bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2463: Enhanced anti-tumor activity of an Auristatin-based antibody-drug conjugate in combination with PI3K/mTOR inhibitors or taxanes: Translational implications and mechanistic insights
Authors: Sapra Puja , Shor Boris , Dougher Maureen , Kahler Jennifer , Mack Michelle , Xu Jane , Lu Shuyan , Melamud Eugene , Wang Fang , Rosfjord Edward 
Published: August 2015

Abstract
Targeted treatment with antibody-drug conjugates (ADCs) can lead to dramatic regressions of solid tumors; combination therapies with the ADCs that could potentially help achieve long-term disease control remain largely unexplored. The aim of the study is to investigate most promising combination regimens of auristatin-based conjugates in preclinical models of cancer.
A tool ADC, an auristatin-based anti-5T4 antibody conjugate (5T4-ADC) and permeable auristatin analogs were combined with dual PI3K/mTOR catalytic site inhibitor PF-05212384 (PF-384) or taxanes in a panel of common cancer cell lines of breast, lung or ovarian origin. Drug combinations were tested for their effects in vitro on cell viability, apoptosis, cell cycle or modulation of PI3K/mTOR pathway markers. Anti-tumor efficacy of selected combinations was also evaluated in a 5T4-positive human breast or lung tumor xenografts in vivo.
Remarkably, ADC and auristatin analogs resulted in synergistic or additive effects on cell cytotoxicity when combined with PF-384 or with taxanes in vitro. ADC/PF-384, auristatin/PF-384 and ADC/Paclitaxel (PTX), auristatin/PTX combinations showed enhanced induction of apoptosis and selective attenuation of the downstream phospho-markers of the PI3K/mTOR pathway. Quantitative proteomic analysis of cells treated with auristatin-based agents and PF-384 alone or in combination revealed novel and unique effects on key components of mRNA translation, including translation initiation or elongation factors. In human lung or breast cancer xenograft models, dual targeting with 5T4-ADC/PF-384 or 5T4-ADC/PTX produced substantially greater antitumor effects with longer average survival as compared to monotherapy treatments.
Our results provide strong rationale for combining 5T4-ADC with PI3K/mTOR pathway inhibitors or taxanes. New biological insights into molecular mechanisms underlying synergistic effects of ADC - drug combinations suggest/reveal that synergies are mediated by payload's mode of action. These findings can be applicable to several ADCs employing microtubule inhibitors that are undergoing clinical evaluation.
Citation Format: Puja Sapra, Boris Shor, Maureen Dougher, Jennifer Kahler, Michelle Mack, Jane Xu, Shuyan Lu, Eugene Melamud, Fang Wang, Edward Rosfjord. Enhanced anti-tumor activity of an Auristatin-based antibody-drug conjugate in combination with PI3K/mTOR inhibitors or taxanes: Translational implications and mechanistic insights. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2463. doi:10.1158/1538-7445.AM2015-2463
Abstract 247: Comparing radiation therapy and ipilimumab to ipilimumab alone in metastatic melanoma patients
Authors: Patel Kirtesh R. , Oliver Daniel E. , Okwan-Dadu Derick , Liu Yuan , Kudchadkar Ragini R. , Lawson David H. , Khan Mohammad K. 
Published: August 2015

Abstract
Purpose/Objective:
With evidence suggesting ipilimumab and intracranial stereotactic radiosurgery (SRS) improves survival compared to SRS alone, we compared toxicity, response rates (RRs), and outcomes of metastatic melanoma patients receiving radiation (RT) and ipilimumab to ipilimumab alone.
Methods and Materials:
We reviewed records of metastatic melanoma patients receiving ipilimumab 3mg/kg between 2010-2014. RRs, measured by immune RECIST criteria, and toxicity were compared by Fischer's exact text. Overall survival (OS) was estimated by the Kaplan Meier method.
Results:
61 patients received ipilimumab, with 35 (57.4%) also receiving radiation within 4 months of ipilimumab. The radiation cohort was similar at baseline except for greater systemic burden of disease (82.9% vs. 42.3%, p = 0.005), higher dexamethasone use (14.3% vs. 0%, p = 0.048), and more brain involvement (74.3% vs. 0% p&lt;0.001). 92.3% of brain metastases received SRS. Grade 3 toxicity was not statistically different between cohorts (5.9% vs. 20.0%, p = 0.113); one grade 4 was experienced (1.6%), while no grade 5 occurred. While the ipilimumab alone group demonstrated a trend toward higher 1-year OS (49.4% vs. 73.2%, p = 0.090), the cohort did not have any patients with brain metastases; therefore, comparing only patients with extra-cranial metastases, 1-year OS was similar (76.2% vs. 73.2%, p = 0.587). RR between both cohorts was similar (20.0% vs. 11.5%, p = 0.494). Pre-ipilimumab absolute lymphocyte count greater than 1000 was the only significant predictor for increased RR in multivariable analysis (Odds Ratio: 8.56, 95% CI: 1.82-40.42; p = 0.007). Comparing 2-5 fractions of radiation to ipilimumab alone demonstrated a trend towards higher response rate (42.9% vs. 11.5%, p = 0.074).
Conclusion:
Despite poorer prognostic characteristics in the RT with ipilimumab cohort, toxicity, RR and OS were similar between the arms. Prospective studies investigating the ideal radiation fractionation to improve ipilimumab response rates are warranted. ALC &lt; 1000 should be considered an exclusion criteria for these trials.
Citation Format: Kirtesh R. Patel, Daniel E. Oliver, Derick Okwan-Dadu, Yuan Liu, Ragini R. Kudchadkar, David H. Lawson, Mohammad K. Khan. Comparing radiation therapy and ipilimumab to ipilimumab alone in metastatic melanoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 247. doi:10.1158/1538-7445.AM2015-247
Abstract 2497: Immune checkpoint inhibitors enhance benefits of modified vaccinia virus Ankara to improve survival in preclinical models of cancer
Authors: Rittner Karola , Remy-Ziller Christelle , Hortelano Julie , Farine Isabelle , de Meyer Micael , Nourtier Virginie , Gantzer Murielle , Thioudellet Christine , Slos Philippe , Preville Xavier 
Published: August 2015

Abstract
TG4010 is a Modified Vaccinia virus Ankara (MVA) expressing human interleukin 2 and the human mucin1 (MUC1) tumor associated antigen. TG4010 has demonstrated clinical benefit for advanced non small cell lung cancer patients in combination with standard of care chemotherapy in two phase 2 randomized and controlled clinical trials (NCT00415818 and NCT1383148).
Immunotherapy based on the use of immune checkpoint blockers such as anti PD-1 and anti PD-L1 has also demonstrated efficacy in phase 2 trials. Hence, the combination of both approaches appears to be of great interest considering the high unmet medical need of this pathology. We developed experimental primary tumor and lung metastasis models to evaluate the rationale of combining both approaches at the preclinical level. Using two CT26 cell lines expressing different target antigens (β-galactosidase and MUC1) we evaluated the impact on overall survival of combined MVA-based and immune checkpoint-based immunotherapies. Synergistic increase in overall survival was observed in the therapeutic CT26-CL25 primary tumor and lung metastasis models upon treatment of mice with the combination of MVA-βgal and anti CTLA4 or anti PD-1 in comparison with either treatment alone. We provide evidence that TG4010 synergized with immune checkpoint inhibitors to increase overall survival in the therapeutic CT26-MUC1 tumor models in comparison with either treatment administrated independently. These observations were associated with an increase in the frequency and the quality of antigen-specific tumor infiltrating CD8+ T cells.
These studies pave the way for the evaluation of combinatorial therapies including TG4010 and immune checkpoint blockers in the clinic.
Citation Format: Karola Rittner, Christelle Remy-Ziller, Julie Hortelano, Isabelle Farine, Micael de Meyer, Virginie Nourtier, Murielle Gantzer, Christine Thioudellet, Philippe Slos, Xavier Preville. Immune checkpoint inhibitors enhance benefits of modified vaccinia virus Ankara to improve survival in preclinical models of cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2497. doi:10.1158/1538-7445.AM2015-2497
Abstract 2500: Identification of promiscuous oncofetal antigen (IMP-3)-derived long peptides, bearing both Th cell and CTL epitopes
Authors: Hirayama Masatoshi , Yuno Akira , Tomita Yusuke , Sayem Mohammad Abu , Tsukamoto Hirotake , Irie Atsushi , Senju Satoru , Yoshitake Yoshihiro , Fukuma Daiki , Shinohara Masanori , Yuba Eiji , Kono Kenji , Yoshida Koji , Nakamura Yusuke , Nakayama Hideki , Nishimura Yasuharu 
Published: August 2015

Abstract
We recently identified CTL epitopes derived from an oncofetal antigen, insulin-like growth factor II mRNA-binding protein 3 (IMP-3) which was frequently overexpressed in head-and-neck cancers (HNCs) and lung cancers, but not in many normal adult organs, by using genome-wide cDNA microarray analyses. Several phase I/II clinical trials using IMP-3-derived short peptides (SPs) vaccination against several types of malignant tumor are ongoing. Recently we reported the phase I/II clinical trial of multiple tumor-associated-antigen (TAA)-derived SPs vaccinations including IMP-3-SP for advanced HNC patients. In this trial, we observed the vaccinated SPs-specific CTL responses and the prolongation of overall survival of HNC patients (Clin Cancer Res; Nov. 12, 2014 in press). In order to further develop peptides-based cancer immunotherapy, we attempted to identify IMP-3-derived long peptides (LPs) containing both CTL and Th cell epitopes in this study. We successfully identified two promiscuous IMP-3-derived LPs, and one of them encompasses two natural CTL epitopes, and these LPs can stimulate IMP-3-LP-specific Th1 cells restricted by 7 frequent HLA class II molecules. We confirmed that Th cells induced by two LPs responded to autologous dendritic cells (DCs) loaded with IMP-3 protein, suggesting that these IMP-3-derived LPs were possibly naturally processed from IMP-3 protein and presented by DCs. We also demonstrated that one of the IMP-3-derived LPs could cross-prime IMP-3-SP-specific CTLs in vitro in human and in vivo in HLA-A2 transgenic mice. The same LP encapsulated in newly developed pH-sensitive liposome, that can deliver LPs from endosome to cytoplasm, was also found to be efficiently cross presented in vitro to stimulate IMP-3-SP-specific human CTLs. Furthermore, we could induce IMP-3-LP-specific Th cells from a HNC patient vaccinated with an IMP3-derived SP. Immune response to these LPs in many other HNC patients is now under investigation. Taken together, IMP-3-derived LPs may be applicable to cancer immunotherapy.
Citation Format: Masatoshi Hirayama, Akira Yuno, Yusuke Tomita, Mohammad Abu Sayem, Hirotake Tsukamoto, Atsushi Irie, Satoru Senju, Yoshihiro Yoshitake, Daiki Fukuma, Masanori Shinohara, Eiji Yuba, Kenji Kono, Koji Yoshida, Yusuke Nakamura, Hideki Nakayama, Yasuharu Nishimura. Identification of promiscuous oncofetal antigen (IMP-3)-derived long peptides, bearing both Th cell and CTL epitopes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2500. doi:10.1158/1538-7445.AM2015-2500
Abstract 2524: Combination with vorinostat overcomes ABT-263 resistance of small cell lung cancer
Authors: Nakajima Wataru , Hicks Mark A. , Sharma Kanika , Le Ngoc , Krystal Geoffrey W. , Harada Hisashi 
Published: August 2015

Abstract
Lung cancer is the most common cause of cancer related mortality worldwide, with small cell lung cancer (SCLC) representing 15% of cases, accounting for 30,000 new cases in the US each year. While SCLC is initially a highly chemotherapy-responsive disease, relapse and progressive development of chemotherapy resistance is the rule. One promising approach to overcome the therapeutic resistance would be to utilize agents targeting molecular abnormalities regulating resistance to apoptosis.
Tumor cell death induced by chemotherapy or lack of appropriate cellular survival signals is mediated by the BCL-2 family-dependent mitochondrial apoptotic pathway. We and others have shown that the pro-survival member BCL-2, as well as BCL-XL and MCL-1, is overexpressed in SCLC. BH3 mimetic antagonists have been developed to block the function of pro-survival BCL-2 family members. ABT-737 and its orally available derivative ABT-263 bind to and block BCL-2 and BCL-XL, but not MCL-1 function. Although SCLC is the only non-hematologic malignancy against which ABT-737/ABT-263 are effective as single agents, the sensitivity of SCLC to these drugs varies over a broad range in vitro and in clinical trials. We have shown in a model SCLC system that expression of Noxa, a BH3-only pro-apoptotic BCL-2 family protein, is a critical determinant of ABT-737 sensitivity, demonstrating that Noxa specifically binds to and recruits MCL-1 from the cytosol to the mitochondria.
Recent integrative genome analysis in SCLC implicates histone modification as a major feature of SCLC. It has also been demonstrated that Noxa is transcriptionally activated by HDAC inhibitors. Thus, we hypothesized that alteration of histone modification by a HDAC inhibitor, vorinostat could induce Noxa to enhance cell death by ABT-737/263 treatment. We have found that combination of ABT-263 and vorinostat efficiently induces apoptosis in a variety of SCLC cell lines, even in the ABT-263 resistant cells. Cell death induced by combined treatment is Noxa- and/or BIM-dependent in some cell lines but in others appears to be mediated by an alternative mechanism. These results suggest that combination of HDAC inhibitors and BCL-2 inhibitors could be an alternative effective regimen for SCLC treatment.
Citation Format: Wataru Nakajima, Mark A. Hicks, Kanika Sharma, Ngoc Le, Geoffrey W. Krystal, Hisashi Harada. Combination with vorinostat overcomes ABT-263 resistance of small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2524. doi:10.1158/1538-7445.AM2015-2524
Abstract 2541: Preclinical results of SGN-CD19A in combination with R-ICE or R-CHOP in non-Hodgkin lymphoma models
Authors: Van Epps Heather A. , Klussman Kerry , Anderson Martha , Zeng Weiping , Olson Devra , Ryan Maureen , Albertson Tina , Law Che-Leung 
Published: August 2015

Abstract
SGN-CD19A is an antibody drug conjugate (ADC) that recognizes CD19, a B-cell specific marker expressed in B-cell malignancies including non-Hodgkin lymphoma (NHL). SGN-CD19A is currently in a phase I clinical trial for adult patients with relapsed refractory B-cell NHL (CT.gov NCT01786135) in which it has shown evidence of single-agent activity (1). This ADC binds CD19, internalizes, and releases cys-mcMMAF, which ultimately induces apoptosis in targeted cells (2). Lymphoma tumor xenografts treated with SGN-CD19A show growth delay in a dose dependent manner. Here we show that SGN-CD19A in combination with standard of care [rituximab/ifosfamide/carboplatin/etoposide (R-ICE), rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP), or components] exceeds the activity of SGN-CD19A alone and results in impressive anti-tumor activity in multiple xenograft models. It was notable that in some xenograft models, SGN-CD19A + R-CHOP or SGN-CD19A + R-ICE yielded activity that was similar to SGN-CD19A plus rituximab alone. This strong interaction between rituximab and SGN-CD19A was modeled in vitro. SGN-CD19A synergized with rituximab, in the absence of cross-linking, to cause decreased cell viability in NHL cell lines. These data suggest that cell autonomous signaling contributes to the unique interaction between rituximab and SGN-CD19A. Our in vivo and in vitro data support R-CHOP, R-ICE, or rituximab as viable combination therapies for NHL patients with SGN-CD19A.
1) Uma Borate et al. A first-in-human phase 1 study of the antibody-drug conjugate SGN-CD19A in relapsed or refractory B-lineage acute leukemia and highly aggressive lymphoma. Blood 2013 122:1437
2) Che-Leung Law et al. Preclinical characterization of an auristatin-based anti-CD19 drug conjugate, SGN-19A. Abstract number 625. In: Proceedings of the 102th Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL.
Citation Format: Heather A. Van Epps, Kerry Klussman, Martha Anderson, Weiping Zeng, Devra Olson, Maureen Ryan, Tina Albertson, Che-Leung Law. Preclinical results of SGN-CD19A in combination with R-ICE or R-CHOP in non-Hodgkin lymphoma models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2541. doi:10.1158/1538-7445.AM2015-2541
Abstract 2549: Tyrosyl-DNA phosphodiesterase 1 (TDP1) is critical for the repair of DNA breaks induced by sapacitabine, a nucleoside antimetabolite in clinical trials targeted to ATM- and BRCA-deficient tumors
Authors: Al Abo Muthana , Liu Xiaojun , Plunkett William , Pommier Yves 
Published: August 2015

Abstract
2′-C-cyano-2′-deoxy-1-β-D-arabino-pentofuranosylcytosine (CNDAC) is a nucleoside analogue and the active metabolite of the anticancer drug, sapacitabine. The cytotoxic activity of CNDAC is achieved by incorporation of its nucleoside triphosphate metabolite into genomic DNA during replication, which subsequently undergoes beta-elimination that generates a single-strand break with 3′-end blocking DNA lesion. Subsequent DNA replication converts the nick into a double strand break. Earlier investigations demonstrated that cells lacking homologous recombination function are sensitized 20- to 100-fold to CNDAC. Because tyrosyl-DNA phosphodiesterase 1 (TDP1) efficiently hydrolyzes 3′-blocking ends, we tested its role in the repair of CNDAC-induced DNA lesions and the potential cellular tolerance to CNDAC. Here we show that cells lacking TDP1 (TDP1-/- DT40 cells) exhibited marked hypersensitivity to CNDAC indicating the importance of TDP1 for the repair of CNDAC-induced DNA damage. Although the 3′-end blocking DNA lesions caused by another arabinosyl-nucleoside analog, cytosine arabinoside (cytarabine, AraC) and the topoisomerase I inhibitor camptothecin (CPT) are also repaired by TDP1, inactivation of homologous recombination, including BRCA1 and BRCA2, rendered cells hypersensitive to CNDAC and CPT but not to AraC. On the other hand, cells lacking PARP1/2 were hypersensitive to CPT only. Consistent with earlier findings, DT40 cells deficient in BRCA1, BRCA2, FANCD2, and ATM were sensitized to CNDAC. Thus, the present study has identified TDP1 as an additional mechanism that contributes to the repair of CNDAC-induced DNA lesions. It also demonstrates the differential involvement of DNA repair pathways that underlie the resistance to CNDAC, AraC and camptothecins, and provides a rationale for using sapacitabine to treat various types of cancers with preexisting defects in DNA repair pathways.
Citation Format: Muthana Al Abo, Xiaojun Liu, William Plunkett, Yves Pommier. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is critical for the repair of DNA breaks induced by sapacitabine, a nucleoside antimetabolite in clinical trials targeted to ATM- and BRCA-deficient tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2549. doi:10.1158/1538-7445.AM2015-2549
Abstract 2559: Optimisation of EGFR TKI efficiency wild-type EGFR lung cancer
Authors: Raimbourg Judith , Cabart Mathilde , Joalland Marie-Pierre , Decaudin Didier , Deplater Ludmilla , Lanoe Didier , Douillard Jean-Yves , Bennouna Jaafar , Vallette François , Lalier Lisenn 
Published: August 2015

Abstract
Background : Lung cancer is the first cause of cancer death worldwide. EGFR tyrosine kinase inhibitors (EGFR-TKI) have improved the survival of patient harboring EGFR activating mutations. Besides, EGFR-TKIs have shown clinical activity for patients with wild type EGFR (wtEGFR) tumors as maintenance treatment and for a fraction of them as second line treatment. These observations impel us to objective and document the mechanisms implicated in order to optimize the use of EGFR-TKI in the treatment of wtEGFR lung cancer.
Methods : In vitro experiments rely on lung cancer cell lines expressing either wtEGFR or mutated EGFR. Their sensitivity to erlotinib in control conditions or short after a sublethal cisplatin treatment was studied. In vitro results were validated on lung patients-derived xenografts (PDX) with four wtEGFR human adenocarcinomas.
Results : Cisplatin pretreatment enhances erlotinib toxicity in wtEGFR cells (providing its robust expression) but not in EGFR-mutated cells. Cisplatin priming increases erlotinib toxicity either through apoptosis or autophagy depending on the cell line. This sensitization correlates with an increase in EGFR expression and phosphorylation and a raise in AKT and Erk phosphorylation. The sensitization is also observed during long-term cisplatin treatment in a cisplatin-resistant subpopulation, together with concomitant EGFR pathway activation.
The in vivo experiments conducted in PDX confirm that cisplatin pretreatment potentiates erlotinib in three of the four wtEGFR lung tumors models.
Of note, the sensitization to erlotinib occured independently from KRas status.
Conclusion : The sensitivity of the wtEGFR lung cancer cells and lung cancer xenografts to erlotinib is enhanced by cisplatin pretreatment, whatever the type of induced cell death. Cisplatin induces activation of EGFR and his downstream kinases AKT and Erk. This sensitization is independent from the tumor K-Ras status. EGFR phosphorylation could be a potential marker of this sensitization and might be predicitive of the optimal efficiency of EGFR TKI. In vivo validation of this marker is still ongoing.
This study was supported by Roche laboratory and by the foundation for medical research.
Citation Format: Judith Raimbourg, Mathilde Cabart, Marie-Pierre Joalland, Didier Decaudin, Ludmilla Deplater, Didier Lanoe, Jean-Yves Douillard, Jaafar Bennouna, François Vallette, Lisenn Lalier. Optimisation of EGFR TKI efficiency wild-type EGFR lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2559. doi:10.1158/1538-7445.AM2015-2559