The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl.

Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist.

Identification of novel molecular regulators of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in breast cancer cells by RNAi screening.

INTRODUCTION: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to its receptors, TRAIL-receptor 1 (TRAIL-R1) and TRAIL-receptor 2 (TRAIL-R2), leading to apoptosis by activation of caspase-8 and the downstream executioner caspases, caspase-3 and caspase-7 (caspase-3/7). Triple-negative breast cancer (TNBC) cell lines with a mesenchymal phenotype are sensitive to TRAIL, whereas other breast cancer cell lines are resistant. The underlying mechanisms that control TRAIL sensitivity in breast cancer cells are not well understood. Here, we performed small interfering RNA (siRNA) screens to identify molecular regulators of the TRAIL pathway in breast cancer cells. METHODS: We conducted siRNA screens of the human kinome (691 genes), phosphatome (320 genes), and about 300 additional genes in the mesenchymal TNBC cell line MB231. Forty-eight hours after transfection of siRNA, parallel screens measuring caspase-8 activity, caspase-3/7 activity, or cell viability were conducted in the absence or presence of TRAIL for each siRNA, relative to a negative control siRNA (siNeg). A subset of genes was screened in cell lines representing epithelial TNBC (MB468), HER2-amplified breast cancer (SKBR3), and estrogen receptor-positive breast cancer (T47D). Selected putative negative regulators of the TRAIL pathway were studied by using small-molecule inhibitors. RESULTS: The primary screens in MB231 identified 150 genes, including 83 kinases, 4 phosphatases, and 63 nonkinases, as potential negative regulators of TRAIL. The identified genes are involved in many critical cell processes, including apoptosis, growth factor-receptor signaling, cell-cycle regulation, transcriptional regulation, and DNA repair. Gene-network analysis identified four genes (PDPK1, IKBKB, SRC, and BCL2L1) that formed key nodes within the interaction network of negative regulators. A secondary screen of a subset of the genes identified in additional cell lines representing different breast cancer subtypes and sensitivities to TRAIL validated and extended these findings. Further, we confirmed that small-molecule inhibition of SRC or BCL2L1, in combination with TRAIL, sensitizes breast cancer cells to TRAIL-induced apoptosis, including cell lines resistant to TRAIL-induced cytotoxicity. CONCLUSIONS: These data identify novel molecular regulators of TRAIL-induced apoptosis in breast cancer cells and suggest strategies for the enhanced application of TRAIL as a therapy for breast cancer.

Mouse models of BRCA1 and their application to breast cancer research.

Germline mutations of human breast cancer-associated gene 1 (BRCA1) predispose women to breast and ovarian cancers. In mice, over 20 distinct mutations, including null, hypomorphic, isoform, conditional, and point mutations, have been created to study functions of Brca1 in mammary development and tumorigenesis. Analyses using these mutant mice have yielded an enormous amount of information that greatly facilitates our understanding of the gender- and tissue-specific tumor suppressor functions of BRCA1, as well as enriches our insights into applying these preclinical models of disease to breast cancer research. Here, we review features of these mutant mice and their applications to cancer prevention and therapeutic treatment.

Understanding the patient experience and treatment benefits in patients with non-small-cell lung cancer with brain metastasis.

BACKGROUND: Despite the high prevalence of brain metastases (BM) secondary to non-small-cell lung cancer (NSCLC) (NSCLC/BM), patients' experiences (symptoms and impacts) are not fully understood. This study sought to understand the patient experience with NSCLC/BM and identify a patient-reported outcome (PRO) measure fit to capture the most important NSCLC/BM symptoms and impacts. METHODS: A targeted literature review was completed; the National Comprehensive Cancer Network (NCCN)/Functional Assessment of Cancer Therapy-Brain Symptom Index, 24-item version (NFBrSI-24) was identified as a relevant measure that assessed the core symptoms and impacts associated with NSCLC/BM. Qualitative interviews composed of concept elicitation and cognitive debriefing with oncologists (n = 3) and adult patients (n = 16) with NSCLC/BM were conducted to confirm the content validity and evaluate the relevance and appropriateness of the NFBrSI-24 for this condition. RESULTS: The NSCLC/BM symptoms and impacts identified in the literature and reported by oncologists and patients were consistent and captured in the NFBrSI-24. Study participants reported significant burden associated with the symptoms (commonly fatigue, headache) and impacts of NSCLC/BM. Participants indicated that the NFBrSI-24 captured their most salient experiences with NSCLC/BM and that symptom improvement or a delay in progression, as measured by the NFBrSI-24, would be meaningful. During the cognitive debriefing, participants generally indicated that the NFBrSI-24 was comprehensive and easy to understand/answer and that it assessed symptoms they considered most important to treat. CONCLUSIONS: These results suggest that the NFBrSI-24 adequately captures an appropriate measure of NSCLC/BM symptoms and impact.

Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy.

The tumor necrosis factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells via death receptor (DR) activation with little toxicity to normal cells or tissues. The selectivity for activating apoptosis in cancer cells confers an ideal therapeutic characteristic to TRAIL, which has led to the development and clinical testing of many DR agonists. However, TRAIL/DR targeting therapies have been widely ineffective in clinical trials of various malignancies for reasons that remain poorly understood. Triple negative breast cancer (TNBC) has the worst prognosis among breast cancers. Targeting the TRAIL DR pathway has shown notable efficacy in a subset of TNBC in preclinical models but again has not shown appreciable activity in clinical trials. In this review, we will discuss the signaling components and mechanisms governing TRAIL pathway activation and clinical trial findings discussed with a focus on TNBC. Challenges and potential solutions for using DR agonists in the clinic are also discussed, including consideration of the pharmacokinetic and pharmacodynamic properties of DR agonists, patient selection by predictive biomarkers, and potential combination therapies. Moreover, recent findings on the impact of TRAIL treatment on the immune response, as well as novel strategies to address those challenges, are discussed.

Exploring life engagement from the perspective of patients with major depressive disorder: a study using patient interviews.

BACKGROUND: Patient-reported outcomes can measure health aspects that are meaningful to patients, such as 'life engagement' in major depressive disorder (MDD). Expert psychiatrists recently identified ten items from the Inventory of Depressive Symptomatology Self-Report (IDS-SR) that can be used to measure patient life engagement. This study aimed to explore the concept of patient life engagement and provide support for the IDS-SR10 Life Engagement subscale from the patient perspective. METHODS: Semi-structured video interviews were conducted with adults with MDD in the United States. Patients were asked if they ever felt engaged with life, and how this affected their feelings, activities, socializing, and thoughts. Then, patients discussed the ten expert-selected IDS-SR items, and rated the relevance of all 30 items to patient life engagement on a 4-point scale. RESULTS: Patients (N = 20) understood the 'engaged with life' concept and could provide examples from their own lives, such as increased energy/motivation (100%), being more social/spending time with others (85%), being more communicative (80%), and having better mood (75%). Nineteen patients (95%) indicated that all ten IDS-SR10 Life Engagement items were relevant to patient life engagement, and nine of the ten items had a mean score ≥ 3 (moderately relevant). Four additional items (all relating to mood) also scored ≥ 3. CONCLUSIONS: Patients found the concept of life engagement to be important and relatable, and confirmed the IDS-SR10 captures the defining non-mood-related aspects of patient life engagement. This research supports the relevance of patient life engagement as a potential clinical outcome beyond core mood symptoms, and the use of the IDS-SR10 Life Engagement subscale in patient-oriented research.

Nursing education on lymphedema self-management and self-monitoring in a South African oncology clinic.

Breast cancer is the leading cause of cancer in South African women. Without comprehensive national and provincial breast health programs, survivorship issues are in need of being addressed. Lymphedema secondary to breast cancer treatment (BCLE) is one of the most physically and psychologically devastating outcomes of treatment. Nurses at a South African oncology clinic educated survivors with BCLE in cost-effective self-management and self-monitoring techniques. The purpose of this paper is to describe these techniques and their relevance to diverse South African survivors. A case study analysis was performed. The need for cost-effective survivorship programs is discussed.

Development of the impact of weight on daily activities questionnaire: A patient-reported outcome measure.

While patient-reported outcome measures are available to evaluate health-related quality of life and functioning in obesity, existing measures do not evaluate the impact of excess weight and weight loss on the ability to perform regularly occurring daily activities. Three iterative sets of qualitative interviews were conducted in two countries (United States, n = 23; United Kingdom, n = 23) with individuals with body mass index ≥30 kg/m2 to inform development of the Impact of Weight on Daily Activities Questionnaire (IWDAQ) for use in clinical trials to evaluate daily activity limitations associated with excess weight. Candidate concepts were selected based on the literature, expert opinion, and previously conducted qualitative research, after which the draft IWDAQ was developed and tested. Interviews included a brief concept elicitation phase, followed by cognitive debriefing during which the IWDAQ was refined based upon participants' feedback. The IWDAQ uses a novel, adaptive questionnaire design, such that clinical trial participants choose the three IWDAQ activities they would most like to improve with weight loss and rate the degree of limitation in each of these activities at baseline. By allowing individuals participating in trials to identify and monitor changes in the activities they most want to see improve with weight loss, the 19-item IWDAQ has the potential to detect the benefits of weight-loss treatment that individuals with obesity value most.

Immune Checkpoint Inhibitors: An Innovation in Immunotherapy for the Treatment and Management of Patients with Cancer.

Cancer survival rates are generally increasing in the United States. These trends have been partially attributed to improvement in therapeutic strategies. Cancer immunotherapy is an example of one of the newer strategies used to fight cancer, which primes or activates the immune system to produce antitumor effects. The first half of this review paper concisely describes the cell mechanisms that control antitumor immunity and the major immunotherapeutic strategies developed to target these mechanisms. The second half of the review discusses in greater depth immune checkpoint inhibitors that have recently demonstrated tremendous promise for the treatment of diverse solid tumor types, including melanoma, non-small cell lung cancer, and others. More specifically, the mechanisms of action, side effects, and patient and family management and education concerns are discussed to provide oncology nurses up-to-date information relevant to caring for cancer-affected patients treated with immune checkpoint inhibitors. Future directions for cancer immunotherapy are considered.