cuproplasia impacts patient survival. Utilising RNA-sequencing data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) datasets, we generated gene regulatory networks to identify the critical cuproplasia-related genes across 23 different cancer types. From this, we identified a novel 8-gene cuproplasia-related gene signature associated with pan-cancer survival, and a 6-gene prognostic risk score model in low grade glioma. These findings highlight the use of gene regulatory networks to identify cuproplasia-related gene signatures that could be used to generate risk score models. This can potentially identify patients who could benefit from copper-chelation therapy and identifies novel targeted therapeutic strategies.

Copper chelation suppresses epithelial-mesenchymal transition by inhibition of canonical and non-canonical TGF-ß signaling pathways in cancer.

BACKGROUND: Metastatic cancer cells exploit Epithelial-mesenchymal-transition (EMT) to enhance their migration, invasion, and resistance to treatments. Recent studies highlight that elevated levels of copper are implicated in cancer progression and metastasis. Clinical trials using copper chelators are associated with improved patient survival; however, the molecular mechanisms by which copper depletion inhibits tumor progression and metastasis are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Here, we propose that copper chelation inhibits metastasis by reducing TGF-ß levels and EMT signaling. Given that many drugs targeting TGF-ß have failed in clinical trials, partly because of severe side effects arising in patients, we hypothesized that copper chelation therapy might be a less toxic alternative to target the TGF-ß/EMT axis. RESULTS: Our cytokine array and RNA-seq data suggested a link between copper homeostasis, TGF-ß and EMT process. To validate this hypothesis, we performed single-cell imaging, protein assays, and in vivo studies. Here, we used the copper chelating agent TEPA to block copper trafficking. Our in vivo study showed a reduction of TGF-ß levels and metastasis to the lung in the TNBC mouse model. Mechanistically, TEPA significantly downregulated canonical (TGF-ß/SMAD2&3) and non-canonical (TGF-ß/PI3K/AKT, TGF-ß/RAS/RAF/MEK/ERK, and TGF-ß/WNT/ß-catenin) TGF-ß signaling pathways. Additionally, EMT markers of MMP-9, MMP-14, Vimentin, ß-catenin, ZEB1, and p-SMAD2 were downregulated, and EMT transcription factors of SNAI1, ZEB1, and p-SMAD2 accumulated in the cytoplasm after treatment. CONCLUSIONS: Our study suggests that copper chelation therapy represents a potentially effective therapeutic approach for targeting TGF-ß and inhibiting EMT in a diverse range of cancers.

A phase IIA trial of acupuncture to reduce chemotherapy-induced peripheral neuropathy severity during neoadjuvant or adjuvant weekly paclitaxel chemotherapy in breast cancer patients.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially dose-limiting side-effect of neurotoxic chemotherapy for cancer patients. We evaluated the preliminary efficacy of acupuncture in preventing worsening CIPN in patients receiving paclitaxel. METHODS: In this phase IIA single-arm clinical trial, we screened stage I-III breast cancer patients receiving neoadjuvant/adjuvant weekly paclitaxel for development of CIPN. The primary objective was to assess acupuncture's efficacy in preventing the escalation of National Cancer Institute-Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0, grade II CIPN to higher grades. Acupuncture was deemed worthy of further study if 23 or more of the 27 enrolled patients did not develop grade III CIPN. Outcome measures (NCI-CTCAE CIPN grade, Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity [FACT/GOG-Ntx], Neuropathic Pain Scale [NPS]) were obtained weekly during the intervention. RESULTS: Of 104 patients screened, 37 developed grade II CIPN (36%), and 28 (27%) enrolled into the intervention phase; one was removed due to protocol violation. Of the 27 patients receiving acupuncture, 26 completed paclitaxel treatment without developing grade III CIPN, meeting our prespecified success criteria for declaring acupuncture worthy of further study. FACT/GOG-Ntx and NPS scores remained stable during the intervention while continuing weekly paclitaxel. Acupuncture treatment was well tolerated; 4 of 27 (15%) patients reported grade I bruising. CONCLUSIONS: Acupuncture was safe and showed preliminary evidence of effectiveness in reducing the incidence of high grade CIPN during chemotherapy. A follow-up randomised controlled trial is needed to establish definitive efficacy in CIPN prevention for patients at risk.

Glutamine for the treatment of vincristine-induced neuropathy in children and adolescents with cancer.

BACKGROUND: Vincristine is an integral treatment component of many childhood tumors with potentially dose-limiting sensory and/or motor neuropathy. Results from a pilot study on the incidence of vincristine-induced peripheral neuropathy (VIPN) as well as the efficacy and safety of glutamine in reducing signs and symptoms of VIPN in children with cancer are presented. METHODS: Fifty-six patients between the ages of 5-21 with newly diagnosed leukemia, lymphoma, extracranial solid tumor or medulloblastoma and expected to receive a minimum cumulative dose of 6 mg/m2 of vincristine over a 30-week period were eligible. Patients' neurological functioning was monitored every 3 weeks using clinical history, exam, and assessment of motor functioning. Upon identification of neuropathy, patients were randomized to either glutamine (6 g/m2 per dose twice daily, maximum 10 g/dose) or placebo for a 3-week period followed by 3-week wash out period (Time 3). RESULTS: Forty-nine patients were fully evaluable and 100 % developed neuropathy per study definitions. No significant differences in demographics or side effects were noted between the randomized groups. The distribution of sensory neuropathy scores between the two groups was statistically significant after the intervention (p = 0.022). Children receiving glutamine also rated their quality of life (QoL) as 8.42 points higher on the PedsQL total score than those receiving placebo (p = 0.031). CONCLUSIONS: Glutamine supplementation is well tolerated and associated with improvements in sensory function and self-reported overall quality of life. Future studies are warranted to confirm the efficacy of glutamine for the treatment of vincristine-related sensory neuropathy in pediatric cancer patients.

Influencing the Tumor Microenvironment: A Phase II Study of Copper Depletion Using Tetrathiomolybdate in Patients with Breast Cancer at High Risk for Recurrence and in Preclinical Models of Lung Metastases.

PURPOSE: Bone marrow-derived progenitor cells, including VEGFR2+ endothelial progenitor cells (EPCs) and copper-dependent pathways, model the tumor microenvironment. We hypothesized that copper depletion using tetrathiomolybdate would reduce EPCs in high risk for patients with breast cancer who have relapsed. We investigated the effect of tetrathiomolybdate on the tumor microenvironment in preclinical models. EXPERIMENTAL DESIGN: Patients with stage II triple-negative breast cancer (TNBC), stage III and stage IV without any evidence of disease (NED), received oral tetrathiomolybdate to maintain ceruloplasmin (Cp) between 8 and 17 mg/dL for 2 years or until relapse. Endpoints were effect on EPCs and other biomarkers, safety, event-free (EFS), and overall survival (OS). For laboratory studies, MDA-LM2-luciferase cells were implanted into CB17-SCID mice and treated with tetrathiomolybdate or water. Tumor progression was quantified by bioluminescence imaging (BLI), copper depletion status by Cp oxidase levels, lysyl oxidase (LOX) activity by ELISA, and collagen deposition. RESULTS: Seventy-five patients enrolled; 51 patients completed 2 years (1,396 cycles). Most common grade 3/4 toxicity was neutropenia (3.7%). Lower Cp levels correlated with reduced EPCs (P = 0.002) and LOXL-2 (P < 0.001). Two-year EFS for patients with stage II-III and stage IV NED was 91% and 67%, respectively. For patients with TNBC, EFS was 90% (adjuvant patients) and 69% (stage IV NED patients) at a median follow-up of 6.3 years, respectively. In preclinical models, tetrathiomolybdate decreased metastases to lungs (P = 0.04), LOX activity (P = 0.03), and collagen crosslinking (P = 0.012). CONCLUSIONS: Tetrathiomolybdate is safe, well tolerated, and affects copper-dependent components of the tumor microenvironment. Biomarker-driven clinical trials in high risk for patients with recurrent breast cancer are warranted. Clin Cancer Res; 23(3); 666-76. ©2016 AACR.

Ixabepilone plus capecitabine in advanced breast cancer patients with early relapse after adjuvant anthracyclines and taxanes: a pooled subset analysis of two phase III studies.

BACKGROUND: Metastatic breast cancer (MBC) patients with rapid disease relapse after neo/adjuvant chemotherapy including anthracyclines and taxanes have limited treatment options and their efficacy is marginal. Two phase III studies compared ixabepilone plus capecitabine vs. capecitabine alone as first-line treatment in MBC patients pretreated with anthracyclines and taxanes in the neo/adjuvant setting. Here we report the efficacy and safety of these treatments in a prespecified subset of patients whose disease relapsed within 12 months. PATIENTS AND METHODS: Of 1973 patients across two studies, 293 relapsed within 12 months of neo/adjuvant treatment and received ixabepilone plus capecitabine (n = 149) or capecitabine alone (n = 144) as first-line chemotherapy for MBC. Analysis included progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and toxicity. RESULTS: In 293 patients, ixabepilone plus capecitabine, as compared to capecitabine alone, increased PFS (median: 5.6 months vs. 2.8 months; hazard ratio, 0.58; p < 0.0001), ORR (46% vs. 24%) and OS (median: 15.1 months vs. 12.5 months; hazard ratio, 0.84; p = 0.208). Major toxicities of this regimen included neuropathy, neutropenia and hand-foot syndrome, but were manageable. CONCLUSIONS: Patients with breast cancer with early relapse following neo/adjuvant treatment with anthracyclines and taxanes may benefit from ixabepilone plus capecitabine. (ClinicalTrials.gov identifiers: NCT00080301 and NCT00082433.).

The effect of a contemplative self-healing program on quality of life in women with breast and gynecologic cancers.

Stress-related symptoms-intense fear, avoidance, intrusive thoughts--are common among breast and gynecologic cancer patients after chemotherapy and radiation. The objective of this pilot study was to determine the impact of a 20-week contemplative self-healing program among breast and gynecologic cancer survivors on self-reported quality of life (QOL), the main outcome. Assessments were performed at the first session and at 20 weeks, including QOL (FACIT-G, FACIT subscales, SF-36), anxiety, and depression (HADS). Biologic markers of immune function were obtained. A 20-week program was implemented: the initial 8 weeks addressed open-mindfulness, social-emotional self-care, visualization, and deep breathing followed by 12 weeks of exposing stress-reactive habits and developing self-healing insights. Daily practice involved CD-guided meditation and manual contemplations. Sixty-eight women were enrolled, and 46 (68%) completed the program. Participants had significant within-patient changes on FACIT-G, improving by a mean of 6.4 points. In addition, they reported clinically important improvement in emotional and functional domains and social, role-emotional, and mental health status domains on SF-36. Biologic data revealed significant improvement in maximum AM cortisol and a reduction in resting heart rate at 20 weeks. These findings suggest a contemplative self-healing program can be effective in significantly improving QOL and reducing distress and disability among female breast and gynecologic cancer survivors.

Prevention of chemotherapy and radiation toxicity with glutamine.

GOALS OF THE WORK: Malignancy produces a state of physiologic stress that is characterized by a relative deficiency of glutamine, a condition that is further exacerbated by the effects of cancer treatment. Glutamine deficiency may impact on normal tissue tolerance to antitumor treatment, and may lead to dose reductions and compromised treatment outcome. Providing supplemental glutamine during cancer treatment has the potential to abrogate treatment-related toxicity. We reviewed the available data on the use of glutamine to decrease the incidence and severity of adverse effects due to chemotherapy and/or radiation in cancer patients. METHODS: We performed a search of the MEDLINE database during the time period 1980-2003, and reviewed the English language literature of both human and animal studies pertaining to the use of glutamine in subjects with cancer. We also manually searched the bibliographies of published articles for relevant references. MAIN RESULTS: The available evidence suggests that glutamine supplementation may decrease the incidence and/or severity of chemotherapy-associated mucositis, irinotecan-associated diarrhea, paclitaxel-induced neuropathy, hepatic veno-occlusive disease in the setting of high dose chemotherapy and stem cell transplantation, and the cardiotoxicity that accompanies anthracycline use. Oral glutamine supplementation may enhance the therapeutic index by protecting normal tissues from, and sensitizing tumor cells to chemotherapy and radiation-related injury. CONCLUSIONS: The role of glutamine in the prevention of chemotherapy and radiation-induced toxicity is evolving. Glutamine supplementation is inexpensive and it may reduce the incidence of gastrointestinal, neurologic, and possibly cardiac complications of cancer therapy. Further studies, particularly placebo-controlled phase III trials, are needed to define its role in chemotherapy-induced toxicity.