Table of Contents

Volume 9, Issue 8

  April 15, 2010

  Pages 563 - 653

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REVIEWS

Open Access Article

Monoclonal antibodies for targeted therapy in colorectal cancer.

Sreeparna Banerjee and Hernan Flores-Rozas
Pages 563 - 571
http://dx.doi.org/10.4161/cbt.9.8.11403
PDF

Open Access Article

Acquired resistance of lung adenocarcinoma to EGFR-tyrosine kinase inhibitors gefitinib and erlotinib

Yan Xu, Hongyu Liu, Jun Chen and Qinghua Zhou
Pages 572 - 582
http://dx.doi.org/10.4161/cbt.9.8.11881
Abstract | PDF

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, are the first targeted therapy drugs approved for the treatment of advanced non-small-cell lung cancer (NSCLC).  Interestingly, treatment with these small molecule, reversible EGFR-TKIs leads to more positive response rates in patients with adenocarcinoma, in females, in Asians, and in patients with no history of smoking.  Positive responses to treatment in these populations may be due to the increased prevalence of mutations in the EGFR gene.  Several distinct mutations in the EGFR gene have been identified in specimens from patients with NSCLC who responded to treatment with anilinoquinazoline EGFR inhibitors.  However, despite the dramatic initial response to TKIs, most lung cancer patients relapse and subsequently become resistant to the drug, a process termed acquired resistance.  The precise mechanisms underlying acquired resistance remain unclear. Resistance to EGFR-TKIs could result from several potential mechanisms, including development of a secondary mutation in EGFR (such as T790M), amplification of the MET receptor tyrosine kinase gene, or overexpression of other receptor tyrosine kinases.




JOURNAL CLUB

Open Access Article

A novel regulator (USP10) of p53: Implications for tumor suppression and therapeutic targeting

Kelie M. Reece and William D. Figg
Pages 583 - 584
http://dx.doi.org/10.4161/cbt.9.8.11690
Abstract | PDF

p53 is a tumor suppressor protein that plays a central role in oncogenesis by regulating cell fate after cellular stress and repressing the proliferation of damaged cells.¹ The importance of p53 in preventing tumor development is highlighted by the fact that the p53 pathway is mutated in most types of human cancers, thus making it a desirable target for cancer therapeutics.^2,3 p53 promotes tumor suppression through its ability to function as a sequence-specific transcription factor that induces the expression of genes involved in a variety of cellular functions including cell growth arrest, apoptosis, DNA repair, and cell senescence.^4,2,1




CLINICAL STUDY

Open Access Article

Elevation in serum lactate at the time of Febrile Neutropenia (FN) in hemodynamically-stable patients with Hematologic Malignancies (HM) is associated with the development of septic shock within 48 hours

Anthony R. Mato, Selina M. Luger, Daniel F. Heitjan, Mark E. Mikkelson, Erin Olson, Chaitra Ujjani, Samantha Jacobs, Andrea N. Miltiades, Payal Shah, Stephen J. Schuster, Martin Carroll, Ann Duskin Chauffe and Barry D. Fuchs
Pages 585 - 589
http://dx.doi.org/10.4161/cbt.9.8.11270
Abstract | PDF

Background: Hospitalized patients who develop febrile neutropenia (FN) are treated empirically with antibiotics due to a high risk of developing septic shock. Currently, there is no method to predict which patients are at greatest risk. This study was designed to determine whether serum lactate, measured at the time of FN, is associated with the development of septic shock in hospitalized hematologic malignancy (HM) patients. Methods: Vital signs and lactate were measured during episodes of FN. The primary endpoint was the development of septic shock.  Using a prospective, nested, case-control design, controls were matched on length of stay at the time of septic shock to achieve 80% power to detect an OR of ≥ 2.5. Using logistic regression, we evaluated the association of vital signs and lactate with the subsequent development of septic shock. Results: Of the 547 patients enrolled, 46 (8.4%; 95% CI 6.2-10.9) developed septic shock. Baseline characteristics were similar between the groups. In univariate analysis, tachypnea (OR 5.9; 95% CI: 2.0-16.9, p =.001) and lactate (OR 18.4; 95% CI: 4.1-81.6, p <.001) were significantly associated with the development of septic shock. In multivariate analysis, lactate and tachypnea remained independently associated with the development of septic shock.  By ROC analysis, lactate provided incremental prognostic value compared to vital signs alone. Conclusions: In FN patients, measurement of lactate during FN adds significant prognostic information about the risk of developing septic shock. Routine measurement of lactate may help identify patients who may benefit from increased monitoring and early intervention strategies.




COMMENTARY

Open Access Article

Serum lactate in febrile neutropenia: What can it tell us?

Rebecca Elstrom
Pages 590 - 591
http://dx.doi.org/10.4161/cbt.9.8.11532
Abstract | PDF

Commentary to:

Elevation in serum lactate at the time of Febrile Neutropenia (FN) in hemodynamically-stable patients with Hematologic Malignancies (HM) is associated with the development of septic shock within 48 hours

Anthony R. Mato, Selina M. Luger, Daniel F. Heitjan, Mark E. Mikkelson, Erin Olson, Chaitra Ujjani, Samantha Jacobs, Andrea N. Miltiades, Payal Shah, Stephen J. Schuster, Martin Carroll, Ann Duskin Chauffe and Barry D. Fuchs




RESEARCH PAPER

Open Access Article

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells

Siddik Sarkar, Abhijit Mazumdar, Rupesh Dash, Devanand Sarkar, Paul B. Fisher and Mahitosh Mandal
Pages 592 - 603
http://dx.doi.org/10.4161/cbt.9.8.11103
Abstract | PDF

Abnormalities in gene expression and signaling pathways downstream of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) contribute to the progression, invasion, and maintenance of the malignant phenotype in human cancers, including breast. Consequently, the dual kinase inhibitor of EGFR and VEGFR ZD6474 represents a promising biologically-based treatment that is currently undergoing clinical trials for non-small cell lung cancer. Patients suffering from breast cancers have a poor prognosis because of the lack of effective agents and treatment strategies. We hypothesized that inhibition of phosphorylation of the EGFR and VEGFR by ZD6474 would inhibit breast cancer cell proliferation and induce apoptosis. This hypothesis was tested using human breast cancer cell lines. ZD6474 inhibited cell proliferation in a dose-dependent manner, by blocking cell progression at the G0-G1 stage, through down-regulation of expression of cyclin D1 and cyclin E. In vitro, ZD6474 inhibited growth factor-induced phosphorylation of EGFR, VEGFR-2, MAPK, and Akt. ZD6474 also down regulated anti-apoptotic markers including Bcl-2, up-regulated pro-apoptotic signaling events involving expression of bax, activation of caspase-3, and induction of poly (ADP-ribose) polymerase during apoptosis. ZD6474 inhibited anchorage independent colony formation using soft agar assays, and invasion of breast cancer cells in vitro using Boyden chamber assays.  In a xenograft model using human MDA-MB-231 breast cancer cells, ZD6474 inhibited tumor growth and induced cancer-specific apoptosis. Collectively, these data imply that ZD6474 a dual kinase inhibitor has potential for the targeted therapy of breast cancer.




COMMENTARY

Open Access Article

ZD6474 coerces breast cancer for an apoptotic journey

Binoj C. Nair and Ratna K. Vadlamudi
Pages 604 - 606
http://dx.doi.org/10.4161/cbt.9.8.11318
Abstract | PDF

Commentary to:

ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK/ERK and AKT/PI3-K and induces apoptosis in breast cancer cells

Siddik Sarkar, Abhijit Mazumdar, Rupesh Dash, Paul B. Fisher and Mahitosh Mandal




RESEARCH PAPER

Open Access Article

Bone-specific growth inhibition of prostate cancer metastasis by Atrasentan

Justin M. Drake, Joshua R. Danke and Michael Henry
Pages 607 - 614
http://dx.doi.org/10.4161/cbt.9.8.11112
Abstract | PDF

Advanced prostate cancer frequently metastasizes to bone and remains an uncurable disease.  One recent experimental therapy involves endothelin receptor A (ETA) antagonists (e.g. atrasentan).  Clinical results to date have been mixed, with atrasentan not meeting its primary endpoints in a Phase III trial.  It remains an open question whether some patients might benefit from this therapy, while others may not.  Preclinical data supports the concept that the endothelin signaling axis may be particularly important for tumor growth in bone, but the extent to which it is involved in metastatic colonization of other organ sites in prostate cancer remains unclear.   Here we evaluate the efficacy of atrasentan in a mouse model of prostate cancer metastatic colonization.  Using bioluminescence imaging, we show that atrasentan does inhibit tumor growth in, but not the initial colonization of, bony sites in intracardially-injected 22Rv1 prostate cancer cells.  However, atrasentan shows little efficacy in soft tissues such as adrenal gland or liver.  Our studies show that whether atrasentan exhibits significant overall anti-tumor efficacy and survival benefit depends on the presence of bone metastasis evident in that animal.  Though in contrast to previous findings, efficacy is apparent in a prostate tumor model that elicits mixed osteoblastic/osteolytic lesions.  These data confirm the notion that atrasentan may exhibit selective activity against prostate cancer bone metastasis, mirroring clinical findings, and suggest that the role of endothelin signaling in bone metastasis may be more complex than previously appreciated.  The model described here may provide a valuable tool for unraveling this complexity.




COMMENTARY

Open Access Article

Targeting the endothelin receptor in prostate cancer bone metastasis: Back to the mouse?

Meejeon Roh and Sarki A. Abdulkadir
Pages 615 - 617
http://dx.doi.org/10.4161/cbt.9.8.11309
Abstract | PDF

Commentary to:

Bone-specific growth inhibition of prostate cancer metastasis by Atrasentan

Justin M. Drake, Joshua R. Danke and Michael Henry




RESEARCH PAPERS

Open Access Article

Conatumumab, a fully human agonist antibody to death receptor 5, induces apoptosis via caspase activation in multiple tumor types

Paula J. Kaplan-Lefko, Jonathan D. Graves, Stephen J. Zoog, Yang Pan, Jason Wall, Daniel G. Branstetter, Jodi Moriguchi, Angela Coxon, Justin N. Huard, Ren Xu, Matthew L. Peach, Gloria Juan, Stephen Kaufman, Qing Chen, Allison Bianchi, Jennifer J. Kordich, Mark Ma, Ian N. Foltz and Brian C. Gliniak
Pages 618 - 631
http://dx.doi.org/10.4161/cbt.9.8.11264
Abstract | PDF

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binds to death receptors 4 and 5 (DR4, DR5) to transduce apoptotic signals.  Conatumumab (AMG 655) is an investigational, fully human monoclonal agonist antibody (IgG₁) to human DR5, which induces apoptosis via caspase activation.  In this study, we demonstrate that conatumumab binds to DR5, activating intracellular caspases in vitro in the presence of a cross-linker.  We also show that conatumumab has activity in vivo and inhibits tumor growth in colon (Colo205 and HCT-15), lung (H2122), and pancreatic (MiaPaCa2/T2) xenograft models.  Conatumumab also enhances the anti-tumor activity of chemotherapeutics in vivo. Caspase activation in Colo205 tumors is dose-dependent and correlated with serum concentrations of conatumumab.  We demonstrate for the first time that increases in serum caspase-3/7 activity and levels of M30 (neoepitope of caspase-cleaved cytokeratin-18) are linked to activation of the extrinsic apoptotic pathway using conatumumab in a preclinical model.  These data suggest that conatumumab has potential as a therapeutic agent for treating patients with multiple tumor types, and that serum caspase-3/7 and M30 levels may serve as biomarkers of conatumumab activity.

Open Access Article

Antitumor effects of EMAP II against pancreatic cancer through inhibition of fibronectin-dependent proliferation

Roderich E. Schwarz, Niranjan Awasthi, Srivani Konduri, Lauren Caldwell, Danielle Cafasso and Margaret A. Schwarz
Pages 632 - 639
http://dx.doi.org/10.4161/cbt.9.8.11265
Abstract | PDF

Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to conventional chemotherapy. The presence of both cellular and stromal fibronectin (FN) and its interaction with integrins is necessary for PDAC progression. We tested the efficacy of endothelial monocyte-activating polypeptide II (EMAP II) to inhibit PDAC progression and its ability to interfere with FN-integrin angiogenesis signaling. In heterotopic PDAC tumors EMAP II caused a significant reduction (>65%) in tumor growth, accompanied by a >50% and 44% decrease in microvessel density and proliferative activity, respectively. EMAP II therapy caused a 62% and 56% reduction in host and tumor cell FN expression. Cultured PDAC cells expressed aVb3 and a5b1 integrins. In vitro EMAP II had limited antiproliferative effects on ASPC-1, but a pronounced antiproliferative effect on endothellial cells. 3D FN matrices increased ASPC-1 cell proliferation by > 50%, and this induction was significantly blocked by a3, a5, a6 and aV integrin funtional blocking antibodies, while a1, a2 and a4 antibodies had no effect. EMAP II also inhibited 3D FN-matrix induced ASPC-1 proliferation by >43% at 20 mM. These findings suggest that EMAP II demonstrates significant antitumor activity against PDAC cells, and that this effect may be in part mediated through targeted interference with stromal FN-integrin dependent PDAC cell proliferation.

Open Access Article

GDP366, a novel small molecule dual inhibitor of survivin and Op18, induces cell growth inhibition, cellular senescence and mitotic catastrophe in human cancer cells

Xianping Shi, Deping Wang, Ke Ding, Zhongzheng Lu, Yanli Jin, Jin Zhang and Jingxuan Pan
Pages 640 - 650
http://dx.doi.org/10.4161/cbt.9.8.11269
Abstract | PDF

Accumulating evidence indicates that survivin plays a pivotal role in not only cell survival but also cell cycle progression. Op18/stathmin is an oncoprotein that regulates microtubule stabilization. Both survivin and Op18 have been proposed as therapeutic targets for cancer. However, few small molecule inhibitors of survivin and Op18 have been reported. In this study, we have identified a novel small molecule compound (GDP366) which potently and selectively inhibited the expression of both survivin and Op18. It decreased both the mRNA and protein levels of survivin and Op18. This inhibitory effect was not dependent on the status of p53 and p21 although GDP366 potently increased p53 and p21 levels. GDP366 significantly inhibited the growth of tumor cells in vitro and in vivo (nude mouse model) without rapid induction of apoptosis. GDP366 induced polyploidy in multiple types of cancer cell lines. GDP366 increased chromosomal instability, and induced cellular senescence by inhibiting telomerase activity. We conclude that GDP366 is a novel dual inhibitor of survivin and Op18. Our results warrant further translational evaluation of this compound.




ERRATUM

Open Access Article

Phosphatase inhibition and cell survival after DNA damage induced by radiation

Julie Hamilton, Anna M. Grawend and Erin J. Bernhard
Pages 651 - 653
http://dx.doi.org/10.4161/cbt.9.8.10377
Abstract | PDF

It has come to our attention that there are errors in the figure legends to our manuscript. In Figure 5, Panel I was not labeled thus the description of this panel in the legend to Figure 5 should read, “Western blot analysis of AKT (H) shows no effect on the phosphorylation of S473 or total protein levels with either T24 cells (Left) or SQ20B cell (Right).”

In the legend to Figure 6, PHLPP and PHLPPL were inadvertently reversed. Also the description of panel D was omitted. The figure legend should read. “Figure 6. Analysis of PHLPP and PHLPPL expression following siRNA treatment. (A) Western blot analysis was used to determine the knockdown of PHLPP and PHLPPL as well as the phosphorylation status of AKT. 20 μg of total protein was loaded for each western blot and β-actin used as a loading control. Lanes 1 are non-targeting siRNA treated lysates and lanes 2 are specific siRNA treated lysates.  SQ20B, T24, DLD-1 and HT1080 cells were transfected with 40 nM non-targeting siRNA or siRNA against (B) PHLPPL and (C) PHLPP or with a combination of both PHLPPL and PHLPP siRNA (D) for 48 hr. Cells were replated and allowed to adhere before irradiated at 0, 2, 4 and 6 Gy and the medium changed the nextday. Clonogens were allowed to form for 10–14 days before staining with crystal violet. Solid lines indicate non-targeting siRNA and dashed lines indicate targeted siRNA.”

We sincerely regret these errors and any confusion they may cause.  The corrections do not in any way alter the conclusions of the manuscript.





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Open Access Article

Cover caption




http://dx.doi.org/10.4161/cbt.9.8.12069
Abstract

Detection of pancreatic cancer remains a huge obstacle to successful treatment. Currently, resection of the tumor provides the best opportunity for patient survival. Unfortunately, most patients present with advanced disease that is inoperable. Current chemotherapy options rarely keep a patient alive for more than a year. In the current issue of Cancer Biology & Therapy, Schwarz and colleagues target fibronectin, an extracellular matrix protein that can regulate tumor angiogenesis and seems to play a role in the progression of pancreatic adenocarcinoma. They study the effects of EMAP II (endothelial monocyte-activating polypeptide II) on fibronectin expression and tumor progression. On the cover of the current issue of Cancer Biology & Therapy, Schwarz and colleagues stained control-treated pancreatic xenografts for fibronectin expression. The green stain shows mouse fibronectin expression while red indicates human fibronectin expression. Blue shows nuclear staining (DAPI). To see how EMAP II decreased expression of both mouse and human fibronectin, see figure 3 from Schwarz and colleagues.