bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 99: An oncogenic role of Deleted in Liver Cancer 1 (DLC1) in metastatic melanoma
Authors: Yang Xintao , Cheung May , Lung Hong-Lok , Cheung Martin 
Published: August 2018

Abstract
Melanoma is a type of skin malignancy originated from neural crest-derived melanocytes. Although the mortality rate has been significantly reduced due to early cancer diagnosis and treatment, distant metastasis still exhibits much inferior survival rates compared to the early stage of this disorder. Therefore, developing new target for therapy is of particular significance in combating metastatic melanoma. DLC1 is well known for its tumor suppressor role through activating small Rho-GTPases' (RHOA and CDC42) intrinsic capability to convert an active GTP to an inactive GDP-bound state, leading to inhibition of tumor growth and metastasis. So far, downregulation of DLC1 expression has been widely reported to associate with increased risk of various malignancies whereas elevation of its expression prevents tumor progression. In contrast to these studies, our pilot findings reveal that multiple melanoma cell lines exhibit higher levels of DLC1 than benign melanocytes and other cancer types, suggesting its unique expression profile in melanoma. Furthermore, in vitro functional assays demonstrate that silenced DLC1 inhibits proliferative, clonogenic, migratory and invasive capabilities of melanoma cells, whereas restoration of DLC1 rescue the oncogenic properties. More importantly, in lung metastasis model using nude mice, DLC1 knockdown suppresses melanoma cells colonizing to the lungs whereas their pulmonary metastases can be recovered with the reconstitution of DLC1. In addition, the manipulation of DLC1 expression does not alter the RHO-ROCK-MRLC signalling, indicating that its oncogenic effect is mediated through a RHO-independent manner. Thus, our results unravel an unprecedented paradigm-shift of DLC1 functioning as an oncogene instead of a tumor suppressor in metastatic melanoma, which may shed new light on disease pathogenesis and uncover novel therapeutic targets to treat this deadly cancer.
Citation Format: Xintao Yang, May Cheung, Hong-Lok Lung, Martin Cheung. An oncogenic role of Deleted in Liver Cancer 1 (DLC1) in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 99.
Abstract CT138: Open-label personalized targeted intervention to maximize TTFields intensity in recurrent GBM (OptimalTTF Trial)
Authors: Mikic Nikola , Korshøj Anders Rosendal 
Published: August 2018

Abstract
Introduction Tumor Treating Fields (TTFields) is approved for the treatment of recurrent glioblastoma (rGBM). Skull remodeling surgery involves formation of strategically placed craniectomies, burr holes or skull thinning, in order to facilitate electric current flow into the tumor region. Preclinical studies have indicated that these procedures provide a marked and focal enhancement (~100%) of TTFields intensity without significantly compromising patient safety. In this open-label phase 1 investigator-initiated interventional trial, we test the safety, feasibility and efficacy of TTfields plus personalized targeted skull remodeling surgery and best choice chemotherapy. We believe this study has high-impact potential at a low clinical risk and may advance current state-of-the-art therapy of GBM therapy.
Methods The trial will include fifteen patients. Major eligibility criteria include age &gt; 18 years, first recurrence of supratentorial GBM, Karnofsky performance score (KPS) &gt; 60, focal tumor &lt; 2 cm to cortical surface, and lack of uncontrollable epilepsy or significant co-morbidity. Upon inclusion, personalized field calculations will be performed to validate TTFields enhancement &gt; 25% due by skull remodeling surgery. The primary endpoint is toxicity assessed by CTCAEv4.0. Secondary endpoints include overall survival, progression free survival (PFS), PFS at six months (PFS6), objective response rate, quality of life (EORTC QLQ-C30 and BN20), KPS, and steroid dose. Follow-up is 18 months and includes regular toxicity assessment (6-week intervals) as well as quality of life and response assessments (3-month intervals). Endpoint data will be collected at the end of scheduled follow-up, occurrence of suspected unexpected serious adverse reactions (SUSARs) or unacceptable serious adverse events (SAEs), withdrawal of consent, or loss to follow-up. Interim analysis will be performed upon endpoint registration for the first five-10 patients.
Citation Format: Nikola Mikic, Anders Rosendal Korshøj. Open-label personalized targeted intervention to maximize TTFields intensity in recurrent GBM (OptimalTTF Trial) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT138.
Abstract CT151: TTFields and radiosurgery for 1 to 10 brain metastases from NSCLC in the phase III METIS study
Authors: Mehta Minesh , Gondi Vinai , Ahluwalia Manmeet , Brown Paul D. 
Published: August 2018

Abstract
Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality, based on low intensity alternating electric fields. Efficacy of TTFields in non-small cell lung cancer (NSCLC) has been demonstrated in multiple in vitro and in vivo models, and in a phase I/II clinical study. TTFields treatment to the brain was safe and extended overall survival in newly-diagnosed glioblastoma patients.
The study [NCT02831959] objectives are to test the efficacy, safety and neurocognitive outcomes of TTFields in this patient population. Patients (N=270) with 1-10 brain metastases (BM) from NSCLC are randomized 1:1 to stereotactic radio surgery (SRS) followed by TTFields or supportive care. Patients are followed-up every two months until 2nd intracranial progression. Patients in the control arm may cross over to TTFields at the time of 2nd intracranial progression. Key inclusion criteria: KPS ≥70, 1 inoperable or 2-10 brain lesions amenable to SRS, optimal standard therapy for the extracranial disease, no brain-directed therapy, no signs of significantly increased intracranial pressure, and no electronic implantable devices in the brain. Endpoints included time to 1st intracranial progression or neurological death (primary); time to neurocognitive failure, HVLT, COWAT and TMT); overall survival; radiological response rate; quality-of-life; and adverse events. Treatment comprised continuous TTFields at 150 kHz for &gt; 18 hours/day applied to the brain within 7 days of SRS. The treatment system is a portable medical device allowing normal daily activities. The device delivers TTFields to the brain using 4 Transducer Arrays, which may be covered by a wig or hat. Patients receive the best standard of care for their systemic disease. Statistical Considerations: This is a prospective, randomized, multicenter study. The sample size (N=270) was calculated using a log-rank test (Lakatos 1988 and 2002) with 80% power at a two sided alpha of 0.05 to detect a hazard ratio of 0.57.
Citation Format: Minesh Mehta, Vinai Gondi, Manmeet Ahluwalia,, Paul D. Brown. TTFields and radiosurgery for 1 to 10 brain metastases from NSCLC in the phase III METIS study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT151.
Abstract CT155: Design of a dose escalation phase 1/2 trial for a novel combined cell and oncolytic viral therapy
Authors: Contag Pamela R. 
Published: August 2018

Abstract
Ovarian cancer is the sixth most common malignancy in women and the leading cause of death from all gynecological cancers in the United States with epithelial ovarian cancer are often diagnosed with advanced- stage disease. Although clinically complete remissions are obtained in the majority of patients through a combination of cyto-reductive surgery and chemotherapy, relapse is common with 70% of patients exhibiting recurring disease and thus represents a high unmet need. Single-agent therapies used to treat the subset of patients with chemotherapy- resistant/refractory ovarian cancer include paclitaxel, PLD (peglyated liposomal doxorubicin) and topotecan. The response rate is in the 10-15% range and overall survival is approximately 12 months. Our immunotherapy is comprised of cytokine-induced NK-T cells which stealthily delivers a tumor selective vaccinia virus to the tumor microenvironment, attracted by chemokines released by the tumor and binding to tumor stress ligands. The virus is released in the tumor site and is synchronously released to kill tumor cells, reducing or eradicating the tumor. This therapeutic approach is multi-mechanistic and delivery of the oncolytic agent by the immune effector cells together may result in a durable immune response to ovarian tumor- specific antigens through a cytotoxic T-cell mechanism. The two components, vaccinia virus vvDD-CDSR and CIK cells have been tested and investigated in multiple pre-clinical and clinical studies that have demonstrated their antitumor efficacy and overall safety. In our proposed Open Phase I/II clinical study will be a dose escalation to determine a MFD/MTD. The maximum-feasible dose (MFD) will be defined as the top dose level if no MTD is defined. It is expected that a maximum of 22 patients will be required to establish the MTD for one infusion. Once an MFD/and or MTD is determined, the study moves onto Phase II part of the protocol design allowing multiple cycles up to 4, treating 6-22 patients in Arm 1 safety and 20 patients in Arm 2 efficacy.
Citation Format: Pamela R. Contag. Design of a dose escalation phase 1/2 trial for a novel combined cell and oncolytic viral therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT155.
Abstract DDT02-01: FAP-4-1BBL: A next generation, targeted costimulatory agonist for cancer immunotherapy
Authors: Umana Pablo 
Published: August 2018

Abstract
This talk will describe a new drug candidate for cancer immunotherapy, FAP-4-1BBL, a next generation, tissue-targeted agonist of the 4-1BB costimulatory receptor. Agonizing 4-1BB to enhance the activity of antitumor T cells has been successfully exploited by 2nd and 3rd generation CAR T-cell therapies for hematological malignancies. However, the clinical development of first-generation, 4-1BB agonistic antibodies for systemic administration has been hampered by significant hepatic toxicity. Here we describe a next generation, fibroblast activated protein (FAP)-targeted 4-1BB agonist whose activity is independent of Fc-gamma-receptor (FcγR)-binding, is safe in preclinical models (including non-human primates using doses of up to 50 mg/kg) and is significantly more potent and efficacious than first generation, standard 4-1BB agonistic antibodies when compared side-by-side in preclinical models. In preclinical models, combination of FAP-4-1BBL with T-cell bispecific antibodies leads to significant increases in T cell infiltration into the tumor, CD8/Treg ratio and anti-tumoral efficacy. We conclude that the tumor-targeted cross-linking of 4-1BB provides a safe and effective way for co-stimulation of T cells for cancer immunotherapy and its combination with T-cell bispecific antibodies may provide a convenient “off-the-shelf,” systemic cancer immunotherapy approach for many tumor types.
Citation Format: Pablo Umana. FAP-4-1BBL: A next generation, targeted costimulatory agonist for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr DDT02-01.
Abstract LB-001: Development and evaluation of T-Zap: a novel antibody-drug conjugate for the treatment of Her2 positive breast cancer
Authors: Hoffmann Ricarda M. , Crescioli Silvia , Thurston David E. , Karagiannis Sophia N. 
Published: August 2018

Abstract
Background:
Breast cancer is the most common type of cancer worldwide and HER2-overexpressing types are especially associated with poor prognosis. Antibody-drug conjugates (ADCs) have been developed as a targeted approach to deliver toxins to cancer cells specifically with the ADC trastuzumab-emtansine (T-DM1) already in clinical use. A novel ADC T-Zap has been developed by linking the antibody trastuzumab to saporin - a ribosome inactivating protein. This study aims to evaluate the novel ADC T-Zap for the treatment of HER2 positive breast cancer.
Methods:
The plant toxin saporin was linked to the monoclonal antibody tratuzumab via a streptavidin-biotin bridge. Binding kinetics were assessed using flow cytometry, and MTS cell viability assays were performed to compare efficacy to T-DM1. Toxicity towards immune cells was investigated by MTS assays using immune cells.
Results:
Binding to target cells of T-Zap was confirmed. Comparison of T-Zap efficacy in breast cancer cell lines with and without resistance against trastuzumab showed a trend for higher efficacy of cell killing by T-Zap in trastuzumab resistant cells compared to T-DM1. Toxicity assays revealed no impact of T-Zap on cell viability in immune cells.
Conclusions:
Cell viability caused by T-Zap was more efficient compared to T-DM1 in the trastuzumab resistant cell line HCC1945. This strengthens the hyposthesis that T-Zap might have potential as new ADC overcoming trastuzumab resistance. Future work will include the development of a specific linker to link trastuzumab to saporin with the aim to develop an ADC that could prove a novel therapeutic agent for the treatment of HER2 positive breast cancer.
Citation Format: Ricarda M. Hoffmann, Silvia Crescioli, David E. Thurston, Sophia N. Karagiannis. Development and evaluation of T-Zap: a novel antibody-drug conjugate for the treatment of Her2 positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-001.
Abstract LB-019: Empowering preclinical studies: A systematic and quantitative analysis of biodistribution methods to facilitate clinical translation of new drugs
Authors: Nizzero Sara , Li Feng , Venuta Alessandro , Zhang Guodong , Borsoi Carlotta , Wolfram Joy , Mai Junhua , Shen Haifa , Li Zheng , Blanco Elvin , Ferrari Mauro 
Published: August 2018

Abstract
Biodistribution detection methods currently hold a central role in evaluating clinical potential of new drugs and nanomedicine in vivo, either through therapeutic efficacy or toxicity assays. However, the explorative nature of these methods makes it practically difficult to validate them for clinical studies to comply with regulations as determined by the Food and Drug Administration. This work proposes a new systematic comparison of biodistribution methods to facilitate clinical validation and employment in pre-clinical and early stage clinical studies. Several optical methods (detection through IVIS, confocal microscopy, fluorescence emission), direct detection methods (detection through ICP-OES), and radiation-based methods (detection through gamma counter) are systematically tested and validated on cGMP grade microparticles. The classification here proposed quantitatively highlights the advantages and disadvantages of each method, expressing them in terms of: limit of detection, recovery rate, reproducibility, and sensitivity. As a result, this quantitative evaluation of several preclinical biodistribution detection methods leads to a new rational and objective classification of biodistribution methods based on quantitative characteristics, which is essential to facilitate clinical translation of pre-clinical data collection. Their different characteristics and application-specific advantages are also discussed based in light of the results presented. Overall, this work proposes a new and rational quantitative comparison of biodistribution detection methods with the goal to provide a guide to facilitate clinical translation of on-going and future pre-clinical and early-stage clinical studies.
Citation Format: Sara Nizzero, Feng Li, Alessandro Venuta, Guodong Zhang, Carlotta Borsoi, Joy Wolfram, Junhua Mai, Haifa Shen, Zheng Li, Elvin Blanco, Mauro Ferrari. Empowering preclinical studies: A systematic and quantitative analysis of biodistribution methods to facilitate clinical translation of new drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-019.
Abstract LB-024: The effects of chromatin structure on variation in fragment size of cell free DNA
Authors: Xia Hui , Li Xingya , Bao Hua , Ma Xiangyuan , Wu Xue , Shao Yang W. , Wu Feixiang , Zhang Shucai 
Published: August 2018

Abstract
Liquid biopsy using cell-free DNA (cfDNA) has established its clinical utilities in multiple clinical cohorts. However, the exact mechanism by which cell-free DNA (cfDNA) is generated remains undetermined. The fragment size of cfDNA sheds important insights on elucidating the process. Previous studies qualitatively concluded that tumor-derived cfDNA is shorter than cfDNA from healthy cells, but the exact size distribution of tumor-derived cfDNA remains unclear. To better understand the mechanism of cfDNA generation and directly study cfDNA of tumor origins, we analyzed the deep targeted sequencing results of cfDNA from 605 patients with various cancer types, and developed a method that separates tumor cfDNA through identification of somatic variant alleles-containing fragments. We show that tumor-derived cfDNA has an increased proportion of fragments less than 150bp compared to healthy controls, while the most common size is still 166 bp. It has been speculated that differences in nucleosome wrapping may contribute to differing fragment lengths of cfDNA.To better understand the relationship between the magnitude of chromatin packaging and cfDNA length, we quantitatively analyzed the size distribution of cfDNA collected from 5 cancer patients in genomic regions with the varying degree of chromatin openness. We discovered that the fragment size of cfDNA was closely associated with chromatin inaccessibility and chromosome condensation as measured by transcriptional start sites, DNase I hypersensitivity, histone modifications, and Giemsa banding, or as implied by chromosomal sub-nuclear localization. The shortening occurs at both 5' and 3' ends of cfDNA fragments without bias. Taken together, these results collectively established a positive correlation between cfDNA fragment size and chromatin inaccessibility.
Citation Format: Hui Xia, Xingya Li, Hua Bao, Xiangyuan Ma, Xue Wu, Yang W. Shao, Feixiang Wu, Shucai Zhang. The effects of chromatin structure on variation in fragment size of cell free DNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-024.
Abstract LB-037: 3D organoids from milligrams of genitourinary cancer patients tissue retain key features of original tumors
Authors: Wang Yue , Souza Glauco , Amato Robert J. 
Published: August 2018

Abstract
3D organoid culture, especially that generated from patient samples, is becoming prevalent as 2D cell culture models fail to provide clinical relevance. However, a relatively large amount of starting tissue is still required for this process, and the turnover rate and overall success rate vary greatly if relying solely on spontaneous aggregation. Here, we report the successful use of magnetic 3D bioprinting to drive organoid formation derived from fresh tumor samples of patients with prostate cancer, renal cell cancer, and urothelial cancer. Only milligrams to tens of milligrams of starting tissues (from fine-needle biopsies, core biopsies, or surgical excision) were used. Most organoids formed overnight, with a very high overall success rate (&gt95%, n = 25). We have demonstrated that these cultures can be maintained, passed, and cryopreserved like conventional 2D cultures. More importantly, we characterized the organoids derived from prostatic adenocarcinomas and neuroendocrine tumors by the means of immunostaining and showed that the organoids expressed the same signature proteins as the originating tumors. This clinical concordance is crucial for downstream translational and biological research. We also showed that these adenocarcinoma cells responded to enzalutamide, an androgen receptor inhibitor that is used clinically to treat prostatic adenocarcinoma. In summary, we have established an efficient and robust system to create patient-derived 3D organoids; molecular characterization shows clinical concordance with original patient tumors; and our system shows great potential in drug screening with patient-derived 3D cultures.
Citation Format: Yue Wang, Glauco Souza, Robert J. Amato. 3D organoids from milligrams of genitourinary cancer patients tissue retain key features of original tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-037.
Abstract LB-057: Hypoxia regulation of antigen presentation machinery expression in breast cancer
Authors: Ng Mei Rosa , Sabbatino Francesco , Duquette Mark , Naxerova Kamila , Badeaux Mark , Ferraro Gino B. , Chin Shan M. , Bezwada Divya , Brachtel Elena F. , Ferrone Soldano , Jain Rakesh K. 
Published: August 2018

Abstract
Antigen presentation plays a major role in tumor cell recognition and targeting by immune cells, and is critical to the success of many cancer immunotherapies. How the abnormal tumor microenvironment affects tumor cell antigen presentation is unclear. Hypoxia is a prevalent feature of the tumor microenvironment. Here, we showed that the expression of major histocompatibility complex class I (MHCI) is associated with regions of hypoxia in human breast tumors. The association between hypoxia and MHCI is independent of the breast tumor hormone receptor and HER2 expression status. In vitro studies revealed that hypoxia directly regulates the expression levels of MHCI along with other components of the antigen presentation machinery. Multiple kinase regulators of MHCI expression are responsive to hypoxia. These results suggest that hypoxia effects on cancer cell antigen presentation may be a potential mechanism of tumor immune evasion and treatment resistance.
Citation Format: Mei Rosa Ng, Francesco Sabbatino, Mark Duquette, Kamila Naxerova, Mark Badeaux, Gino B. Ferraro, Shan M. Chin, Divya Bezwada, Elena F. Brachtel, Soldano Ferrone, Rakesh K. Jain. Hypoxia regulation of antigen presentation machinery expression in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-057.