bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 625: Preclinical characterization of an auristatin-based anti-CD19 drug conjugate, SGN-19A
Authors: Law Che-Leung , Sutherland May , Miyamoto Jamie , Hayes Dawn , Duniho Steve , Boursalian Tamar , Stone Ivan , Jonas Mechthild , Smith Leia , Benjamin Dennis 
Published: June 2012

Abstract
CD19 has multiple attributes that make it an attractive target for an antibody-drug conjugate (ADC). CD19 is uniformly expressed on the cell surface of almost all malignancies of B cell origin, including non-Hodgkin lymphoma (NHL), B cell precursor acute lymphoblastic leukemia (B-ALL), and chronic lymphocytic leukemia (CLL). In addition, CD19 has very limited normal tissue expression, restricted only to B lymphocytes and their precursors, and it internalizes rapidly, which are favorable characteristic for targeted drug delivery. SGN-19A is an ADC comprised of a humanized anti-CD19 mAb and the potent cytotoxic drug-linker maleimidocaproyl monomethyl auristatin F (mcMMAF). Here we demonstrate internalization and trafficking, in vivo antitumor activity, and in vivo on-target pharmacodynamic effect of B cell depletion following SGN-19A treatment. Internalization and trafficking of SGN-19A through the endosomal-lysosomal pathway resulted in potent in vitro cytotoxic activity against CD19+ cell lines derived from B-ALL, follicular lymphoma, diffused large B cell lymphoma, Burkitt's lymphoma, and plasma cell leukemia. In mouse xenografts modeling different B-lineage malignancies, SGN-19A demonstrated antitumor activity including tumor regression and prolonged survival at doses well below its maximum tolerated dose. We also show that the in vivo antitumor activity is directly related to the duration of the pharmacokinetic half-life among a panel of ADCs targeting CD19. Since SGN-19A cross-reacts with its ortholog expressed in non-human primates, we examined its pharmacodynamic effect on B cell depletion in cynomolgus monkeys. Depletion of peripheral B cells was observed following SGN-19A and correlated with results from terminal immunohistochemical (IHC) analysis demonstrating the depletion of Ki67+ germinal center B cells. Furthermore, using an antibody against mcMMAF we confirmed delivery of the cytotoxic agent to the B cell areas in peripheral lymphoid tissues. Taken together, these results support the further evaluation of SGN-19A as a therapy for B-lineage derived malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 625. doi:10.1158/1538-7445.AM2011-625
Abstract 642: Novel EGFR inhibitory antibodies directed against EGFR mutants with potentially reduced toxicity
Authors: Wang Fang , McIntosh Donna , Bottega Steve , Zhou Yinghui , Fleet Christina , Jiang Jinwei , Chen Tin , Weiler Solly , Winston William , Heyer Joerg , Clark Steven , Gyuris Jeno , Vincent Sylvie 
Published: June 2012

Abstract
Non-small cell lung cancers (NSCLC) driven by ligand-independent activating mutations in epidermal growth factor receptor (EGFR) often respond to treatment with EGFR tyrosine kinase inhibitors (TKIs). About half of acquired resistance to EGFR-TKI therapy results from a secondary point mutation in the EGFR tyrosine kinase domain at amino acid position 790 (T790M). T790M mutants also display reduced sensitivity to Cetuximab treatment. We have investigated the molecular mechanism responsible for the reduced Cetuximab sensitivity and found that T790M mutant receptors primarily exist and signal as monomers. We have exploited this characteristic of the T790M mutant to isolate novel EGFR inhibitory antibodies with activities against all EGFR variants.
In addition, as opposed to other EGFR inhibitory antibodies, these novel antibodies have reduced ligand binding inhibitory activity and minimal inhibitory effect on EGF induced human primary keratinocyte proliferation, suggesting a potentially reduced skin toxicity profile. The broad activity profile, combined with potentially reduced skin toxicity, suggests that these antibodies will have great potential for combinability with other therapeutic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 642. doi:10.1158/1538-7445.AM2011-642
Abstract 647: TTAC-0001, anti-VEGFR2/KDR monoclonal antibody, inhibits VEGFR signaling and tumor growth in preclinical models
Authors: Jin Younggeon , Jin Juyoun , Yang Heekyoung , Park Minjae , Lee Weon Sup , Kim Sung-Woo , Shim Sang Ryeol , Kim Yeonjoo , Lee Sang Hoon , Yoo Jin-San , Seol Ho Jun , Nam Do-Hyun 
Published: June 2012

Abstract
Tumor angiogenesis is the process that leads to the formation of blood vessels in a tumor and a prognostic indicator in various cancers. Vascular endothelial growth factor (VEGF) and its receptors are considered to be primary regulators of tumor-induced angiogenesis and activation of VEGFR2/KDR is the major signaling pathway for tumor growth. In addition, VEGFR2/KDR is also expressed in many cancer cells, and regulates cell growth and survival through autocrine pathway. In this study, we evaluated the therapeutic potential of TTAC-0001, fully human antibody against VEGFR2/KDR, for the inhibition of tumor growth. In the tube formation assay using HUVEC, TTAC-0001 exhibited a potent anti-angiogenic activity in vitro. In U-87 MG glioblastoma cells, TTAC-0001 significantly inhibited the phosphorylation of VEGFR2/KDR mediated by VEGF. To reveal in vivo efficacy, we have tested TTAC-0001 in glioblastoma and colorectal xenograft models. We demonstrated that antitumor activity of TTAC-0001 in preclinical models correlated with induction of growth arrest and apoptosis as well as the inhibition of angiogenesis. Currently, we are evaluating the combination of TTAC-0001 with chemotherapeutic agents in xenograft models. A single dose study performed in mouse allowed us to establish the relationship between the pharmacokinetics (PK) and efficacy of TTAC-0001. Taken together, our data suggest that targeting VEGFR2 pathway by TTAC-0001 would be a promising candidate for the treatment of cancer. (This study was supported by grants of the Korea Healthcare technology R&D Project, Ministry for Health & Welfare Affairs (A092255 and A040016) and Advanced Medi-cluster R&D Project, DaejeonTechnoPark, Republic of Korea. Seol HJ and Nam DH are co-corresponding authors for this manuscript.)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 647. doi:10.1158/1538-7445.AM2011-647
Abstract 659: Inhibiting autophagy improves the efficacy of VN/12-1 over all-trans retinoic acid in a HER2 over-expressing SK-BR3 breast cancer xenograft model
Authors: Godbole Abhijit M. , Purushottamachar Puranik , Gediya Lalji , Njar Vincent C.O. 
Published: June 2012

Abstract
Purpose: Autophagy is a critical physiological process of cell survival in the presence of stress and is an important cause of resistance to anti-cancer therapy. Drugs that inhibit autophagy (e.g. chloroquine) deprive the cells of this protective mechanism and therefore are promising agents in a combination therapy of breast cancer. Our group has designed and synthesized a novel retinoic acid derivative, VN/12-1. We reported previously that VN/12-1 is a potent inducer of autophagy in estrogen independent, HER2 over-expressing breast cancer cell line SK-BR3 in vitro. In the present study, we used chloroquine in combination with VN/12-1 in an SK-BR3 xenograft model to test the hypothesis that the combination of VN/12-1 and chloroquine would result in greater efficacy against SK-BR3 tumors compared to VN/12-1 alone or all-trans retinoic acid (ATRA) alone.
Experimental Design: To test this hypothesis, 64 female SCID mice (8 mice per group) were inoculated with SK-BR3 cells. Once the tumors formed, the mice were treated with vehicle (control), VN/12-1 and ATRA alone or in combination with chloroquine for 30 days. The two dosages of VN/12-1 for the groups involving VN/12-1 were 2.5 mg/kg and 5 mg/kg. The doses of ATRA and chloroquine were 5 mg/kg and 50 mg/kg, respectively. All the agents were administered subcutaneously (s.c) twice a week.
Results: Out of all the treatment groups, both the dosages of VN/12-1 (2.5 mg/kg and 5mg/kg) when used in combination with chloroquine were the most effective in inhibiting the growth of SK-BR3 tumors (70% and 80% growth inhibition respectively compared to vehicle control). The combination of ATRA with chloroquine did not show statistically significant inhibition of tumor growth. The effect of each treatment on the body weight and the weights of uteri was also determined. No toxicities were observed as noted by no significant changes in the weight of the mice. The data about the tumor samples’ analysis for the effect of each treatment on the expression of various tumor markers and autophagy markers and pharmacokinetic studies on VN/12-1 will be presented.
Conclusion: Our studies have demonstrated for the first time that the combination of VN/12-1 and chloroquine can be used to treat estrogen independent breast cancer. It is hoped that this combination therapy would solve the problem of the development of acquired resistance due to autophagy that typically follows therapeutic treatment of breast cancer. We envision further advanced preclinical development of this combination therapy as potential therapy for breast cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 659. doi:10.1158/1538-7445.AM2011-659
Abstract 670: Bis-nitrophenylphosphate (BNPP) but not phenylmethylsulfonyl fluoride (PMSF) inhibits the activation of the novel anti-cancer pro-drug CZ48
Authors: Markides Constantine S.A , Olszewski Alexa P. , DeJesus Albert , Vardeman Kyle B. , Moore Lauren E. , Vardeman Dana M. , Giovanella Beppino C. 
Published: June 2012

Abstract
CZ48, the 20-O-propionate ester of Camptothecin (CPT), is a non-toxic prodrug of CPT first described by Cao et al. (1998). The propionate side-chain is enzymatically cleaved in target tissues. This gives rise to CPT, an inhibitor of Topoisomerase I, which then blocks cell division causing selective tumor toxicity.
We have previously established the preferential activation of CZ48 in tumor tissues compared to normal tissues and an ultra sensitive assay to detect it (2009). The present studies explore the specifics of that activation in vitro using both cells in culture and surgically removed xenografted tumors from nude mice.
DOY lung adenocarcinoma was grown subcutaneously in nude mice and then surgically excised, homogenized and serially centrifuged to produce specific subcellular fractions. The bulk of esterase activity was found to be concentrated in the cytosol, while the microsomal fraction showed minimal activity. All other fractions tested were below the limit of detection.
HT-29 colon carcinoma cells were grown in culture in the presence and absence of varying concentrations of bis-nitrophenylphosphate (BNPP), a potent inhibitor of carboxylesterase and butyrylcholinesterase (BChE), in an attempt to find the highest possible non-toxic concentration to the cells. This concentration was then included during a 7-day IC50 determination for CZ48. In the presence of BNPP, the IC50 of CZ48 increased 4-fold from 181.4 nM to 710.8 nM. In vitro conversion of CZ48 to CPT by cytosolic fraction of a HT-29 tumor xenograft grown subcutaneously in nude mice was decreased by BNPP in a dose dependent manner. In contrast, the serine protease and carboxylesterase inhibitor phenylmethylsulfonyl fluoride (PMSF) and other esterase inhibitors did not affect the activation of CZ48.
Purified butyrylcholinesterase and acetylcholinesterase (SigmaAldrich, St. Louis MO) did not show any capacity to activate CZ48.
In conclusion, the enzymatic activation of CZ48 is not mediated by butyrylcholinesterase but by another cytosolic enzyme inhibitable by BNPP.
These data constitute a significant step forward in unraveling the exact mechanism for the activation of CZ48. This will help design a pre-treatment assay to establish tumor sensitivity, as well as give us direction for designing new, more potent prodrugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 670. doi:10.1158/1538-7445.AM2011-670
Abstract 679: NDC-1308 nanoparticles inhibit tumor growth by novel mechanisms controlling cancer cell proliferation
Authors: Nye Steven H. , Weitman Steven , Yarger James 
Published: June 2012

Abstract
It has previously been demonstrated that treatment of tumor cells with an estrogen receptor beta (ER-β) agonist can lead to cessation of cell division and cell death. We recently reported the discovery of NDC-1308, a member of our estradiol-related family of ER-β agonists, which is cytotoxic to a broad range of human tumor cell lines (EC50 is 5-20 uM). Although NDC-1308 has similar binding affinity for ER-α and ER-β (70-100 nM), functional studies show that it activates ER-β about 5-fold more compared to ER-α. To understand the mechanism of cytotoxicity, A549 (lung), SKOV-3 (ovary), and Panc-1 (pancreatic) human tumor cell lines were treated with NDC-1308 and gene expression changes evaluated by microarray. In all cell lines, NDC-1308 caused a significant down-regulation of key genes critical for chromosome replication, along with the up-regulation of at least two nucleases, granzyme K (GzmK) and apoptosis enhancing nuclease (AEN). There was also a significant up-regulation of pro-apoptotic pathway genes including BBC3 and GDF15 and an up-regulation of a death receptor pathway gene TNFRSF10B (DR5). These results suggest that ER-β activation by NDC-1308 may be useful to trigger DNA damage, cell cycle arrest and ultimately the death of cancer cells. However, PK studies in rodents showed that NDC-1308 has a short half-life, thereby lowering its potential efficacy as a cancer therapeutic. In order to optimize the blood circulation time and to enhance the accumulation of NDC-1308 in tumors, the drug was formulated into several different types of nanoparticles (50-100 nm), including an amorphous drug particle, a lipid-containing particle and a micelle-based particle. Whole body imaging studies showed that NDC-1308 nanoparticles conjugated with AlexaFluor 750 could localize to human tumors such as colon adenocarcinomas, renal cell carcinomas and lung adenocarcinomas in nude mice (N=4 per tumor type). To determine the efficacy of NDC-1308 as an anti-cancer therapy, nude mice bearing A549 human tumors (N=12 per group) were dosed every other day with NDC-1308 nanoparticles (up to 24 mg/kg of the active drug) via tail vein injection. During treatment, this led to a significant, dose-dependent reduction in tumor size in drug treated animals versus untreated controls. We conclude that intravenous administration of NDC-1308 nanoparticles can inhibit the rate of human tumor growth in a mouse model of cancer. Our future development plans include large animal safety and toxicity studies, followed by IND submission and Phase 1 clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 679. doi:10.1158/1538-7445.AM2011-679
Abstract 714: A potential epigenetic regulation of PDGFRβ overexpression in melanomas acquiring resistance to PLX4032
Authors: Nazarian Ramin , Ferrari Roberto , Kong Xiangju , Kurdistani Siavash K. , Lo Roger S. 
Published: June 2012

Abstract
Activating B-RAF V600E kinase mutations occur in ∼7% of human malignancies and ∼60% of melanomas. Clinical experience with a novel B-RAF inhibitor, PLX4032, demonstrated an unprecedented 80% anti-tumor response rate among patients with V600EB-RAF-positive melanomas, but acquired drug resistance frequently develops after initial responses. In previous work, we showed that PLX4032 acquired resistance does not occur by V600EB-RAF secondary mutations. Instead, resistant melanomas develop mutually exclusive upregulation of PDGFRβ (activating MAPK-alternative survival) or N-RAS (reactivating MAPK). PDGFRβ over-expression at the RNA and protein levels does not result from genomic DNA copy number gain or correlate with mutational activation, suggesting a non-genetic cause. In contrast to N-RAS-upregulated, PLX4032-resistant cells, PDGFRβ-upregulated, PLX4032-resistant melanoma (PPRM) cell lines display a global switch in cellular morphology and gene expression patterns when compared to their drug-sensitive, parental counterparts. Specifically, this switch involves a loss of melanocytic differentiation and a gain of epithelial-to-mesenchymal gene expression. We show that PLX4032 and the HDAC inhibitor LBH589 (panobinostat) rapidly and reversibly control the levels of PDGFRβ RNA and protein. We thus used PPRM cell lines and short-term cell culture to dissect a potential epigenetic mechanism of PDGFRβ over-expression. In ChIP assays, PPRM cell lines and culture, when treated with LBH589, displayed significant deacetylation of histone H3K9, H3K18 and H4K16 in conserved acetylation peaks in the PDGFRβ gene body. Continued progress in characterizing this potential epigenetic pathway of PLX4032 acquired resistance may reveal novel therapeutic opportunities.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 714. doi:10.1158/1538-7445.AM2011-714
Abstract 715: TGF-beta blockade improves the distribution and efficacy of chemotherapeutic agents in breast carcinoma
Authors: Liu Jieqiong , Liao Shan , Diop Benjamin , Chen Wei , Goel Shom , Huang Yuhui , Boucher Yves , Jain Rakesh K. , Xu Lei 
Published: June 2012

Abstract
Although the role of TGF-β has been studied extensively, its impact upon drug delivery within tumors remains poorly understood. In this study, we blocked the TGF-β pathway in mouse models of breast cancer and studied the effect on delivery and efficacy of chemotherapeutics. We used both genetic (overexpression of sTβRII, a soluble TGF-β type II receptor) and pharmaceutical (1D11, a TGF-β antibody) approaches to block the TGF-β signaling in two orthotopic breast cancer models (human MDA-MB-231 cells and murine 4T1 cells). TGF-β blockade significantly decreased the growth and metastasis of orthotopic human breast carcinoma xenografts. In addition, TGF-β blockade increased the recruitment and incorporation of myofibroblasts into tumor blood vessels and restored vascular perfusion. Moreover, TGF-β blockade normalized the tumor extracellular matrix (ECM) by decreasing collagen I content. As a result of this vessel and ECM normalization, TGF-β blockade improved the transvascular and interstitial transport of both small and large molecular weight chemotherapeutic agents, and consequently enhanced their efficacy. In conclusion, our study shows that TGF-β blockade might represent a new approach to improve delivery of both low molecular weight conventional drugs as well as nanomedicines in order to maximize therapeutic outcomes.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 715. doi:10.1158/1538-7445.AM2011-715
Abstract 722: Acquired resistance to vorinostat in acute myeloid leukemia
Authors: Dupéré-Richer Daphné , Retrouvey Hélène , Pettersson Filippa Pettersson , Miller Wilson Miller 
Published: June 2012

Abstract
Histone deacetylase inhibitors (HDACi) have recently emerged as promising anticancer agents. Some HDACi have advanced into Phase II and III clinical trials, both as a single agent and in combination with cytotoxics for a variety of malignancies. Encouraging results have been obtained in acute myeloid leukemia (AML). However, HDACi target many pathways and the full mechanism responsible for their anti-neoplastic activity is still far from clear. An understanding of the molecular mechanisms underlying resistance to HDACi may help to elucidate their mechanism of action and may be of relevance in an attempt to design more effective combination strategies.
The purpose of this study is to understand the molecular alterations associated with resistance to vorinostat (Zolinza®).
A vorinostat resistant clone (U937-VR) was derived from the AML cell line U937 using a dose escalation protocol. The vorinostat-resistant cells (U937-VR) are able to grow in 2 µM vorinostat without induction of apoptosis. U937-VR cells are cross-resistant to the cytotoxic effects of other HDACi, as measured by propidium iodide staining and caspase 3/7 activation. Using western blot, we observed that vorinostat exposure increases tubulin acetylation in U937-VR cells while being incapable of inducing histone acetylation. These data demonstrate effective drug import into the cells, an event that is otherwise commonly altered in drug resistant cells. Furthermore, western blotting reveals a drastic difference in the protein level of the histone acetyltransferase CBP (CREB binding protein) between VR-U937 and parental U937 cells, whereas no alterations in the protein levels of the main HDACs targeted by vorinostat is seen. This indicates that the balance between HDAC and HAT activity might be perturbed.
Finally, the resistance index (the ratio between the LD50 of resistant and sensitive cells) of different drugs was evaluated by measuring apoptosis using propidium iodide staining. U937 parental and U937-VR cells have equivalent LD50 for the DNA damaging agent cisplatin and for the microtubule stabilizing agent taxol. In contrast, we observed that U937-VR cells exhibit increased sensitivity toward the proteasome inhibitors MG132 and Bortezomib. This increased sensitivity correlates with a higher level of ubiquitinated protein accumulation in U937-VR.
Cumulatively, our data suggest that the U937-VR cells are not multidrug resistant and that the apoptotic cascade remains functional. The importance of the alteration in HAT level and the acquired sensitivity to proteasome inhibitor by chronic exposure to HDACi need further investigation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 722. doi:10.1158/1538-7445.AM2011-722