Inter-Individual Variation and Cardioprotection in Anthracycline-Induced Heart Failure

Anthracyclines are one of the most widely used and effective chemotherapies in oncology, but their most important side effect is the cumulative, dose-related cardiotoxicity leading to congestive heart failure in ~5% of individuals. Methodology and pharmacogenetic studies for predicting which individuals are at high risk and subsequently the development of targeted and individualized cardioprotective plans are beginning to make progress. Here, we review current putative risk genes and variants, the strength of evidence for each genetic association and the interaction between risk genes, in the context of known clinical risk factors and potential novel cardioprotective strategies

Immunophenotyping of Waldenströms Macroglobulinemia Cell Lines Reveals Distinct Patterns of Surface Antigen Expression: Potential Biological and Therapeutic Implications

<div><p>Waldenströms macroglobulinemia (WM) is a subtype of Non-Hodgkin’s lymphoma in which the tumor cell population is markedly heterogeneous, consisting of immunoglobulin-M secreting B-lymphocytes, plasmacytoid lymphocytes and plasma cells. Due to rarity of disease and scarcity of reliable preclinical models, many facets of WM molecular and phenotypic architecture remain incompletely understood. Currently, there are 3 human WM cell lines that are routinely used in experimental studies, namely, BCWM.1, MWCL-1 and RPCI-WM1. During establishment of RPCI-WM1, we observed loss of the CD19 and CD20 antigens, which are typically present on WM cells. Intrigued by this observation and in an effort to better define the immunophenotypic makeup of this cell line, we conducted a more comprehensive analysis for the presence or absence of other cell surface antigens that are present on the RPCI-WM1 model, as well as those on the two other WM cell lines, BCWM.1 and MWCL-1. We examined expression of 65 extracellular and 4 intracellular antigens, comprising B-cell, plasma cell, T-cell, NK-cell, myeloid and hematopoietic stem cell surface markers by flow cytometry analysis. RPCI-WM1 cells demonstrated decreased expression of CD19, CD20, and CD23 with enhanced expression of CD28, CD38 and CD184, antigens that were differentially expressed on BCWM.1 and MWCL-1 cells. Due to increased expression of CD184/CXCR4 and CD38, RPCI-WM1 represents a valuable model in which to study the effects anti-CXCR4 or anti-CD38 targeted therapies that are actively being developed for treatment of hematologic cancers. Overall, differences in surface antigen expression across the 3 cell lines may reflect the tumor clone population predominant in the index patients, from whom the cell lines were developed. Our analysis defines the utility of the most commonly employed WM cell lines as based on their immunophenotype profiles, highlighting unique differences that can be further studied for therapeutic exploit.</p></div

A FZD7-specific Antibody-Drug Conjugate Induces Ovarian Tumor Regression in Preclinical Models.

Although WNT signaling is frequently dysregulated in solid tumors, drugging this pathway has been challenging due to off-tumor effects. Current clinical pan-WNT inhibitors are nonspecific and lead to adverse effects, highlighting the urgent need for more specific WNT pathway-targeting strategies. We identified elevated expression of the WNT receptor Frizzled class receptor 7 (FZD7) in multiple solid cancers in The Cancer Genome Atlas, particularly in the mesenchymal and proliferative subtypes of ovarian serous cystadenocarcinoma, which correlate with poorer median patient survival. Moreover, we observed increased FZD7 protein expression in ovarian tumors compared with normal ovarian tissue, indicating that FZD7 may be a tumor-specific antigen. We therefore developed a novel antibody-drug conjugate, septuximab vedotin (F7-ADC), which is composed of a chimeric human-mouse antibody to human FZD7 conjugated to the microtubule-inhibiting drug monomethyl auristatin E (MMAE). F7-ADC selectively binds human FZD7, potently kills ovarian cancer cells in vitro, and induces regression of ovarian tumor xenografts in murine models. To evaluate F7-ADC toxicity in vivo, we generated mice harboring a modified Fzd7 gene where the resulting Fzd7 protein is reactive with the human-targeting F7-ADC. F7-ADC treatment of these mice did not induce acute toxicities, indicating a potentially favorable safety profile in patients. Overall, our data suggest that the antibody-drug conjugate approach may be a powerful strategy to combat FZD7-expressing ovarian cancers in the clinic

Comparative immunophenotyping analysis of RPCI-WM1, BCWM.1 and MWCL-1 WM cell lines.

<p>A total of 65 extracellular and 4 intracellular antigens, comprising B-cell, plasma cell, T-cell, NK-cell, myeloid and hematopoietic stem cell surface markers were analyzed by flow cytometry analysis. Quantification of % gated antigen expression and density of antigen expression is detailed in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122338#pone.0122338.t004" target="_blank">Table 4</a>. Blue line indicates RPCI-WM1 antigen expression, red line indicates MWCL-1 antigen expression and green line indicates antigen expression in BCWM.1 cell line.</p

Presence of stem-cell markers on RPCI-WM1.

<p>A total of 8 surface antigens that are typically expressed on the surface of stem cells were examined. Notably, more than 90% of RPCI-WM1 cells gated were CD110+low and CXCR4/CD184+low. A comparison of these and the remaining stem-cell antigens in BCWM.1 and MWCL-1 cell lines is presented in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0122338#pone.0122338.t004" target="_blank">Table 4</a>.</p

Pattern of surface antigen expression (>20%) across all 3 WM models.

<p>Pattern of surface antigen expression (<u>></u>20%) across all 3 WM models.</p

Immunophenotype comparison of common WM models with various B/plasma cell cancers.

<p>Abbreviations: +, present in >20% gated cells;-, present in <20% of gated cells; LPL/WM, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia; SMZL, splenic marginal zone lymphoma; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; FL, follicular lymphoma; HCL, hairy cell leukemia; MALT, mucosa-associated lymphoid tissue; MM, multiple myeloma.</p><p>Immunophenotype comparison of common WM models with various B/plasma cell cancers.</p

Most widely expressed antigens on RPCI-WM1 cells.

<p>Most widely expressed antigens on RPCI-WM1 cells.</p