bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 613: Combining PI3K and 5alpha-reductase inhibitors improves the treatment response in a mouse model of PTEN-deficient prostate cancer
Authors: Kura Yurie , Velasco Marco A. De , Ando Naomi , Fukushima Emiko , Yamamoto Yutaka , Hatanaka Yuji , Shimizu Nobutaka , Nozawa Masahiro , Yoshimura Kazuhiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: May 2015

Abstract
Testosterone is converted to dihydrotestosterone (DHT) by the enzymes 5alpha-reductase types 1 and 2. Inhibition of both 5alpha-reducatase enzymes with dutasteride was effective in reducing the incidence of prostate cancer in high risk patients. This suggests that suppression of DHT with dutasteride may have a potential therapeutic effect on prostate cancer. In this study, we examined the antitumor effects of dutasteride in vivo using a preclinical model of prostate cancer that is based on the PSA-Cre mediated inactivation of PTEN. Our findings show that monotherapy with dutasteride significantly inhibited prostate tumor growth by approximately 25%. Furthermore, the combination of dutasteride with the mTOR inhibitor, everolimus, improved tumor growth suppression compared to monotherapy with either drug. Treatment with dutasteride had a minimal effect on tumor cell proliferation; however, it significantly increased the apoptotic rate in tumors. Interestingly, treatment with dutasteride resulted in increased activation of PI3K/mTOR signaling and a reduction of STAT3 pathway activation. Moreover, increased activation of MAPK, which occurs after treatment with mTOR inhibitors, was effectively reduced with the co-administration of dutasteride. The findings from our study suggest that inhibitors of 5alpha-reductase types 1 and 2 enzymes may have a potential therapeutic value in PTEN deficient prostate cancers, in particular when co-administered with PI3K inhibitors.
Citation Format: Yurie Kura, Marco A. De Velasco, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Combining PI3K and 5alpha-reductase inhibitors improves the treatment response in a mouse model of PTEN-deficient prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 613. doi:10.1158/1538-7445.AM2014-613
Abstract 616: Transcription-regulating kinases CDK8 and CDK19 as novel therapeutic targets for advanced prostate cancer
Authors: Chen Mengqian , Kaza Vimala , Liang Jiaxin , McDermott Martina , Roninson Igor 
Published: May 2015

Abstract
Most of castration-refractory prostate cancers (CRPC) continue to express androgen receptor (AR) that maintains its activity at low levels or even in the absence of androgen, driving tumor cell proliferation. Androgen-depleting drugs and androgen antagonists have little or no effect against AR+ cancers that are fully androgen-independent (AI). On the other hand, experimental compounds that cause AR degradation prevent AR-mediated repression of tumor-promoting genes, a tumor-suppressive effect of AR. We report a novel druggable target for CRPC, which mediates the induction but not the repression of gene expression by AR and inhibits the growth of AI prostate cancer (PCa) cells. This target is two closely related transcription-regulating kinases CDK8/CDK19 that unlike some other members of the CDK family are not required for cell cycle progression but play critical roles in several transcriptional signaling pathways. CDK8 and CDK19 are highly expressed in AR+ PCa cells and elevated under the conditions of androgen deprivation; CDK19 is overexpressed in AR+ PCa cell lines and in metastatic clinical PCa. A novel selective CDK8/19 kinase inhibitor (Senexin B) blocks ligand-induced AR-mediated transcriptional activation in androgen-dependent (AD) PCa cells but does not affect the AR-mediated gene repression. The CDK8/19 inhibitor also inhibits ligand-independent AR activation and AI cell growth in AI-PCa cells resistant to the anti-androgenic drug enzalutamide, both in vitro and in a mouse xenograft model. We have also discovered that CDK8/19 inhibition decreases NFκB mediated transcriptional activation of a group of tumor-promoting chemokines, such as CXCL1, CXCL2 and IL8, suggesting that CDK8/19 may promote prostate cancer chemoresistance and metastasis through the NFκB pathway. The above results suggest that CDK8/19 is an especially attractive therapeutic target for advanced PCa, which controls both AR-driven cell proliferation and other oncogenic pathways.
Citation Format: Mengqian Chen, Vimala Kaza, Jiaxin Liang, Martina McDermott, Igor Roninson. Transcription-regulating kinases CDK8 and CDK19 as novel therapeutic targets for advanced prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 616. doi:10.1158/1538-7445.AM2014-616
Abstract 627: Immunogenic cell death as novel immune response mechanism to EGFR-targeted therapy in CRC
Authors: Penna Giuseppe , Pozzi Chiara , Magni Elena , Curigliano Giuseppe , Zampino Maria Giulia , Rescigno Maria 
Published: May 2015

Abstract
Colorectal cancer (CRC) is the third most common cancer worldwide. The major improvement in the median overall survival of mCRC patients was mainly due to the introduction of new active chemotherapeutic and biomolecular targeting agents. Most chemotherapeutic agents and radiotherapy kill tumor cells through an apoptotic pathway, which is considered as a non-immunogenic. However, anthracyclines, oxaliplatin or ionizing irradiation are able to induce a potent immune response in vivo, when injected in immunocompetent mice. Dying cells are readily taken up by dendritic cells (DC) that then cross-present their associated antigens for effective T cell activation.
Herein we propose that the treatment with an anti-EGFR antibody (Cetuximab) in combination with chemotherapy FOLFIRI (5-fluorouracile, leucovorin, irinotecan) induces a immunogenic cell death (ICD) modality, which contributes to its clinical efficacy in patients with mCRC expressing EGFR and the wild type (wt) form of the viral oncogene v-Ki ras2.
Our results, obtained on CRC cell lines provide evidence, for the first time, that treatment with Cetuximab alone or in combination with a chemotherapeutic regimen (FOLFIRI) directs dying cells towards an ICD process characterized by phosphorylation of eIF2α and, most important, increased phagocytosis by DCs. However, not all cell lines wt for KRAS (expressing EGFR) displayed the same response. As expected, Cetuximab blocked the pathways leading to AKT and ERK phosphorylation. However, we also observed that Cetuximab, and to a lesser extent the F(ab)2 fragments of Cetuximab, was inducing some phosphorylation of the EGFR in KRAS wt responding cell line, which was lower than that induced by EGF . Hence Cetuximab is uncoupling the activation of the signaling pathway induced via EGFR from EGFR phosphorylation, suggesting an alternative activation of the receptor. This allowed us to postulate that Cetuximab-induced phagocytosis may be the effect of an alternative activation of the EGFR. Indeed, we could not detect any phagocytosis in cell lines where the phosphorylation of the receptor did not occur in response to Cetuximab.
These results identify ICD as novel immune response mechanism to EGFR targeted therapy alone or in combination with chemotherapy and possibly genetic alterations of the EGFR-signalling pathway, could interfere with the induction of ICD.
Citation Format: Giuseppe Penna, Chiara Pozzi, Elena Magni, Giuseppe Curigliano, Maria Giulia Zampino, Maria Rescigno. Immunogenic cell death as novel immune response mechanism to EGFR-targeted therapy in CRC. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 627. doi:10.1158/1538-7445.AM2014-627
Abstract 630: Induction of anti-melanoma immunity after intralesional ablative therapy
Authors: Liu Hao , Kodumudi Krithika , Weber Amy , Sarnaik Amod A. , Pilon-Thomas Shari 
Published: May 2015

Abstract
Immunotherapeutic strategies incorporating intralesional (IL) ablative therapy to elicit a tumor specific immune response are under investigation as a non-surgical option to induce tumor regression of cutaneous neoplasms. Rose Bengal (RB) is a water-soluble xanthene dye that was originally used as an intravenous liver diagnostic and is in use by ophthalmologists to stain damaged cells in the eye. In murine models of breast cancer and melanoma, we have shown that IL injection of PV-10 (10% RB in saline solution) leads to ablation of injected tumors and regression of non-injected bystander tumors. In these models, increased anti-tumor T cell responses were measured, supporting the induction of systemic anti-tumor immunity after tumor ablation with PV-10. In our ongoing phase I clinical trial exploring melanoma regression in patients, IL PV-10 has led to a significant decrease of melA positive melanoma cells in the biopsies of both PV10-injected and non-injected lesions. This regression correlated with increased circulating CD3+T cells (p=0.03) in peripheral blood mononuclear cells (PBMC). T cells purified from PBMC from a melanoma patient produced increased IFN-gamma in response to autologous tumor after treatment with PV-10. Ex vivo models implemented to investigate this phenomenon indicate that the cytotoxicity induced by PV-10 is not apoptosis-dependent as evidenced by Annexin staining of melanoma cells following PV-10 treatment. PV-10 directly induced necrosis of melanoma cells at 50 uM, but was not toxic to healthy fibroblasts at the same dose. Further preclinical translational testing has shown that treatment of murine B16 cells with PV-10 leads to release of HMGB1, a soluble Damage Associated Molecule Pattern (DAMP) that is important for activation of dendritic cells (DCs). In the murine B16 melanoma model, there is a significant increase in the number of DCs infiltrating the tumor-draining lymph nodes after IL injection of PV-10. These findings suggest that PV-10 treatment leads to the release of DC activating factors and DC recruitment. Further studies to determine the role of PV-10 on T cell activation are ongoing. In sum, these clinical and preclinical results increase our understanding of the cytotoxic and immunological mechanisms that may play a role in systemic immunity induced by PV-10 tumor ablation.
Citation Format: Hao Liu, Krithika Kodumudi, Amy Weber, Amod A. Sarnaik, Shari Pilon-Thomas. Induction of anti-melanoma immunity after intralesional ablative therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 630. doi:10.1158/1538-7445.AM2014-630
Abstract 641: Targeted inhibition of BRAF signaling in melanoma enhances the activity of a multivalent immunotherapeutic vaccine
Authors: Suriano Robert , Tuli Neha , Geliebter Jan , Tiwari Raj K. , Wallack Marc K. 
Published: May 2015

Abstract
Development of a successful immunotherapeutic vaccine targeting melanoma requires the use of multiple melanoma associated antigens (MAA). Expression of several MAAs is regulated by the micropthalmia transcription factor (MITF), which in turn is regulated by members of the MAPK pathway, such as ERK. It is also known that 70% of melanomas express the genetic lesion BRAFV600E. Based on this knowledge, we hypothesize that the use of a specific BRAFV600E inhibitor would enhance MITF mediated MAA expression and thus serve as a viable target for immunotherapy. We have developed a vaccinia virus based melanoma vaccine using patient derived primary melanoma cells that are rich in MAAs such as gp100, tyrosinase, and TRP-1. Our results indicated that our cells were either homozygous or heterozygous for the mutated BRAF gene. In addition, our cells were responsive to treatment by PLX-4032, an FDA approved treatment for melanoma, as evidenced by inhibition of phosphorylation of MEK and ERK, two key players in the MAPK pathway. Phenotypically, the migratory and invasive properties of our cell lines were also altered by PLX-4032. Most interestingly was the observation that upon treatment with PLX-4032, the expression of various MAAs was altered. Specifically, the expression of gp100, MART-1, and tyrosinase increased both on the RNA level as well as on the protein level. Our results warrant further investigation into a combinatorial therapeutic approach to treat melanoma by which increasing the expression of various immunologically relevant MAAs, upon treatment with PLX-4032, followed by vaccination may lead to a more robust and targeted anti-melanoma immune response.
Citation Format: Robert Suriano, Neha Tuli, Jan Geliebter, Raj K. Tiwari, Marc K. Wallack. Targeted inhibition of BRAF signaling in melanoma enhances the activity of a multivalent immunotherapeutic vaccine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 641. doi:10.1158/1538-7445.AM2014-641
Abstract 673: A Monoclonal Antibody, MORAb-075, Targeting Claudin-3 & Claudin-4 Inhibits human ovarian, pancreatic and prostate cancer progression in mice
Authors: Lin Jian-Min , soto allis , maddage Christopher , Albone earl , zhou yuhong , grasso luigi 
Published: May 2015

Abstract
Claudin (CLDN) is a family of integral membrane proteins. They are crucial for tight junction formation and functions. Studies have found CLDN3 and CLDN4 proteins are overexpressed in majority of primary ovarian, prostate, and pancreatic cancers.
We have generated a rat-human chimeric monoclonal antibody, MORAb-075, which binds to CLDN3 and CLDN4 with high affinity in vitro. In order to evaluate its therapeutic potential in vivo, we have established a number of human cancer models where the tumors are grown orthotopically in nude mice. These tumors were confirmed positive for human CLDN3 or/and CLDN4 expressions via immunohistochemistry staining. The models include a CLDN3/4-expressing prostate cancer PC-3; a CLDN4-expressing pancreatic cancer, BxPc-3; a CLDN3-expressing ovarian cancer, IGROV-1. In these orthotopic tumor models, MORAb-075 demonstrated significant antitumor activities. When the mAb was administered intravenously at 25 mg/kg, twice weekly for 4 weeks, the tumor growth inhibition (TGI) of PC-3 tumors reached 50%; TGI of BxPC-3 tumors was nearly 60% and TGI of IGROV-1 tumors was greater than 75%. Our findings demonstrate the potency of MORAb-075, as a single agent, in inhibiting solid tumor growth in these models. These results suggest that mAb therapy targeting CLDN3 & CLDN4 is a valuable option for therapeutic application in cancer therapy that may be improved in combination with standard of care chemotherapies for CLDN3 or CLDN4 positive cancers.
Citation Format: Jian-Min Lin, allis soto, Christopher maddage, earl Albone, yuhong zhou, luigi grasso. A Monoclonal Antibody, MORAb-075, Targeting Claudin-3 & Claudin-4 Inhibits human ovarian, pancreatic and prostate cancer progression in mice. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 673. doi:10.1158/1538-7445.AM2014-673
Abstract 680: HMGB1 regulates autophagy and apoptosis to promote chemotherapy resistance in multiple myeloma
Authors: Zhang Xingding , Qi Lin , Yang Lin 
Published: May 2015

Abstract
Multiple myeloma is the second most frequently diagnosed hematologic malignancy in the United States after non-Hodgkin lymphoma. Unfortunately, multiple myeloma remains incurable, and virtually all patients eventually relapse with disease that is typically more resistant to therapy than in prior lines of treatment, for which the underlying molecular mechanisms remain unclear. In this study, we showed that high-mobility group box 1 (HMGB1), the best characterized damage-associated molecular pattern, in the development of chemotherapy resistance in multiple myeloma. To examine its potential role of chemotherapy resistance in myeloma, we detected protein expression of HMGB1 treated with anticancer chemotherapy agent doxorubicin and observed that HMGB1 was upregulated by different concentrations of doxorubicin in myeloma cells. Chemosensitivity assay was performed with RPMI 8226 and U266 cells with knockdown/overexpression of HMGB1 and treated with doxorubicin, and cells were detected for their viability by WST-1 assay after 72 hr. Consistently, shRNA interference-mediated knockdown of HMGB1 cells exhibited significant sensitized to doxorubicin treatment compared to non-targeting shRNA cells, and HMGB1-overexpressing cells significantly resistance to doxorubicin. Furthermore, studies in xenograft models showed that shRNA of HMGB1 also sensitized the chemosensitivity of multiple myeloma cells in vivo. At the molecular level, mechanistic investigation showed that shRNA of HMGB1 decreased autophagy, which is an intracellular self-defense mechanism to drug resistance, by inhibition of the autophagic marker microtubule-associated protein light chain 3-II and increasing of sequestosome 1 (p62) and autophagosome formation. Finally, we found that HMGB1 regulated autophagy and apoptosis by binding to p53 and Beclin1, and p53 is a negative regulator of the HMGB1/Beclin1 complex. Taken together, these data support the hypothesis that HMGB1 modulates chemotherapy resistance in myeloma through effects on the pathway of autophagy and apoptosis, as well as a target for strategies to aim at laying the foundation for further clinical studies, and overcome chemoresistance in multiple myeloma.
Note: This abstract was not presented at the meeting.
Citation Format: Xingding Zhang, Lin Qi, Lin Yang. HMGB1 regulates autophagy and apoptosis to promote chemotherapy resistance in multiple myeloma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 680. doi:10.1158/1538-7445.AM2014-680
Abstract 702: DCVex(TM): A novel integration-deficient lentivector technology that incorporates genetic and post-translational elements to target dendritic cells
Authors: Tareen Semih U. , Kelley-Clarke Brenna , Nicolai Christopher J. , Slough Megan M. , Vin Chintan D. , Hoeven Neal Van , Robbins Scott H. , Meulen Jan H. ter , Berglund Peter 
Published: May 2015

Abstract
With the goal of creating antigen-directed immunotherapeutics that can be safely administered directly to patients, Immune Design has developed a platform of novel integration-deficient lentiviral vectors that target and deliver antigen-encoding nucleic acids to dendritic cells (DCs) in order to promote the activation of antigen-specific effector CD8 T cells. This platform, termed DCVex(TM), utilizes a novel genetic variant of a Sindbis virus envelope glycoprotein with post-translational carbohydrate modifications in combination with Vpx, a SIVmac viral accessory protein, to achieve efficient targeting and transduction of DCs. In addition, DCVex(TM) incorporates safety features in its design that include redundant mechanisms to render DCVex(TM) integration-deficient, as well as genetic modifications that eliminate psi-gag recombination between split genome components. The characteristics that allow DCVex(TM) to specifically transduce human DCs and the advances that DCVex(TM) brings to conventional third-generation lentiviral vector design demonstrate its potential as a vaccine designed to utilize DCs for cancer immunotherapy.
Citation Format: Semih U. Tareen, Brenna Kelley-Clarke, Christopher J. Nicolai, Megan M. Slough, Chintan D. Vin, Neal Van Hoeven, Scott H. Robbins, Jan H. ter Meulen, Peter Berglund. DCVex(TM): A novel integration-deficient lentivector technology that incorporates genetic and post-translational elements to target dendritic cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 702. doi:10.1158/1538-7445.AM2014-702
Abstract 704: Comparison of Salmonella typhimurium A1-R and VNP20009 on the Lewis Lung carcinoma
Authors: Zhang Yong , Zhang Nan , Hoffman Robert M. , Zhao Ming 
Published: May 2015

Abstract
Salmonella typhimurium A1-R (A1-R) is auxotrophic for arg and leu, which attenuates growth in normal tissue but allows high tumor virulence. A1-R is effective against metastatic human prostate, breast, and pancreatic cancer as well as osteosarcoma, fibrosarcoma, and glioma in clinically-relevant mouse models. VNP20009 is also a genetically-modified strain of Salmonella typhimurium that has been tested in a Phase I clinical trial, but has more attenuation mutations than A1-R. Lewis-lung mouse lung cancer-bearing mice were treated with A1-R and VNP20009 in nude mice. A1-R and VNP20009 were both eliminated from the liver and spleen approximately 3-5 days after administration via tail vein, however A1-R showed higher tumor targeting and increased mouse survival than VNP20009 with less body weight loss. The mice tolerated A1-R at least 2-fold higher than NVP20009 when bacteria were administered iv. The results of the present study suggest that A1-R has greater clinical potential than VNP20009.
Citation Format: Yong Zhang, Nan Zhang, Robert M. Hoffman, Ming Zhao. Comparison of Salmonella typhimurium A1-R and VNP20009 on the Lewis Lung carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 704. doi:10.1158/1538-7445.AM2014-704