Clinical proteomics reveals vulnerabilities in non-invasive breast ductal carcinoma and drives personalized treatment strategies.

Ductal carcinoma in situ (DCIS) is the most common type (80%) of non-invasive breast lesions in women. The lack of validated prognostic markers, limited patient numbers, and variable tissue quality have a significant impact on diagnosis, risk stratification, patient enrolment, and the results of clinical studies. Here, we performed label-free quantitative proteomics on 50 clinical formalin-fixed, paraffin embedded biopsies, validating 22 putative biomarkers from independent genetic studies.

The Society for Immunotherapy of Cancer Perspective on Tissue-Based Technologies for Immuno-Oncology Biomarker Discovery and Application.

With immuno-oncology becoming the standard of care for a variety of cancers, identifying biomarkers that reliably classify patient response, resistance, or toxicity becomes the next critical barrier towards improving care. Multi-parametric, multi-omics, and computational platforms generating an unprecedented depth of data are poised to usher in the discovery of increasingly robust biomarkers for enhanced patient selection and personalized treatment approaches. Deciding which developing technologies to implement in clinical settings ultimately, applied either alone or in combination, relies on weighing pros and cons, from minimizing patient sampling to maximizing data outputs, and assessing reproducibility and representativeness of findings, while lessening data fragmentation towards harmonization.

Neoadjuvant Capecitabine in Operable HPV-Negative Head and Neck Cancer: Fortuitous Findings in a Resource Constrained Setting.

Objective: Limited progress has occurred in treating operable human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). Accessing timely care remains challenging in public health care systems, potentially resulting in disease progression before treatment initiation.

Study Design: A prospective cohort of patients receiving neoadjuvant capecitabine (NC) was compared to stage-matched patients undergoing standard of care (SC).

Inhibition of the MNK1/2-eIF4E Axis Augments Palbociclib-Mediated Antitumor Activity in Melanoma and Breast Cancer.

Aberrant cell-cycle progression is characteristic of melanoma, and CDK4/6 inhibitors, such as palbociclib, are currently being tested for efficacy in this disease. Despite the promising nature of CDK4/6 inhibitors, their use as single agents in melanoma has shown limited clinical benefit. Herein, we discovered that treatment of tumor cells with palbociclib induces the phosphorylation of the mRNA translation initiation factor eIF4E.

Inhibiting the MNK1/2-eIF4E axis impairs melanoma phenotype switching and potentiates antitumor immune responses.

Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. Using melanoma mouse models, we demonstrated that blocking the MNK1/2-eIF4E axis inhibited melanoma phenotype switching and sensitized melanoma to anti-PD-1 immunotherapy.

Aurora kinase A inhibitor, LY3295668 erbumine: a phase 1 monotherapy safety study in patients with locally advanced or metastatic solid tumors.

Background Aurora A kinase (AurA) overexpression likely contributes to tumorigenesis and therefore represents an attractive target for cancer therapeutics. This phase 1 study aimed to determine the safety, pharmacokinetics, and antitumor activity of LY3295668 erbumine, an AurA inhibitor, in patients with locally advanced or metastatic solid tumors. Methods Patients with locally advanced or metastatic solid tumors, Eastern Cooperative Oncology Group performance status 0-1, and disease progression after one to four prior treatment regimens were enrolled.

Why Tumor Genetic Heterogeneity May Require Rethinking Cancer Genesis and Treatment.

Tumor genetic heterogeneity, in which individual tumors contain both multiple variant cancer-associated and normal genes, has been widely reported, although its significance has yet to be fully understood. We propose a genetic heterogeneity-based selection-centric hypothesis in which genetic heterogeneity, caused by the temporary reduction of DNA repair efficiency, occurs very early in human development, resulting in a small minority of cells in normal tissues acquiring cancer-associated genes that remain dormant. Cancer develops when precancer cells are selected for by altered tissue microenvironments; similar scenarios occur with development of metastases and therapeutic resistance in established cancer.

A Phase I, Dose Escalation, Single Dose Trial of Oral Attenuated Salmonella typhimurium Containing Human IL-2 in Patients With Metastatic Gastrointestinal Cancers.

Salmonella has been shown to preferentially colonize solid tumors. It is known that toxicity limits the systemic administration of immunomodulatory cytokines that have a significant anticancer effect. Therefore, we tested a unique cancer treatment strategy comprised of oral delivery of Saltikva, an attenuated strain of Salmonella typhimurium that contain the human gene for interleukin-2.

The MNK1/2-eIF4E Axis as a Potential Therapeutic Target in Melanoma.

Melanoma is a type of skin cancer that originates in the pigment-producing cells of the body known as melanocytes. Most genetic aberrations in melanoma result in hyperactivation of the mitogen activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. We and others have shown that a specific protein synthesis pathway known as the MNK1/2-eIF4E axis is often dysregulated in cancer.

Developing a model of a patient-group pathway to accessing cancer clinical trials in Canada.

Background: Colorectal Cancer Canada, in partnership with a Scientific Advisory Committee, is developing a Canadian Patient Group Pathway to Accessing Cancer Clinical Trials ("Pathway"). A central element of the Pathway is presented here-namely, a set of recommendations and tools aimed at each stakeholder group.

Methods: A summary of the peer-reviewed and grey literature informed discussions at a meeting, held in June 2017, in which a cross-section of stakeholders reached consensus on the potential roles of patient groups in the cancer clinical trials process, barriers to accessing cancer clinical trials, best practice models for patient-group integration, and a process for developing the Pathway.

Altered Levels of Salivary 8-oxo-7-hydrodeoxyguanosine in Breast Cancer.

Oxidative stress has been implicated in the pathogenesis of breast cancer (BC). To determine whether BC is associated with altered salivary redox homeostasis, we performed a case-control study assessing the relationship between BC and 8-oxo-7-hydrodeoxyguanosine (8-oxodG), a marker for oxidative damage to DNA. Enzyme-linked immunosorbent assay for 8-oxodG was used on whole, unstimulated saliva of 134 BC patients and 226 healthy controls.

Differential regulation of tumor angiogenesis by distinct ErbB homo- and heterodimers.

Interactions between cancer cells and their microenvironment are critical for the development and progression of solid tumors. This study is the first to examine the role of all members of the ErbB tyrosine kinase receptors (epidermal growth factor receptor [EGFR], ErbB-2, ErbB-3, or ErbB-4), expressed singly or as paired receptor combinations, in the regulation of angiogenesis both in vitro and in vivo. Comparison of all receptor combinations reveals that EGFR/ErbB-2 and ErbB-2/ErbB-3 heterodimers are the most potent inducers of vascular endothelial growth factor (VEGF) mRNA expression compared with EGFR/ErbB-3, EGFR/ErbB-4, ErbB-2/ErbB-4, and ErbB-3/ErbB-4.

Genetic alteration of chromosome 8 is a common feature of human mammary epithelial cell lines transformed in vitro with benzo[a]pyrene.

While some epidemiological risk factors for breast cancer have been identified, the environmental factors responsible for transformation of mammary epithelial cells are not clear. We have exposed the spontaneously immortalized human mammary epithelial cell line MCF-10A to benzo[a]pyrene and selected transformed clones based on a loss of contact inhibition and anchorage-dependent growth. Cytogenetic studies showed that each of the transformed sublines possess an isochromosome 8q aberration.

Role of HSP90 in mediating cross-talk between the estrogen receptor and the Ah receptor signal transduction pathways.

Tetrachlorodibenzo-p-dioxin (TCDD)-mediated gene transactivation via the Ah receptor (AhR) has been shown to be dependent upon estrogen receptor (ER) expression in human breast cancer cells. We have investigated the 90-kDa heat shock protein (HSP90) as a mediator of cross-talk between the AhR and the ER signal transduction pathways. The effect of HSP90 overexpression on receptor activity was determined by transient transfection assays using a HSP90 expression vector.

Deficiency of connexin43 gap junctions is an independent marker for breast tumors.

Gap junctions are intercellular channels that are formed from members of a family of proteins, the connexins (Cxs). Gap junctions play an important role in vital functions, including the regulation of cell growth and cell differentiation. Here, we examined the expression of Cx43, a major Cx in breast tissue, in 32 surgical specimens obtained from breast cancer patients who underwent a primary surgical resection prior to chemotherapy or radiotherapy treatments.

Dual effect of erbB-2 depletion on the regulation of DNA repair and cell cycle mechanisms in non-small cell lung cancer cells.

Overexpression of the erbB-2 tyrosine kinase receptor, p185erbB-2, is a common alteration in non-small cell lung cancer (NSCLC) and has been associated with poor prognosis and a tumor drug resistance phenotype. In this study, we have examined the consequences of erbB-2 depletion on DNA repair, cell cycle, and apoptosis using a panel of NSCLC cell lines constitutively overexpressing erbB-2 receptor. Depletion of the erbB-2 was achieved using the tyrosine kinase inhibitor CP127,374 which promotes erbB-2 degradation.

Identification of the Yc1 glutathione S-transferase mRNA as the overexpressed species in a nitrogen mustard-resistant rat mammary carcinoma cell line.

Glutathione transferase (GSTs) have been shown to be overexpressed in a number of tumor cell lines selected for resistance to chemotherapeutic drugs and have been implicated in some studies of clinical specimens. In tumor cell lines selected for resistance to chemicals that alkylate DNA, the isoform most frequently overexpressed is GST-Yc, a member of the alpha class GSTs. To date, two variations of the cDNA designated Yc1 with subtle differences have been described, and Yc2 is shown to be clearly distinct.