Blackburn H.L.,Chan Soon Shiong Institute of Molecular Medicine at Windber |
Ellsworth D.L.,Chan Soon Shiong Institute of Molecular Medicine at Windber |
Shriver C.D.,Bethesda University |
Ellsworth R.E.,Murtha Cancer Center
Breast Cancer: Basic and Clinical Research | Year: 2017
Metastasis is a multistep process that is not well understood. Colonization of a secondary organ requires specific molecular alterations of the host microenvironment. To determine the temporal and spatial changes associated with metastatic dissemination to the axillary lymph nodes, gene expression profiles were compared between histologically normal lymph nodes from node-positive patients and tumor-free nodes from node-negative patients. Using a stringent false discovery rate correction (<0.05) for multiple hypothesis testing, we did not detect any differentially expressed genes between the lymph node groups. Thus, the presence of metastatic cells within the lymphatic system does not elicit widespread changes in gene expression through the axillary basin; rather, lymph nodes independently respond to disseminated tumor cells. © The Author(s) 2017.
PubMed | Penn Medicine and Murtha Cancer Center
Type: Journal Article | Journal: Ethnicity & disease | Year: 2016
Breast cancer mortality rates are higher for African American women (AAW) than for any other ethnic group in the United States. Recent reports suggest that outcome disparities between AAW and European American women (EAW) are present in the ER+HER2- subtype. To improve our understanding, pathological characteristics, mortality and molecular profiles from women treated within an equal-access health care system were evaluated.All AAW (n=90) and EAW (n=308) with ER+HER2- tumors were identified. Gene expression profiles were generated from primary breast tumors from 57 AAW and 181 EAW. Pathological characteristics, survival and gene expression analysis were evaluated using chi-square analysis, log-rank tests and ANOVA.Tumors from AAW were significantly more likely to be PR-, Ki67+ and of higher grade. Tumor stage, size and lymph node status did not differ significantly, nor did mortality rates (P=.879). At the molecular level, genes PSPHL and CRYBB2P1 were expressed at significantly higher levels in tumor tissues as well as normal stroma and blood from AAW. Polymorphisms controlling expression of each gene were identified with minor allele frequencies differing significantly between populations but not between cases and controls within each population.Survival disparities were not detected in patients with ER+HER2- tumors treated within an equal-access health care system and molecular differences in tumors were not causal. Thus, outcome disparities in AAW with ER+HER2- tumors are largely attributable to socioeconomic factors affecting access to screening and treatment, rather than reflecting underlying biological differences.
News Article | January 13, 2016
It wasn't expected to be a major State of the Union address—a final speech from a president in his last term, recounting achievements and expressing hope for the future. And then Obama made some news: "Let’s make America the country that cures cancer once and for all." And to lead the administration's effort, the president picked VP Joe Biden, who recently lost his son Beau to cancer, and who has said that finding a cure is one of his major life goals. Obama compared the effort to a moonshot, and he's not the only one to do this. His State of the Union address came just one day after the launch of another effort, led by big pharma and biotech companies, dubbed Cancer MoonShot 2020. The leader of MoonShot 2020, biotech company NantWorks' controversial founder and CEO Dr. Patrick Soon-Shiong, is one of the people who has met with the vice president to discuss radical cancer-treating approaches and has influenced Biden's thinking on the topic, reports the New York Times. At least one branch of the federal government, the John P. Murtha Cancer Center at Walter Reed Military Hospital, is on record as supporting Soon-Shiong's MoonShot. With details still to come about the administration's moonshot, Soon-Shiong's project offers a few hints of what these new cancer-fighting approaches may entail. His project, formally announced on January 11, is a switch from chemotherapy to immunotherapy; from killing cancer cells directly to helping the body's immune system kill cancer. It is focused on personalized genetic sequencing to develop custom treatments for each patient. And the time frame is at least as aggressive as the race to the moon. Within five years, it aims to not only design but also implement clinical trials of new immunotherapies for 20 tumor types in up to 20,000 patients. By 2020, these trials are expected to get as far as phase 3—widespread participation on an unheard-of timeframe. Though it's a nonprofit, MoonShot 2020 is led by big pharma firms like Celgene and Amgen, and biotech companies including NantKwest, Etubics, Altor Bioscience, and Precision Biologics. Participating hospitals and universities include Massachusetts General Hospital, Johns Hopkins University, the University of Miami, the University of Utah, and the Tufts Cancer Center. One biotech company, NantWorks, is spearheading the effort and is the key link to Biden, who reached out to Soon-Shiong as Beau Biden was still battling the disease. According to the Times, the VP became a believer in Soon-Shiong's radical approach to cancer, which the physician was already calling a moonshot in a two-page proposal he gave to the VP. In announcing that he would not run for president, Biden expressed his support for Soon-Shiong's vision, saying, " I believe that we need a moonshot in this country to cure cancer. It's personal. But I know we can do this." Biden later added, "If I could be anything, I would have wanted to have been the president that ended cancer, because it's possible." Instead, he aspires to be the VP who does. The exact nature of the Obama's administration's support for the moonshot immunotherapy approach remains unclear. Any tests will have to follow federal guidelines, of course, and government can play a role in speeding up approvals. The biggest commitment so far is from the US military through the participation of the John P. Murtha Cancer Center at Walter Reed Military Hospital, in part by sourcing participants. "We validate big science through our clinical trials network," wrote Col. Craig Shriver, M.D., of the Murtha Center in the MoonShot program's press release. "There are 1.2 million active duty military members, 9.3 million beneficiaries that receive military health care. That’s a huge network." Note: An earlier version of this article incorrectly characterized Obama's comments as a formal endorsement of Dr. Soon-Shiong's MoonShot program.
PubMed | University of Michigan, InterWest Partners, View Inc, University of Helsinki and 4 more.
Type: Journal Article | Journal: Biomolecules | Year: 2016
First introduced during the late 1800s, radiation therapy is fundamental to the treatment of cancer. In developed countries, approximately 60% of all patients receive radiation therapy (also known as the sixty percenters), which makes radioresistance in cancer an important and, to date, unsolved, clinical problem. Unfortunately, the therapeutic refractoriness of solid tumors is the rule not the exception, and the ubiquity of resistance also extends to standard chemotherapy, molecularly targeted therapy and immunotherapy. Based on extrapolation from recent clinical inroads with epigenetic agents to prime refractory tumors for maximum sensitivity to concurrent or subsequent therapies, the radioresistant phenotype is potentially reversible, since aberrant epigenetic mechanisms are critical contributors to the evolution of resistant subpopulations of malignant cells. Within the framework of a syllogism, this review explores the emerging link between epigenetics and the development of radioresistance and makes the case that a strategy of pre- or co-treatment with epigenetic agents has the potential to, not only derepress inappropriately silenced genes, but also increase reactive oxygen species production, resulting in the restoration of radiosensitivity.
PubMed | Sloan Kettering Cancer Center, Review Centre, U.S. National Institutes of Health, Murtha Cancer Center and University of Michigan
Type: Journal Article | Journal: British journal of haematology | Year: 2016
Pure red cell aplasia (PRCA) is a rare disorder characterized by inhibition of erythroid precursors in the bone marrow and normochromic, normocytic anaemia with reticulocytopenia. Among 51 PRCA patients, we identified 12 (24%) patients having monoclonal gammopathy, monoclonal gammopathy of undetermined significance or smouldering multiple myeloma, with presence of monoclonal protein or abnormal serum free light chains and atypical bone marrow features of clonal plasmacytosis, hypercellularity and fibrosis. Thus far, three patients treated with anti-myeloma based therapeutics have responded with reticulocyte recovery and clinical transfusion independence, suggesting plasma cells play a key role in the pathogenesis of this specific monoclonal gammopathy-associated PRCA.
Gonzalez-Nieves R.,Uniformed Services University of the Health Sciences |
Desantis A.I.,Uniformed Services University of the Health Sciences |
Cutler M.L.,Uniformed Services University of the Health Sciences |
Cutler M.L.,Murtha Cancer Center
Journal of Cell Communication and Signaling | Year: 2013
Cell adhesion and migration are complex processes that require integrin activation, the formation and dissolution of focal adhesion (FAs), and linkage of actin cytoskeleton to the FAs. The IPP (ILK, PINCH, Parvin) complex regulates FA formation via binding of the adaptor protein ILK to β1 integrin, PINCH and parvin. The signaling protein Rsu1 is linked to the complex via binding PINCH1. The role of Rsu1 and PINCH1 in adhesion and migration was examined in non-transformed mammary epithelial cells. Confocal microscopy revealed that the depletion of either Rsu1 or PINCH1 by siRNA in MCF10A cells decreased the number of focal adhesions and altered the distribution and localization of β1 integrin, vinculin, talin and paxillin without affecting the levels of FA protein expression. This correlated with reduced adhesion, failure to spread or migrate in response to EGF and a loss of actin stress fibers and caveolae. In addition, constitutive phosphorylation of actin regulatory proteins occurred in the absence of PINCH1. The depletion of Rsu1 caused significant reduction in PINCH1 implying that Rsu1 may function by regulating levels of PINCH1. However, while both Rsu1- or PINCH1-depleted cells retained the ability to activate adhesion signaling in response to EGF stimulation, only Rsu1 was required for EGF-induced p38 Map Kinase phosphorylation and ATF2 activation, suggesting an Rsu1 function independent from the IPP complex. Reconstitution of Rsu1-depleted cells with an Rsu1 mutant that does not bind to PINCH1 failed to restore FAs or migration but did promote spreading and constitutive p38 activation. These data show that Rsu1-PINCH1 association with ILK and the IPP complex is required for regulation of adhesion and migration but that Rsu1 has a critical role in linking integrin-induced adhesion to activation of p38 Map kinase signaling and cell spreading. Moreover, it suggests that Rsu1 may regulate p38 signaling from the IPP complex affecting other functions including survival. © 2013 The International CCN Society.
PubMed | Bethesda University, Murtha Cancer Center and Chan Soon Shiong Institute of Molecular Medicine at Windber
Type: | Journal: BMC obesity | Year: 2016
Obesity is a risk factor for breast cancer in postmenopausal women and is associated with decreased survival and less favorable clinical characteristics such as greater tumor burden, higher grade, and poor prognosis, regardless of menopausal status. Despite the negative impact of obesity on clinical outcome, molecular mechanisms through which excess adiposity influences breast cancer etiology are not well-defined.Affymetrix U133 2.0 gene expression data were generated for 405 primary breast tumors using RNA isolated from laser microdissected tissues. Patients were classified as normal-weight (BMI<25), overweight (BMI 25-29.9) or obese (BMI30). Statistical analysis was performed by ANOVA using Partek Genomics Suite version 6.6 using a false discovery rate <0.05 to define significance.Obese patients were significantly more likely to be diagnosed 50years or with African American ancestry compared to lean or overweight women. Pathological characteristics including tumor stage, size or grade, lymph node status, intrinsic subtype, and breast cancer mortality did not differ significantly between groups. No significant gene expression differences were detected by BMI in a non-stratified analysis which included all subtypes or within luminal B, HER2-enriched or basal-like subtypes. Within luminal A tumors, however, 44 probes representing 42 genes from pathways such as cell cycle, p53 and mTOR signaling, DNA repair, and transcriptional misregulation were differentially expressed.Identification of transcriptome differences in luminal A tumors from normal-weight compared to obese women suggests that obesity alters gene expression within ER+ tumor epithelial cells. Alterations of pathways involved in cell cycle control, tumorigenesis and metabolism may promote cellular proliferation and provide a molecular explanation for less favorable outcome of obese women with breast cancer. Targeted treatments, such as mTOR inhibitors, may allow for improved treatment and survival of obese women, especially African American women, who are more likely to be obese and suffer outcome disparities.
PubMed | Uniformed Services University of the Health Sciences and Murtha Cancer Center
Type: Journal Article | Journal: Case reports in oncology | Year: 2017
Poorly differentiated neuroendocrine carcinomas (NECs) are rare tumors that can arise anywhere along the gastrointestinal tract. They often present in advanced stage and portend a poor prognosis when compared to adenocarcinomas of the same stage. Characterization of these tumors is best accomplished with tissue biopsy, as peripheral tumor markers commonly used in NECs are of little utility. Therapeutic strategies often involve chemotherapeutic regimens that have been used to treat small-cell lung cancer. Recent studies have shown that programmed death-ligand 1 (PD-L1) expression within poorly differentiated NECs is a poor prognostic indicator. However, PD-L1 expression may represent a possible target for immunotherapy drugs, often called checkpoint inhibitors, such as anti-PD-1 inhibitors.
Blackburn H.L.,Windber Research Institute |
Ellsworth D.L.,Windber Research Institute |
Shriver C.D.,U.S. National Institutes of Health |
Ellsworth R.E.,Murtha Cancer Center
Cancer Causes and Control | Year: 2015
Purpose: The cytochrome P450 (CYP) genes are oxygenases involved in estrogen biosynthesis and metabolism, generation of DNA damaging procarcinogens, and response to anti-estrogen therapies. Since lifetime estrogen exposure is an established risk factor for breast cancer, determining the role of CYP genes in breast cancer etiology may provide critical information for understanding tumorigenesis and response to treatment.Methods: This review summarizes literature available in PubMed published between 1993 and 2013 that focuses on studies evaluating the effects of DNA variants in CYP genes on estrogen synthesis, metabolism, and generation of procarcinogens in addition to response to anti-estrogen therapies.Results: Evaluation of DNA variants in estrogen metabolism genes was largely inconclusive. Meta-analyses of data from CYP19A1 support an association between the number of (TTTA)n repeats in intron 4 and breast cancer risk, but the biological mechanism for this relationship is unknown. Associations between single nucleotide polymorphism in CYP1B1 and DNA damage caused by procarcinogenic estrogen metabolites were ambiguous. Variants in CYP2D6 are associated with altered metabolism tamoxifen; however, current data do not support widespread clinical testing. The effect of variants in CYP19A1 in response to aromatase inhibitors is also questionable.Conclusion: Evaluation of DNA variants in CYP genes involved with estrogen metabolism or treatment response has been inconclusive, reflecting small samples sizes, tumor heterogeneity, and differences between populations. Better-powered studies that account for genetic backgrounds and tumor phenotypes are thus necessary. © 2014, Springer International Publishing Switzerland.
Shriver C.D.,Murtha Cancer Center |
Hueman M.T.,Murtha Cancer Center |
Ellsworth R.E.,Murtha Cancer Center
Journal of Experimental and Clinical Cancer Research | Year: 2014
Background: Identification of a gene expression signature in primary breast tumors that could classify patients by lymph node status would allow patients to avoid the morbidities of surgical disruption of the lymph nodes. Attempts to identify such a signature have, to date, been unsuccessful. Because breast tumor subtypes have unique molecular characteristics and different sites of metastasis, molecular signatures for lymph node involvement may vary by subtype. Methods: Gene expression data was generated from HG U133A 2.0 arrays for 135 node positive and 210 node negative primary breast tumors. Intrinsic subtype was assigned using the BreastPRS. Differential gene expression analysis was performed using one-way ANOVA using lymph node status as the variable with a False-discovery rate <0.05, to define significance. Results: Luminal A tumors were most common (51%) followed by basal-like (27%), HER2-enriched (14%) luminal B (7%) and normal-like (1%). Basal-like and luminal A tumors were less likely to have metastatic lymph nodes (35% and 37%, respectively) compared to luminal B or HER2-enriched (52% and 51%, respectively). No differentially expressed genes associated with lymph node status were detected when all tumors were considered together or within each subtype. Conclusions: Gene expression patterns from the primary tumor are not able to stratify patients by lymph node status. Although the primary breast tumor may influence tumor cell dissemination, once metastatic cells enter the lymphatics, it is likely that characteristics of the lymph node microenvironment, such as establishment of a pre-metastatic niche and release of pro-survival factors, determine which cells are able to colonize. The inability to utilize molecular profiles from the primary tumor to determine lymph node status suggest that other avenues of investigation, such as how systemic factors including diminished immune response or genetic susceptibility contribute to metastasis, may be critical in the development of tools for non-surgical assessment of lymph node status with a corresponding reduction in downstream sequelae associated with disruption of the lymphatics. © 2015 Shriver et al.