bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT172: Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC)
Authors: Mehta Minish P , Gondi Vinai , Ahluwalia Manmeet , Brown Paul D. 
Published: August 2019

Abstract
Background: Tumor Treating Fields (TTFields) are non-invasive, loco-regional, anti-mitotic treatment modality comprising low intensity alternating electric fields. TTFields has demonstrated efficacy in non-small cell lung cancer (NSCLC) in 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. This prospective, multicenter study [NCT02831959] investigated the efficacy, safety and neurocognitive outcomes of TTFields in NSCLC patients with brain metastases.
Methods: NSCLC patients (N=270) with 1-10 brain metastases are randomized 1:1 to stereotactic radio surgery (SRS) followed by continuous TTFields ((150 kHz, &gt; 18 hours/day) within 7 days of SRS or supportive care. The TTFields portable device delivers TTFields to the brain using 4 transducer arrays and allows normal daily activities. Patients receive the best standard-of-care for their systemic disease. Patients are followed every two months until second intracranial progression. Patients in the control arm are allowed to cross over to TTFields arm at the time of second intracranial progression. Key inclusion criteria: KPS ≥70, new diagnosis of 1 inoperable or 2-10 supra- and/or infratentorial brain metastases from NSCLC amenable to SRS; KPS ≥70; and optimal therapy for extracranial disease. Prior WBRT or surgical resection of metastases, a single resectable lesion or recurrent brain metastases were exclusionary. Primary endpoint was time to 1st intracranial progression. Secondary endpoints included time to neurocognitive failure (HVLT, COWAT and TMT), overall survival, radiological response rate (RANO-BM and RECIST V1.1); quality-of-life; adverse events; time to first/second intracranial progression for patients with 1-4 and 5-10 brain metastases; bi-monthly intracranial progression rate from 2-12 months; and time to second intracranial and distant progression. 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: Minish P Mehta, Vinai Gondi, Manmeet Ahluwalia, Paul D. Brown. Phase III METIS study: Tumor Treating Fields (150 kHz) and radiosurgery for supra- and/or infratentorial brain metastases (1-10) from non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT172.
Abstract CT175: HEPANOVA Phase II study design for advanced hepatocellular carcinoma: Tumor treating fields concomitant with sorafenib
Authors: Grosu Anca-Ligia , Gkika Eleni , Brunner Thomas , Thimme Robert , Weinberg Uri 
Published: August 2019

Abstract
Background Tumor Treating Fields (TTFields) are a non-invasive, regional antimitotic treatment modality, which has been approved for the treatment of glioblastoma by the FDA. TTFields predominantly act by disrupting the formation of the mitotic spindle during metaphase. TTFields were effective in multiple preclinical models of hepatocellular carcinoma (HCC), leading to a significant increase in cell death. The Phase II HEPANOVA study is the first trial testing TTFields in HCC patients, and is designed to test the safety and efficacy of adding TTFields to sorafenib in advanced HCC.
Methods Trial Design: Patients (N=25) with unresectable HCC who are not amenable to any local treatment will be enrolled in this prospective, single-arm study. The study enrolls patients with ECOG score of 0-2 and Barcelona clinic liver cancer (BCLC) stage 0-C. Patients must have a measurable disease per RECIST Criteria. Having implanted electronic devices in the torso is exclusionary. Sorafenib will be administered at standard dose (400 mg daily). TTFields (150 kHz) will be delivered for 18 hours/day until local disease progression per RECIST Criteria. Clinical follow up will be performed q4w, and a CT/MRI scan q12w. Following disease progression in the liver, patients will discontinue TTFields and be followed monthly for survival. Overall response rate will be the primary endpoint and in-field control rate, progression-free survival rate at 12 month (PFS12), OS rate at 1 year and toxicity will all be secondary endpoints. Sample size was calculated using an Exact test for proportions considering the weighted average of ORR of patients who had either complete or partial response per RECIST criteria in historical studies with sorafenib is 4.5%. A sample size of 25 patients was required to achieve a power of approximately 80% at a one-sided alpha level of 0.05 using a single sample Exact test for proportions.
Citation Format: Anca-Ligia Grosu, Eleni Gkika, Thomas Brunner, Robert Thimme, Uri Weinberg. HEPANOVA Phase II study design for advanced hepatocellular carcinoma: Tumor treating fields concomitant with sorafenib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT175.
Abstract LB-002: SQ3370 enhances the safety of chemotherapeutics via local activation therapy
Authors: Yee Nathan A. , Srinivasan Sangeetha , Royzen Maksim , Oneto Jose M. Mejia 
Published: August 2019

Abstract
With systemic chemotherapy, only 1-2% of the administered dose actually reaches a localized tumor, while the remaining leads to adverse off-target toxicities, including immunosuppression. Hence, there is a critical need to locally deliver cytotoxics directly to the tumor. Our patented approach (SQ3370) consists of:
(1) SQL70 - a drug-activating biomaterial carrying no payload
(2) SQP33 - a chemically-modified prodrug of doxorubicin (Dox) with attenuated activity.
SQL70 is injected at the tumor site followed by SQP33 administered systemically. The prodrug first concentrates to the biomaterial at the tumor site due to their complementary chemical reactivities. The active drug is then spontaneously released over multiple days, providing sustained local delivery directly to the tumor region while reducing systemic side effects.
Previously, we have shown that the greater safety of SQP33 allows it to be given at over 38 times the dose of standard Dox in SQL70-injected mice. Pharmacokinetic and biodistribution studies in SQ3370-treated rodents and dogs show that SQP33 disappears from plasma within the first hour of administration, likely due to the rapid concentration to SQL70. Without SQL70, SQP33 shows minimal spontaneous conversion to activated Dox. These studies also indicate that a single injection of SQL70 can activate multiple doses of SQP33, maximizing the local therapeutic index.
Recent studies demonstrate that SQ3370 treatment enhances therapeutic response and survival in tumor-bearing mice: In a syngeneic MC38 colorectal cancer model, SQ3370 slowed tumor progression in 8/10 mice, showing improved efficacy compared to standard Dox or anti-PD-1 therapy.
In mice bearing dual tumors, with one tumor site injected locally with SQL70, we observed that SQP33 can induce a response in both primary and secondary tumors, suggestive of an anti-tumor immune activation effect. Furthermore, we found that SQ3370 synergizes with anti-PD-1, expanding potential treatment options in the clinic and highlighting the advantages of immune-sparing cytotoxic therapy.
Collectively, our results demonstrate that SQ3370 enables delivery of cytotoxic drugs to a target site while limiting exposure in off-target tissues in small and large animals, leading to improvements in both safety and efficacy.
Citation Format: Nathan A. Yee, Sangeetha Srinivasan, Maksim Royzen, Jose M. Mejia Oneto. SQ3370 enhances the safety of chemotherapeutics via local activation therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-002.
Abstract LB-016: Radiochemotherapy combined with NK cells followed by a second-line PD-1 inhibition in a patients with NSCLC stage IIIb induces long-term tumor control
Authors: Multhoff Gabriele , Kokowski Konrad , Hildebrandt Martin , Vaupel Peter , Stangl Stefan 
Published: August 2019

Abstract
Advanced stage NSCLC is a fatal disease with poor prognosis. Following radiochemotherapy (RCT) tumor progression occurs after 5.6 months in stage III NSCLC patients. We identified membrane heat shock protein 70 (mHsp70) as a biomarker for high-risk NSCLC. Furthermore, mHsp70 serves as a tumor-specific target for NK cells that had been stimulated with Hsp70-peptide (TKD) and IL-2. In this study, a patient with mHsp70 positive inoperable NSCLC (cT4, cN3, cM0, stage IIIb) was treated for the first time with a combined therapy consisting of RCT (64.8 Gy), 4 cycles of mHsp70-targeting, autologous NK cells and PD-1 antibody, as a second-line therapy.
Adoptive transfer of ex vivo Hsp70-activated NK cells after RCT combined with PD-1 inhibition was well tolerated and resulted in a superior OS. No viable tumor cells, but a massive immune cell infiltration of T and NK cells in fibrotic tissue were detected after therapy. Neither tumor progression nor distant metastases were detectable by CT-scanning 35 months after diagnosis. Therapy response was associated with significantly increased CD3-/NKG2D+/CD94+ NK cell counts, elevated CD8+ to CD4+ T cell, CD3-/CD56bright to CD3-/CD56dim NK cell ratios, and significantly reduced regulatory T cells (Tregs) in the peripheral blood. In summary, a combined immunotherapy consisting of RCT, mHsp70-targeting NK cells and PD-1 antibody inhibition is well tolerated, induces anti-tumor immune responses and results in long-term tumor control in a patient with advanced NSCLC.
Citation Format: Gabriele Multhoff, Konrad Kokowski, Martin Hildebrandt, Peter Vaupel, Stefan Stangl. Radiochemotherapy combined with NK cells followed by a second-line PD-1 inhibition in a patients with NSCLC stage IIIb induces long-term tumor control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-016.
Abstract LB-018: Orally active small molecule PD-L1 inhibitor demonstrating similar efficacy as Durvalumab in human knock-in MC38 model
Authors: Wang Yuguang , Zhang Nong , Wang Feilan , Zhao Qiang , Li Zenggang 
Published: August 2019

Abstract
Cancer immunotherapy with PD-1/PD-L1 antibody drugs has made tremendous progress in clinical application. It was also recognized by the scientific community with awarding of the 2018 Nobel Price. However, the discovery of orally active, small molecule drugs targeting PD-1/PD-L1 pathway remains highly challenging. We wish to report for the first time the similar efficacy as measured by TGI between small molecule inhibitor Max-10181 and Durvalumab in the head to head test of human PD-L1 knock-in MC38 cell line in human PD-1 knock-in mice. In addition, we would also like to report the superior efficacy of Max-10181 to mouse anti-PD-1 Ab in PD-L1 expression low syngeneic mouse 4T1 model. Our data indicated that small molecule drugs may have different dependency of PD-L1 expression level. As a result, they may have different therapeutic application in clinics. Furthermore, the data related to the mechanistic aspect of these observed results will also be discussed.
Citation Format: Yuguang Wang, Nong Zhang, Feilan Wang, Qiang Zhao, Zenggang Li. Orally active small molecule PD-L1 inhibitor demonstrating similar efficacy as Durvalumab in human knock-in MC38 model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-018.
Abstract LB-027: Evaluation of EGFR induced on-target and target-mediated adverse effects in a 3D human lung tumour/skin microphysiological co-culture system
Authors: Huebner Juliane , Raschke Marian , Schimek Katharina , Ruetschle Isabel , Graessle Sarah , Schnurre Susanne , Lauster Roland , Maschmeyer Ilka , Steger-Hartmann Thomas , Marx Uwe 
Published: August 2019

Abstract
Organs-on-a-chip or microphysiological systems (MPS) are increasingly contributing to the preclinical characterization of mode of action and adverse events of drug candidates. The recent advent of robust human multi-organ-chip systems enables the establishment of co-cultures of human drug target tissues with healthy organ equivalents prone to off-target effects of the respective drug. The prediction of side effects, such as those occurring in the skin during cancer therapies with antibodies against the epithelial growth factor receptor (EGFR), is currently not possible in conventional in vitro systems and limited in existing animal models due to phylogenetic differences between species.
Here we present a chip-based 5-day co-culture of human lung tumour spheroids (mucoepidermoid carcinoma H292) and human skin equivalents. We investigated the impact of repeated cetuximab exposure, an antibody against the EGF receptor to the co-culture and compared it with the effects on individual tissue cultures. Cetuximab showed an increased pro-apoptotic related gene expression in the tumor microtissues, and, simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated. Additionally, we compared the tumor-target related antibody effects with response data for afatinib - a small molecule EGFR inhibitor. Cetuximab showed an increased pro-apoptotic related gene expression in the tumor microtissues, and, simultaneously, proliferative keratinocytes in the basal layer of the skin microtissues were eliminated.
The described MPS has the potential to provide a single platform for in vitro evaluation of the therapeutic window of drug candidates.
Citation Format: Juliane Huebner, Marian Raschke, Katharina Schimek, Isabel Ruetschle, Sarah Graessle, Susanne Schnurre, Roland Lauster, Ilka Maschmeyer, Thomas Steger-Hartmann, Uwe Marx. Evaluation of EGFR induced on-target and target-mediated adverse effects in a 3D human lung tumour/skin microphysiological co-culture system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-027.
Abstract LB-029: Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow
Authors: Xu Haiyan , Muise Eric S. , Javaid Sarah , Chen Lan , Cristescu Razvan , Mansueto My Sam , Follmer Nicole , Cho Jennifer , Kerr Kimberley , Altura Rachel , Machacek Michelle , Nicholson Benjamin , Addona George , Kariv Ilona , Chen Hongmin 
Published: August 2019

Abstract
Acute myeloid leukemia (AML) is a malignancy with complex genetics, poor survival rates and high rates of chemotherapy resistance. This study reports the establishment of a novel bone marrow mononuclear cell 3D-culture model and the application of this model to define sensitivity and resistance biomarkers as evident by DNA and RNA expression signatures in response to standard Cytarabine (Ara-C) chemotherapy. By simulating the bone marrow microenvironment, we optimized the growth conditions using frozen bone marrow mononuclear cells (BMMC) derived from healthy donors. We validated our platform by demonstrating that healthy BMMCs are capable of differentiating into all hematopoietic lineages and various types of stromal cells. Using this platform, we then characterized BMMC samples from 47 AML patients. Sixty percent of AML samples were capable of proliferating and 23 samples demonstrated robust growth. RNA sequencing was performed for 3D and 2D cultures to determine which conditions are superior at maintaining original gene expression signatures as compared to the uncultured bone marrow, To elucidate specific genetic mutations and/or gene expression signatures associated with the ability of ex vivo growth of these AML donors, whole exosome sequencing and RNA Sequencing were performed. The model identified unique gene expression signatures that correlated with sensitive as well as resistant donors in response to Ara-C treatment. These data demonstrate the translational value of our platform which should be widely applicable to evaluate other therapies in AML.
Citation Format: Haiyan Xu, Eric S. Muise, Sarah Javaid, Lan Chen, Razvan Cristescu, My Sam Mansueto, Nicole Follmer, Jennifer Cho, Kimberley Kerr, Rachel Altura, Michelle Machacek, Benjamin Nicholson, George Addona, Ilona Kariv, Hongmin Chen. Identification of predictive genetic signatures of Cytarabine responsiveness in acute myeloid leukemia using a novel 3D translational culture model of primary bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-029.
Abstract LB-041: Targeting AKT2 and ERK decline the drug/radiation resistance in neuroblastoma
Authors: Kim Kwang Woon , Chung Dai , Qiao Jingbo , Kim Julia , Poewers Camille , Correa Hernan , Park Kyungho , Lee Sora 
Published: August 2019

Abstract
Introduction: Neuroblastoma is highly heterogeneous, containing cancer cells with very different molecular characteristics. Activation of distinct signal transduction pathways can induce neuroblastoma cells to transform cells with neuronal, chromaffin, or schwannian phenotypes, further supporting the existence of cancer stem cells. We previously demonstrated that AKT2 plays critical roles in regulation of neuroblastoma tumorigenesis. Here we hypotheize that targeting AKT2 would block the signal transduction pathways enhanced in drug/radiation resistant neuroblastoma cancer stem cells.
Methods: We generated cisplatin (CDDP) resistant and radiation (Rad) resistant neuroblastoma cells under the treatment or irradiation with a concentration of IC 50 of CDDP and 137Cs irradiator respectively. Cell viability was assessed with CCK-8 kit daily. Extreme limiting dilution analysis (ELDA) was performed for quantification of tumor sphere formation. Immunoblotting detected the expression of stem cell markers CD133, Sox2, ALDH, ALDH, Nestin, Oct4 and Nanog, as well as survival signaling pathway key molecules AKT2, MAPK and P38 MAPK.
Results: We founded that two important cell proliferation and survival signaling pathways mTOR, downstream of AKT2 and MAPK enhanced in CDDP-resistant and Rad-resistant neuroblastoma cells. Blocking these two pathways with chemical inhibitors, CCT128930, AKT2 selective inhibitor and PD98059, MEK inhibitor decreased cell proliferation, angiogenesis, cell migration and soft agar conoly growth in these resistant cells. We further demonstrated that these resistant cells showed higher capacity of sphere-forming with increased expression of stem cell markers CD133, Sox2, ALDH, ALDH, Nestin, Oct4 and Nanog. Improtantly, the sphere formation of these resistant cells is sensitive to the inhibitors of AKT2 and MAPK.
Conclusion: Our results suggest that selected CDDP-resistant and radiation-resistant neuroblastoma cells might serve as an useful tool to improve understanding of the molecular mechanisms of therapeutic resistance and develop more effective novel treatment strategies, and further to reaching better clinical outcomes of patients with neuroblastoma.
Citation Format: Kwang Woon Kim, Dai Chung, Jingbo Qiao, Julia Kim, Camille Poewers, Hernan Correa, Kyungho Park, Sora Lee. Targeting AKT2 and ERK decline the drug/radiation resistance in neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-041.
Abstract LB-065: A high quality neoantigen fitness model cooperates with T lymphocyte infiltrates to identify glioblastoma patients with the longest survival
Authors: Zhang Jing , Caruso Francesca P. , Sa Jason K. , Justesen Sune , Nam Do-Hyun , Sims Peter , Ceccarelli Michele , Lasorella Anna , Iavarone Antonio 
Published: August 2019

Abstract
Malignant glioma (glioblastoma, GBM) is a lethal cancer resistant to multimodality therapeutic approaches. A high burden of tumor-specific mutant peptides (neoantigens) correlates with a more favorable prognosis and response to immunotherapies in selected solid tumors but the role of neoantigens and how they impact clinical outcome in most tumors including GBM remains unclear. Here, we exploited the similarity between tumor neoantigens and infectious disease-derived immune epitopes and applied a neoantigen fitness model for the identification of high quality neoantigens in human GBM. The neoantigen quality fitness model stratified GBM patients with more favorable clinical outcome and, together with tumor infiltration of CD8 T lymphocytes, identified a subgroup of GBM patients with the longest survival, thus exhibiting optimal performance. Conversely, neither tumor neoantigen burden from a quantity model nor the isolated enrichment of CD8 T lymphocytes could predict better survival of GBM patients. The GBM subgroup that emerged from the neoantigen quality model displays distinct genomic and transcriptomic features that should guide patient stratification for immunotherapy and maximal benefit of GBM patients.
Citation Format: Jing Zhang, Francesca P. Caruso, Jason K. Sa, Sune Justesen, Do-Hyun Nam, Peter Sims, Michele Ceccarelli, Anna Lasorella, Antonio Iavarone. A high quality neoantigen fitness model cooperates with T lymphocyte infiltrates to identify glioblastoma patients with the longest survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-065.
Abstract LB-092: TKI insensitive role of EGFRconfers TKI resistance via PKCδ
Authors: Lee Pei-chih , Hung Mien-chie 
Published: August 2019

Abstract
EGFR TKI-insensitive pathway confers heterogeneous mechanisms of TKI resistance via PKCδ in EGFR-mutant lung cancer. Multiple mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been identified in EGFR-mutant non-small cell lung cancer (NSCLC); however, recurrent resistance to EGFR TKIs due to the heterogeneous mechanisms underlying resistance within a single patient remains a major challenge in the clinic. Here, we report a role of EGFR heterodimer-mediated nuclear PKCδ as a common axis across multiple known TKI-resistance mechanisms. Specifically, we demonstrate that TKI-inactivated EGFR dimerizes with other membrane receptors implicated in TKI resistance to promote PKCδ nuclear translocation. Moreover, the level of nuclear PKCδ is upregulated in a significant portion of patients (~41.5%) with TKI-resistant NSCLC and is associated with TKI response in patients. The combined inhibition of PKCδ and EGFR induces marked regression of resistant NSCLC tumors with EGFR mutations. These results provide mechanistic insights into the role of the EGFR-PKCδ axis in TKI-resistance and suggest an EGFR addiction in TKI-resistant EGFR-mutant NSCLC.
Citation Format: Pei-chih Lee, Mien-chie Hung. TKI insensitive role of EGFRconfers TKI resistance via PKCδ [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-092.