Medicine and Health Sciences Commons^™

New Interleukin-15 Superagonist (Il-15sa) Significantly Enhances Graft-Versus-Tumor Activity., Cavan P Bailey, Tulin Budak-Alpdogan, Christopher T Sauter, Michelle M Panis, Cihangir Buyukgoz, Emily K Jeng, Hing C Wong, Neal Flomenberg, Md, Onder Alpdogan

Department of Medical Oncology Faculty Papers

Interleukin-15 (IL-15) is a potent cytokine that increases CD8+ T and NK cell numbers and function in experimental models. However, obstacles remain in using IL-15 therapeutically, specifically its low potency and short in vivo half-life. To help overcome this, a new IL-15 superagonist complex comprised of an IL-15N72D mutation and IL-15RαSu/Fc fusion (IL-15SA, also known as ALT-803) was developed. IL-15SA exhibits a significantly longer serum half-life and increased in vivo activity against various tumors. Herein, we evaluated the effects of IL-15SA in recipients of allogeneic hematopoietic stem cell transplantation. Weekly administration of IL-15SA to transplant recipients significantly increased the number …

The Effects Of Cep-37440, An Inhibitor Of Focal Adhesion Kinase, In Vitro And In Vivo On Inflammatory Breast Cancer Cells., Israa Salem, Manal Alsalahi, I Chervoneva, Lucy D Aburto, Sankar Addya, Gregory R Ott, Bruce A Ruggeri, Massimo Cristofanilli, Sandra V Fernandez

Department of Medical Oncology Faculty Papers

BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive type of advanced breast cancer with a poor prognosis. We recently found that focal adhesion kinase 1 (FAK1) is upregulated and phosphorylated (active) in IBC. In this study, we investigated the effect of CEP-37440, a dual inhibitor of FAK1 and anaplastic lymphoma kinase (ALK), using human IBC cell lines and preclinical models of IBC.

METHODS: Cell proliferation assays were performed in the presence of several concentrations of CEP-37440 using IBC and triple-negative breast cancer non-IBC cell lines. In vitro, we studied the expression of total FAK1, phospho-FAK1 (Tyr 397), total ALK and …

Romidepsin For The Treatment Of Relapsed/Refractory Peripheral T Cell Lymphoma: Prolonged Stable Disease Provides Clinical Benefits For Patients In The Pivotal Trial., Francine Foss, Steven Horwitz, Barbara Pro, H Miles Prince, Lubomir Sokol, Barbara Balser, Julie Wolfson, Bertrand Coiffier

Kimmel Cancer Center Faculty Papers

BACKGROUND: Achievement of durable responses in patients with relapsed/refractory peripheral T cell lymphoma (PTCL) is challenging with current therapies, and there are few data regarding the potential benefits of continuing treatment in patients with the best response of stable disease (SD). Histone deacetylase inhibitors are a novel class of drugs with activity in T cell malignancies. Romidepsin was approved by the US Food and Drug Administration for the treatment of relapsed/refractory PTCL based on a pivotal trial demonstrating an objective response rate of 25 % (33/130), including 15 % with confirmed/unconfirmed complete response and a median duration of response of …

Analysis Of Tumor Template From Multiple Compartments In A Blood Sample Provides Complementary Access To Peripheral Tumor Biomarkers., William M Strauss, Chris Carter, Jill Simmons, Erich Klem, Nathan Goodman, Behrad Vahidi, Juan Romero, Michael Masterman-Smith, Ruth O'Regan, Keerthi Gogineni, Lee Schwartzberg, Laura Austin, Paul W Dempsey, Massimo Cristofanilli

Kimmel Cancer Center Faculty Papers

Targeted cancer therapeutics are promised to have a major impact on cancer treatment and survival. Successful application of these novel treatments requires a molecular definition of a patient's disease typically achieved through the use of tissue biopsies. Alternatively, allowing longitudinal monitoring, biomarkers derived from blood, isolated either from circulating tumor cell derived DNA (ctcDNA) or circulating cell-free tumor DNA (ccfDNA) may be evaluated. In order to use blood derived templates for mutational profiling in clinical decisions, it is essential to understand the different template qualities and how they compare to biopsy derived template DNA as both blood-based templates are rare …

Igf-I Induces Upregulation Of Ddr1 Collagen Receptor In Breast Cancer Cells By Suppressing Mir-199a-5p Through The Pi3k/Akt Pathway., Roberta Matà, Chiara Palladino, Maria Luisa Nicolosi, Anna Rita Lo Presti, Roberta Malaguarnera, Marco Ragusa, Daniela Sciortino, Andrea Morrione, Marcello Maggiolini, Veronica Vella, Antonino Belfiore

Kimmel Cancer Center Faculty Papers

Discoidin Domain Receptor 1 (DDR1) is a collagen receptor tyrosine-kinase that contributes to epithelial-to-mesenchymal transition and enhances cancer progression. Our previous data indicate that, in breast cancer cells, DDR1 interacts with IGF-1R and positively modulates IGF-1R expression and biological responses, suggesting that the DDR1-IGF-IR cross-talk may play an important role in cancer.In this study, we set out to evaluate whether IGF-I stimulation may affect DDR1 expression. Indeed, in breast cancer cells (MCF-7 and MDA-MB-231) IGF-I induced significant increase of DDR1 protein expression, in a time and dose dependent manner. However, we did not observe parallel changes in DDR1 mRNA. DDR1 …

Early Results Of Prostate Cancer Radiation Therapy: An Analysis With Emphasis On Research Strategies To Improve Treatment Delivery And Outcomes., Kosj Yamoah, Kwamena Beecham, Sarah E Hegarty, Terry Hyslop, Timothy Showalter, Joel Yarney

Sarah E Hegarty

ABSTRACT: BACKGROUND: There is scant data regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT). METHODS: A total of 379 men with prostate cancer were referred to the National Center for Radiotherapy, Ghana from 2003 to 2009. Data were collected regarding patient-and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score (GS), clinical stage (T), and use of androgen deprivation therapy (ADT). For patients who received EBRT, freedom from biochemical failure (FFbF) …

Kinase Independent Oncogenic Cyclin D1., Mathew C Casimiro, Andrew Arnold, Richard Pestell

Kimmel Cancer Center Faculty Papers

No abstract provided.

Novel Cross Talk Between Igf-Ir And Ddr1 Regulates Igf-Ir Trafficking, Signaling And Biological Responses., Roberta Malaguarnera, Maria Luisa Nicolosi, Antonella Sacco, Alaide Morcavallo, Veronica Vella, Concetta Voci, Michela Spatuzza, Shi-Qiong Xu, Renato V Iozzo, Riccardo Vigneri, Andrea Morrione, Antonino Belfiore

Kimmel Cancer Center Faculty Papers

The insulin-like growth factor-I receptor (IGF-IR), plays a key role in regulating mammalian development and growth, and is frequently deregulated in cancer contributing to tumor initiation and progression. Discoidin domain receptor 1 (DDR1), a collagen receptor tyrosine-kinase, is as well frequently overexpressed in cancer and implicated in cancer progression. Thus, we investigated whether a functional cross-talk between the IGF-IR and DDR1 exists and plays any role in cancer progression.Using human breast cancer cells we found that DDR1 constitutively associated with the IGF-IR. However, this interaction was enhanced by IGF-I stimulation, which promoted rapid DDR1 tyrosine-phosphorylation and co-internalization with the IGF-IR. …

Deregulation Of Mir-34b/Sox2 Predicts Prostate Cancer Progression., Irene Forno, Stefano Ferrero, Maria Veronica Russo, Giacomo Gazzano, Sara Giangiobbe, Emanuele Montanari, Alberto Del Nero, Bernardo Rocco, Giancarlo Albo, Lucia R Languino, Dario C Altieri, Valentina Vaira, Silvano Bosari

Department of Cancer Biology Faculty Papers

Most men diagnosed with prostate cancer will have an indolent and curable disease, whereas approximately 15% of these patients will rapidly progress to a castrate-resistant and metastatic stage with high morbidity and mortality. Therefore, the identification of molecular signature(s) that detect men at risk of progressing disease remains a pressing and still unmet need for these patients. Here, we used an integrated discovery platform combining prostate cancer cell lines, a Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model and clinically-annotated human tissue samples to identify loss of expression of microRNA-34b as consistently associated with prostate cancer relapse. Mechanistically, this was …

Dicer1 Regulated Let-7 Expression Levels In P53-Induced Cancer Repression Requires Cyclin D1., Xin Sun, Shou-Ching Tang, Chongwen Xu, Chenguang Wang, Sida Qin, Ning Du, Jian Liu, Yiwen Zhang, Xiang Li, Gang Luo, Jie Zhou, Fei Xu, Hong Ren

Department of Cancer Biology Faculty Papers

Let-7 miRNAs act as tumour suppressors by directly binding to the 3'UTRs of downstream gene products. The regulatory role of let-7 in downstream gene expression has gained much interest in the cancer research community, as it controls multiple biological functions and determines cell fates. For example, one target of the let-7 family is cyclin D1, which promotes G0/S cell cycle progression and oncogenesis, was correlated with endoribonuclease DICER1, another target of let-7. Down-regulated let-7 has been identified in many types of tumours, suggesting a feedback loop may exist between let-7 and cyclin D1. A potential player in the proposed feedback …

Consequence Of The Tumor-Associated Conversion To Cyclin D1b., Michael A Augello, Lisa D Berman-Booty, Richard Carr, Akihiro Yoshida, Jeffry L Dean, M J Schiewer, Felix Y Feng, Scott A Tomlins, Erhe Gao, Walter J Koch, Jeffrey L Benovic, John Alan Diehl, Karen E Knudsen

Department of Cancer Biology Faculty Papers

Clinical evidence suggests that cyclin D1b, a variant of cyclin D1, is associated with tumor progression and poor outcome. However, the underlying molecular basis was unknown. Here, novel models were created to generate a genetic switch from cyclin D1 to cyclin D1b. Extensive analyses uncovered overlapping but non-redundant functions of cyclin D1b compared to cyclin D1 on developmental phenotypes, and illustrated the importance of the transcriptional regulatory functions of cyclin D1b in vivo. Data obtained identify cyclin D1b as an oncogene, wherein cyclin D1b expression under the endogenous promoter induced cellular transformation and further cooperated with known oncogenes to promote …

Targeting Tumor-Initiating Cells: Eliminating Anabolic Cancer Stem Cells With Inhibitors Of Protein Synthesis Or By Mimicking Caloric Restriction., Rebecca Lamb, Hannah Harrison, Duncan L Smith, Paul A Townsend, Thomas Jackson, Bela Ozsvari, Ubaldo E. Martinez-Outshoorn, Md, Richard Pestell, Anthony Howell, Michael P. Lisanti, Federica Sotgia

Kimmel Cancer Center Faculty Papers

We have used an unbiased proteomic profiling strategy to identify new potential therapeutic targets in tumor-initiating cells (TICs), a.k.a., cancer stem cells (CSCs). Towards this end, the proteomes of mammospheres from two breast cancer cell lines were directly compared to attached monolayer cells. This allowed us to identify proteins that were highly over-expressed in CSCs and/or progenitor cells. We focused on ribosomal proteins and protein folding chaperones, since they were markedly over-expressed in mammospheres. Overall, we identified >80 molecules specifically associated with protein synthesis that were commonly upregulated in mammospheres. Most of these proteins were also transcriptionally upregulated in human …

Classification Of Current Anticancer Immunotherapies., Lorenzo Galluzzi, Erika Vacchelli, José-Manuel Bravo-San Pedro, Aitziber Buqué, Laura Senovilla, Elisa Elena Baracco, Norma Bloy, Francesca Castoldi, Jean-Pierre Abastado, Patrizia Agostinis, Ron N Apte, Fernando Aranda, Maha Ayyoub, Philipp Beckhove, Jean-Yves Blay, Laura Bracci, Anne Caignard, Chiara Castelli, Federica Cavallo, Estaban Celis, Vincenzo Cerundolo, Aled Clayton, Mario P Colombo, Lisa Coussens, Madhav V Dhodapkar, Alexander M Eggermont, Douglas T Fearon, Wolf H Fridman, Jitka Fučíková, Dmitry I Gabrilovich, Jérôme Galon, Abhishek Garg, François Ghiringhelli, Giuseppe Giaccone, Eli Gilboa, Sacha Gnjatic, Axel Hoos, Anne Hosmalin, Dirk Jäger, Pawel Kalinski, Klas Kärre, Oliver Kepp, Rolf Kiessling, John M Kirkwood, Eva Klein, Alexander Knuth, Claire E Lewis, Roland Liblau, Michael T Lotze, Enrico Lugli, Jean-Pierre Mach, Fabrizio Mattei, Domenico Mavilio, Ignacio Melero, Cornelis J Melief, Elizabeth A Mittendorf, Lorenzo Moretta, Adekunke Odunsi, Hideho Okada, Anna Karolina Palucka, Marcus E Peter, Kenneth J Pienta, Angel Porgador, George C Prendergast, Gabriel A Rabinovich, Nicholas P Restifo, Naiyer Rizvi, Catherine Sautès-Fridman, Hans Schreiber, Barbara Seliger, Hiroshi Shiku, Bruno Silva-Santos, Mark J Smyth, Daniel E Speiser, Radek Spisek, Pramod K Srivastava, James E Talmadge, Eric Tartour, Sjoerd H Van Der Burg, Benoît J Van Den Eynde, Richard Vile, Hermann Wagner, Jeffrey S Weber, Theresa L Whiteside, Jedd D Wolchok, Laurence Zitvogel, Weiping Zou, Guido Kroemer

Kimmel Cancer Center Faculty Papers

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into "passive" and "active" based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification …

Camk2n1 Inhibits Prostate Cancer Progression Through Androgen Receptor-Dependent Signaling., Tao Wang, Shuiming Guo, Zhuo Liu, Licheng Wu, Mingchao Li, Jun Yang, Ruibao Chen, Xiaming Liu, Hua Xu, Shaoxin Cai, Hui Chen, Weiyong Li, Shaohua Xu, Liang Wang, Zhiquan Hu, Qianyuan Zhuang, Liping Wang, Kongming Wu, Jihong Liu, Zhangqun Ye, Jun-Yuan Ji, Chenguang Wang, Ke Chen

Department of Cancer Biology Faculty Papers

Castration resistance is a major obstacle to hormonal therapy for prostate cancer patients. Although androgen independence of prostate cancer growth is a known contributing factor to endocrine resistance, the mechanism of androgen receptor deregulation in endocrine resistance is still poorly understood. Herein, the CAMK2N1 was shown to contribute to the human prostate cancer cell growth and survival through AR-dependent signaling. Reduced expression of CAMK2N1 was correlated to recurrence-free survival of prostate cancer patients with high levels of AR expression in their tumor. CAMK2N1 and AR signaling form an auto-regulatory negative feedback loop: CAMK2N1 expression was down-regulated by AR activation; while …

The Induction Of The P53 Tumor Suppressor Protein Bridges The Apoptotic And Autophagic Signaling Pathways To Regulate Cell Death In Prostate Cancer Cells., Lymor Ringer, Paul Sirajuddin, Lucas Tricoli, Sarah Waye, Muhammad Umer Choudhry, Erika Parasido, Angiela Sivakumar, Mary Heckler, Aisha Naeem, Iman Abdelgawad, Xuefeng Liu, Adam S Feldman, Richard J Lee, Chin-Lee Wu, Venkata Yenugonda, Bhaskar Kallakury, Anatoly Dritschilo, John Lynch, Richard Schlegel, Olga Rodriguez, Richard Pestell, Maria Laura Avantaggiati, Chris Albanese

Kimmel Cancer Center Faculty Papers

The p53 tumor suppressor protein plays a crucial role in influencing cell fate decisions in response to cellular stress. As p53 elicits cell cycle arrest, senescence or apoptosis, the integrity of the p53 pathway is considered a key determinant of anti-tumor responses. p53 can also promote autophagy, however the role of p53-dependent autophagy in chemosensitivity is poorly understood. VMY-1-103 (VMY), a dansylated analog of purvalanol B, displays rapid and potent anti-tumor activities, however the pathways by which VMY works are not fully defined. Using established prostate cancer cell lines and novel conditionally reprogrammed cells (CRCs) derived from prostate cancer patients; …

The Tumor Suppressive Role Of Camk2n1 In Castration-Resistant Prostate Cancer., Tao Wang, Zhuo Liu, Shuiming Guo, Licheng Wu, Mingchao Li, Jun Yang, Ruibao Chen, Hua Xu, Shaoxin Cai, Hui Chen, Weiyong Li, Liang Wang, Zhiquan Hu, Qianyuan Zhuang, Shaohua Xu, Liping Wang, Jihong Liu, Zhangqun Ye, Jun-Yuan Ji, Chenguang Wang, Ke Chen

Jihong Liu

Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumorigenesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant decrease in human prostate cancers comparing to normal prostate tissues. Re-expression of CAMK2N1 in prostate cancer cells reduced cellular proliferation, arrested cells in G0/G1 phases, and induced apoptotic cell …

Association Of Leukocyte Mitochondrial Dna Content With Glioma Risk: Evidence From A Chinese Case-Control Study., Jie Zhang, Deyang Li, Falin Qu, Yibing Chen, Gang Li, Hequn Jiang, Xiaojun Huang, Hushan Yang, Jinliang Xing

Department of Cancer Biology Faculty Papers

BACKGROUND: Increasing evidence suggests that alterations in mitochondrial DNA (mtDNA) content may be implicated in the tumorigenesis of several malignancies. However, the association between mtDNA content in peripheral blood lymphocytes (PBLs) and glioma risk has not been investigated.

METHODS: Real-time PCR was used to examine the mtDNA content in PBLs of 414 glioma patients and 414 matched controls in a hospital-based case-control study. The association between mtDNA content and glioma risk was evaluated using an unconditional multivariate logistic regression model.

RESULTS: We found that glioma patients exhibited a significantly higher median mtDNA content than healthy controls (0.99 vs. 0.71, P …

Parp-2 And Parp-3 Are Selectively Activated By 5' Phosphorylated Dna Breaks Through An Allosteric Regulatory Mechanism Shared With Parp-1., Marie-France Langelier, Amanda A Riccio, John M Pascal

Department of Biochemistry and Molecular Biology Faculty Papers

PARP-1, PARP-2 and PARP-3 are DNA-dependent PARPs that localize to DNA damage, synthesize poly(ADP-ribose) (PAR) covalently attached to target proteins including themselves, and thereby recruit repair factors to DNA breaks to increase repair efficiency. PARP-1, PARP-2 and PARP-3 have in common two C-terminal domains-Trp-Gly-Arg (WGR) and catalytic (CAT). In contrast, the N-terminal region (NTR) of PARP-1 is over 500 residues and includes four regulatory domains, whereas PARP-2 and PARP-3 have smaller NTRs (70 and 40 residues, respectively) of unknown structural composition and function. Here, we show that PARP-2 and PARP-3 are preferentially activated by DNA breaks harboring a 5' phosphate …

The Tumor Suppressive Role Of Camk2n1 In Castration-Resistant Prostate Cancer., Tao Wang, Zhuo Liu, Shuiming Guo, Licheng Wu, Mingchao Li, Jun Yang, Ruibao Chen, Hua Xu, Shaoxin Cai, Hui Chen, Weiyong Li, Liang Wang, Zhiquan Hu, Qianyuan Zhuang, Shaohua Xu, Liping Wang, Jihong Liu, Zhangqun Ye, Jun-Yuan Ji, Chenguang Wang, Ke Chen

Department of Cancer Biology Faculty Papers

Prostate cancer at advanced stages including metastatic and castration-resistant cancer remains incurable due to the lack of effective therapies. The CAMK2N1 gene, cloned and characterized as an inhibitor of CaMKII (calcium/calmodulin-dependent protein kinase II), has been shown to affect tumorigenesis and tumor growth. However, it is still unknown whether CAMK2N1 plays a role in prostate cancer development. We first examined the protein and mRNA levels of CAMK2N1 and observed a significant decrease in human prostate cancers comparing to normal prostate tissues. Re-expression of CAMK2N1 in prostate cancer cells reduced cellular proliferation, arrested cells in G0/G1 phases, and induced apoptotic cell …

Micrornas: The Short Link Between Cancer And Rt-Induced Dna Damage Response., Christopher M Wright, Tu Dan, Adam Dicker Md, Phd, Nicole L Simone

Department of Radiation Oncology Faculty Papers

No abstract provided.

Results Of A Phase I Study Of Bendamustine In Combination With Ofatumumab, Carboplatin And Etoposide (Boce) For Refractory Of Relapsed Aggressive B-Cell Non Hodgkin's Lymphomas (Nhl), Sameh Gaballa, Md, Neil D. Palmisiano, Md, Aakanksha Asija, Md, Andrew Chapman, Do, Jennifer K. Cloud, Bs, Joanne Filicko-O'Hara, Md, Lewis Rose, Md, Michael Ramirez, Md, Onder Alpdogan, Md, Neal Flomenberg, Md, Barbara Pro, Md, Elena Gitelson, Md, Phd, Mark Weiss, Md

Department of Medical Oncology Faculty Papers

Introduction:

• There are a number of regimens used to treat relapsed/refractory aggressive lymphomas and little consensus exists on the best salvage treatment.
• No regimen has shown clear superiority but uniformly there was an inferior outcome among patients who had relapsed after a prior rituximab containing regimen.
• Ofatumumab is a fully human IgG1k monoclonal anti-CD20 antibody. It recognizes a distinct epitope on the human CD20 molecule. In vitro studies with ofatumumab have shown more complement dependent cytotoxicity than rituximab.
• Bendamustine has single agent activity in relapsed aggressive lymphomas and has a favorable safety profile.

Objectives:

• We conducted a phase I trial …

Mir-221/222 Promotes S-Phase Entry And Cellular Migration In Control Of Basal-Like Breast Cancer., Yuan Li, Chunli Liang, Haizhong Ma, Qian Zhao, Ying Lu, Zhendong Xiang, Li Li, Jie Qin, Yihan Chen, William C Cho, Richard G Pestell, Li Liang, Zuoren Yu

Department of Cancer Biology Faculty Papers

The miR-221/222 cluster has been demonstrated to function as oncomiR in human cancers. miR-221/222 promotes epithelial-to-mesenchymal transition (EMT) and confers tamoxifen resistance in breast cancer. However, the effects and mechanisms by which miR-221/222 regulates breast cancer aggressiveness remain unclear. Here we detected a much higher expression of miR-221/222 in highly invasive basal-like breast cancer (BLBC) cells than that in non-invasive luminal cells. A microRNA dataset from breast cancer patients indicated an elevated expression of miR-221/222 in BLBC subtype. S-phase entry of the cell cycle was associated with the induction of miR-221/222 expression. miRNA inhibitors specially targeting miR-221 or miR-222 both …

Azd8931, An Equipotent, Reversible Inhibitor Of Signaling By Epidermal Growth Factor Receptor (Egfr), Her2, And Her3: Preclinical Activity In Her2 Non-Amplified Inflammatory Breast Cancer Models., Zhaomei Mu, Teresa Klinowska, Xiaoshen Dong, Emily Foster, Chris Womack, Sandra V Fernandez, Massimo Cristofanilli

Department of Medical Oncology Faculty Papers

INTRODUCTION: Epidermal growth factor receptor (EGFR) overexpression has been associated with prognostic and predictive value in inflammatory breast cancer (IBC). Epidermal growth factor receptor 2 (HER2) overexpression is observed at a higher rate in IBC compared with noninflammatory breast cancer. Current clinically available anti-HER2 therapies are effective only in patients with HER2 amplified breast cancer, including IBC. AZD8931 is a novel small-molecule equipotent inhibitor of EGFR, HER2, and HER3 signaling. In this study, we investigated the antitumor activity of AZD8931 alone or in combination with paclitaxel using preclinical models of EGFR-overexpressed and HER2 non-amplified IBC cells.

METHODS: Two IBC cell …

Identification Of A Developmental Gene Expression Signature, Including Hox Genes, For The Normal Human Colonic Crypt Stem Cell Niche: Overexpression Of The Signature Parallels Stem Cell Overpopulation During Colon Tumorigenesis., Seema Bhatlekar, Sankar Addya, Moreh Salunek, Christopher R Orr, Saul Surrey, Steven E. Mckenzie, Jeremy Z Fields, Bruce M Boman

Kimmel Cancer Center Faculty Papers

Our goal was to identify a unique gene expression signature for human colonic stem cells (SCs). Accordingly, we determined the gene expression pattern for a known SC-enriched region--the crypt bottom. Colonic crypts and isolated crypt subsections (top, middle, and bottom) were purified from fresh, normal, human, surgical specimens. We then used an innovative strategy that used two-color microarrays (∼18,500 genes) to compare gene expression in the crypt bottom with expression in the other crypt subsections (middle or top). Array results were validated by PCR and immunostaining. About 25% of genes analyzed were expressed in crypts: 88 preferentially in the bottom, …

Cyclin D1 Determines Estrogen Signaling In The Mammary Gland In Vivo., Mathew C Casimiro, Chenguang Wang, Z Li, Gabriele Disante, Nicole E Willmart, Sankar Addya, Lei Chen, Yang Liu, Michael P. Lisanti, Richard Pestell

Department of Cancer Biology Faculty Papers

The CCND1 gene, which is frequently overexpressed in cancers, encodes the regulatory subunit of a holoenzyme that phosphorylates the retinoblastoma protein. Although it is known that cyclin D1 regulates estrogen receptor (ER)α transactivation using heterologous reporter systems, the in vivo biological significance of cyclin D1 to estrogen-dependent signaling, and the molecular mechanisms by which cyclin D1 is involved, are yet to be elucidated. Herein, genome-wide expression profiling conducted of 17β-estradiol-treated castrated virgin mice deleted of the Ccnd1 gene demonstrated that cyclin D1 determines estrogen-dependent gene expression for 88% of estrogen-responsive genes in vivo. In addition, expression profiling of 17β-estradiol-stimulated cyclin …

Cancer Metabolism: New Validated Targets For Drug Discovery., Federica Sotgia, Ubaldo E. Martinez-Outshoorn, Md, Michael P. Lisanti

Kimmel Cancer Center Faculty Papers

Recent studies in cancer metabolism directly implicate catabolic fibroblasts as a new rich source of i) energy and ii) biomass, for the growth and survival of anabolic cancer cells. Conversely, anabolic cancer cells upregulate oxidative mitochondrial metabolism, to take advantage of the abundant fibroblast fuel supply. This simple model of "metabolic-symbiosis" has now been independently validated in several different types of human cancers, including breast, ovarian, and prostate tumors. Biomarkers of metabolic-symbiosis are excellent predictors of tumor recurrence, metastasis, and drug resistance, as well as poor patient survival. New pre-clinical models of metabolic-symbiosis have been generated and they genetically validate …

Circulating Tumor Dna To Monitor Metastatic Breast Cancer., Massimo Cristofanilli, Paolo Fortina

Kimmel Cancer Center Faculty Papers

No abstract provided.

Early Results Of Prostate Cancer Radiation Therapy: An Analysis With Emphasis On Research Strategies To Improve Treatment Delivery And Outcomes., Kosj Yamoah, Kwamena Beecham, Sarah E Hegarty, Terry Hyslop, Timothy Showalter, Joel Yarney

Department of Radiation Oncology Faculty Papers

ABSTRACT: BACKGROUND: There is scant data regarding disease presentation and treatment response among black men living in Africa. In this study we evaluate disease presentation and early clinical outcomes among Ghanaian men with prostate cancer treated with external beam radiotherapy (EBRT). METHODS: A total of 379 men with prostate cancer were referred to the National Center for Radiotherapy, Ghana from 2003 to 2009. Data were collected regarding patient-and tumor-related factors such as age, prostate specific antigen (PSA), Gleason score (GS), clinical stage (T), and use of androgen deprivation therapy (ADT). For patients who received EBRT, freedom from biochemical failure (FFbF) …

Glutamine Supplementation Alleviates Vasculopathy And Corrects Metabolic Profile In An In Vivo Model Of Endothelial Cell Dysfunction., Francesco Addabbo, Qiuying Chen, Dhara P Patel, May Rabadi, Brian Ratliff, Frank Zhang, Jean-Francois Jasmin, Michael Wolin, Michael Lisanti, Steven S Gross, Michael S Goligorsky

Kimmel Cancer Center Faculty Papers

Endothelial Cell Dysfunction (ECD) is a recognized harbinger of a host of chronic cardiovascular diseases. Using a mouse model of ECD triggered by treatment with L-Nω-methylarginine (L-NMMA), we previously demonstrated that renal microvasculature displays a perturbed protein profile, including diminished expression of two key enzymes of the Krebs cycle associated with a Warburg-type suppression of mitochondrial metabolism. We hypothesized that supplementation with L-glutamine (GLN), that can enter the Krebs cycle downstream this enzymatic bottleneck, would normalize vascular function and alleviate mitochondrial dysfunction. To test this hypothesis, mice with chronic L-NMMA-induced ECD were co-treated with GLN at different concentrations for 2 …

Evaluating Changes In Radiation Treatment Volumes From Post-Operative To Same-Day Planning Mri In High-Grade Gliomas., Colin E Champ, Joshua Siglin, Mark V Mishra, Xinglei Shen, Maria Werner-Wasik, David W Andrews, Sonal U Mayekar, Haisong Liu, Wenyin Shi

Department of Radiation Oncology Faculty Papers

BACKGROUND: Adjuvant radiation therapy (RT) with temozolomide (TMZ) is standard of care for high grade gliomas (HGG) patients. RT is commonly started 3 to 5 weeks after surgery. The deformation of the tumor bed and brain from surgery to RT is poorly studied. This study examined the magnitude of volume change in the postoperative tumor bed and the potential impact of RT planning.

METHOD AND MATERIALS: This study includes 24 patients with HGG who underwent craniotomy and adjuvant RT with TMZ at our institution. All patients had immediate postoperative MRI and repeat MRI during the day of RT simulation. Gross …