bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B117: Phase II study of brentuximab vedotin and bevacizumab in GCT
Authors: Gupta Shilpa , Maughan Benjamin L. 
Published: August 2018

Abstract
Background: Outcomes in refractory germ cell tumors (GCT) after failure of platinum-based chemotherapy are poor with complete responses with salvage chemotherapy being rare and short-lived. Patients progressing after ≥2 lines of chemotherapy have a dismal prognosis and die from disease. Novel therapies and combination strategies are urgently needed. Cluster of Differentiation antigen-30 (CD30) is expressed in embryonal carcinoma, implicating CD-30 as a target in CD-30+ GCT. Brentuximab vedontin (BV) is an antibody-drug conjugate that combines mono-methyl auristatin E (MMAE) with a CD-30 specific monoclonal antibody, and has shown promising activity in CD30+ GCT. VEGF is involved in tumor development, angiogenesis, and metastasis in GCT, and anti-VEGF monoclonal antibody, bevacizumab, has shown activity in GCT. BV and bevacizumab may be synergistic in refractory CD30+ GCT with no potentially overlapping toxicities. Methods: This is a multicenter phase II study of BV and bevacizumab for the treatment of refractory CD-30+ GCT after disease progression on imaging and/or tumor marker progression with serially rising AFP or bHCG. Patients must have received ≥ 2 lines of platinum-based chemotherapy, but only 1 prior line will be allowed if the patient is ineligible or refuses further platinum-based chemotherapy. For primary mediastinal GCT, failure of 1st-line chemotherapy is allowed. Expression of CD-30 (1% or more) in archival or fresh biopsy is required for eligibility. Primary objective is objective response rate. Secondary objectives are safety and tolerability, PFS, and OS. Exploratory objectives include correlation of clinical outcomes with CD-30 expression in tumors and blood and VEGF level in blood, and presence of circulating tumor cells (CTCs) and correlation with clinical outcomes. BV and bevacizumab will be given every 21 days at doses of 1.8 mg/kg and 15mg/kg, respectively, until disease progression or unacceptable toxicity; intrapatient dose reduction of BV to 1.2 mg/kg will be allowed. A total of 21 patients will be enrolled and results from this study will provide an insight into the safety and efficacy of this combination in refractory CD-30+ GCT. (NCT02988843)
Citation Format: Shilpa Gupta, Benjamin L. Maughan. Phase II study of brentuximab vedotin and bevacizumab in GCT [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B117.
Abstract B118: Potentiation of IL-2’s antitumor efficacy without compromised tolerability by a novel human antibody
Authors: Johnson Kirk , Li Ou , Liu Xiaohe , Beviglia Lucia 
Published: August 2018

Abstract
IL-2 was the first approved cancer immunotherapy and is still recognized for its durable responses. While IL-2 does mobilize relevant antitumor immune cells such as CD8+ T effector and activated NK cells, its utility is limited by parallel expansion of Treg cells and by dose-limiting toxicities. IL-2 Receptor alpha chain binding by IL-2 may be important in driving Treg expansion and some adverse side effects. Over the last decade, there have been approaches at modifying IL-2 structure-function or selecting antibodies that bind IL-2 and bias its activation of preferential cell types. One candidate (pegylated IL-2, NKTR-214) has moved into clinical development. XOMA mAb19 is a fully human monoclonal antibody to IL-2 that selectively compromises binding to IL-2R alpha chains, but not beta-gamma chains, thus potentially expanding IL-2’s antitumor therapeutic index. mAb19 binding characteristics and efficacy in a mouse Lewis Lung Carcinoma model were described at SITC 2016. In the current studies, a CT26 mouse colon carcinoma model was utilized to assess antitumor efficacy and tolerability of combined mAb19 + low-dose IL-2 dosing and to compare such with standard high-dose IL-2 regimens. The CT26 study results presented here demonstrate that mAb19 and IL-2 coadministration potentiates IL-2’s antitumor activity, expands CD8+ T effector and activated NK cells but not Treg cells, and is well tolerated. Specifically, treatment of tumor-bearing mice with about 1 mg/kg mAb19 plus about 0.1 mg/kg IL-2 yielded significant antitumor efficacy, which was at least as substantial as high-dose (e.g. 5 mg/kg) IL-2 regimens wherein significant body weight loss and ~10% mortality were observed. Notably, the mAb19 + IL-2 regimen had no dose-limiting toxicity. Moreover, the magnitude of antitumor response of the combination mAb19+IL2 was superior to that reported for NKTR-214 in the same model (AACR 2015). Preclinical development continues, including assessment for enhanced efficacy with checkpoint inhibitor(s).
Citation Format: Kirk Johnson, Ou Li, Xiaohe Liu, Lucia Beviglia. Potentiation of IL-2’s antitumor efficacy without compromised tolerability by a novel human antibody [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B118.
Abstract B146: A novel TNIK inhibitor potently downregulates cancer stem cell population through attenuation of Wnt signaling
Authors: Uno Yuko , Moriyama Hideki , Kashimoto Shigeki , Masuda Mari , Sawa Masaaki , Yamada Tesshi 
Published: August 2018

Abstract
Background: TNIK (Traf2- and Nck-interacting kinase) has been identified as a component of the β-catenin and T-cell factor 4 (TCF4) complex that regulates the downstream of Wnt signaling. Recent studies indicated that the Wnt pathway is highly activated in cancer stem cells (CSCs), which have been recognized as the driving force of tumorigenesis and mediating tumor recurrence. Thus, eradicating CSCs by inhibiting Wnt signaling may become a new therapeutic option for a complete cure of cancers. Recently we have demonstrated that TNIK is required for the tumor-initiating function of colorectal CSCs, and therefore TNIK is considered to be attractive targets for drug discovery. We have discovered a thiazole-based TNIK inhibitor having potent inhibitory activity for the Wnt signaling. Further optimization of the thiazole-based TNIK inhibitor resulted in an orally available novel TNIK inhibitor, NC-1. In this study, we evaluated in vivo efficacy of the TNIK inhibitor in mouse models as well as its effects on CSCs in vitro. Materials and Methods: To evaluate the effects of NC-1 on the CSCs in SW620, human colon cancer cells, the enzymatic activity of aldehyde dehydrogenase (ALDH) was analyzed by flow cytometry using an Aldefluor assay. The expression of CSCs surface marker protein, CD133, was analyzed using flow cytometry. Antitumor efficacy of NC-1 was evaluated in a human colorectal tumor xenograft mouse model. Results: We demonstrated that treatment of cancer cells with NC-1 significantly downregulated ALDH positive cell population in a dose-dependent manner. In addition, NC-1 suppressed cell surface expression of CD133 in a dose-dependent manner, suggesting that NC-1 preferentially killed CSCs population in vitro. Furthermore, NC-1 inhibited tumor growth in the HCT116 xenograft mouse model.
Citation Format: Yuko Uno, Hideki Moriyama, Shigeki Kashimoto, Mari Masuda, Masaaki Sawa, Tesshi Yamada. A novel TNIK inhibitor potently downregulates cancer stem cell population through attenuation of Wnt signaling [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B146.
Abstract B178: Targeting Myc in triple-negative breast cancer models through the dual inhibition of PIM kinases and CDK9
Authors: Haws Hillary , Kim Wontak , Siddiqui-Jain Adam , Bearss David J. , Warner Steven L. , Whatcott Clifford J. 
Published: August 2018

Abstract
Of the more than 240,000 estimated new cases of breast cancer in 2016 (US), triple-negative breast cancer (TNBC) was expected to comprise roughly 12%. So named because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression, TNBCs pose a unique therapeutic challenge, with only chemotherapeutic options currently available. New therapeutic options are desperately needed for patients with TNBC. Recent reports have identified a cellular addiction of TNBCs to PIM1, suggesting that the addiction is mediated by PIM regulation of Myc and BH3 proteins MCL-1 or BCL-2. The PIM family of serine/threonine kinases are highly conserved and the link between PIM and Myc function has been well studied. The second-generation PIM inhibitor, TP-3654, has been shown to suppress Myc expression in vitro. Additionally, CDK9 inhibitors are also known to suppress Myc expression. CDK9 inhibition mediates specific reductions in transcription of short-lived mRNAs such as Myc and MCL-1. The CDK9/cyclin T complex is a critical component of the P-TEFb complex, promoting productive RNA elongation through phosphorylation of serine 2 of the heptapeptide repeats of the C-terminal domain of RNA Polymerase II (RNAPII-CTD). We are developing a potent CDK9 inhibitor, alvocidib, and an oral prodrug form of alvocidib named TP-1287, and are investigating the potential clinical utility of CDK9 inhibition in acute myeloid leukemia (AML). We hypothesized that PIM and CDK9 inhibition would be an active combination in models of TNBC due to the added effect of targeting Myc through two independent mechanisms. In the TNBC cell line, MDA-MB-231, TP-3654 reduced relative Myc protein expression by 74%, while alvocidib reduced expression by 71%. The combination of TP-3654 and alvocidib reduced detectable expression 100%, as measured by standard immunoblotting, at concentrations of 100 nM with a 3-hour treatment. To test this hypothesis in vivo, TP-3654 and TP-1287 were tested in the MDA-MB-231 xenograft. Single-agent TP-3654 (150 mg/kg) reduced tumor growth (%TGI) 40.7%, while TP-1287 (3.75 mg/kg) reduced tumor growth 11.6%. The combined-treatment regimen reduced tumor growth by 58.3% at day 18 of treatment. These results support a rationale for further clinical investigation of PIM and CDK9 inhibitors for the suppression of Myc in patients with TNBC.
Citation Format: Hillary Haws, Wontak Kim, Adam Siddiqui-Jain, David J. Bearss, Steven L. Warner, Clifford J. Whatcott. Targeting Myc in triple-negative breast cancer models through the dual inhibition of PIM kinases and CDK9 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B178.
Abstract B188: DNA topoisomerase-mediated transcription-replication conflicts cause DNA damage by a transient increase of R loops and proteasome activity
Authors: Marinello Jessica , Delcuratolo Maria , Pommier Yves , Binaschi Monica , Pellacani Andrea , Capranico Giovanni 
Published: August 2018

Abstract
DNA topoisomerases have an important function in preventing replication/transcription (R/T) conflicts caused by RNA polymerases elongating in the opposite (or same) direction of advancing replication fork. Published data demonstrated that such persistent R/T conflicts can be rescued by overexpression of RNase H1, which specifically degrades the RNA of DNA:RNA hybrids present in R-loop structures. R loops are a common non-B DNA structure of cellular genomes that mainly occur during transcription. R loops can lead to genome instability; however, they also play a role in important cellular functions. Here, we have determined the dynamics of cellular R loops generated by chemical poisoning of DNA topoisomerases (TOP1 and TOP2) and the role of the proteasome in DNA damage induction by performing detailed kinetics analyses of cellular R loops by immunofluorescence microscopy. Treatment of HeLa and U2OS cells with clinically used topoisomerase inhibitors (camptothecin, LMP-776, MJ-III-65, doxorubicin, sabarubicin) triggers an immediate increase of nucleoplasmic R loops from 2 to 10-20 minutes of treatment, followed by a dramatic reduction of R-loop levels at 1 hour. Concomitantly with the reduction of R-loop structures, DNA damage was detected as phosphorylation of histone H2AX, a marker of DNA double-stranded breaks (DSB). Pretreating cells with MG132 (a proteasome inhibitor) stabilized the presence of R loops at longer treatment times and concomitantly reduced DSB formation, suggesting that the degradation of poisoned topoisomerases is necessary to trigger the pathway resulting in DSB formation. Overexpression of RNaseH1 in U2OS cells abolishes the transient increase of R loops and the induction of DNA damage. Topoisomerase poisoning is able to effectively kill the studied human cancer cells. However, overexpression of RNaseH1 or MG132 markedly reduced cell killing induced by R/T conflicts generated by topoisomerase inhibitors. The results are overall consistent with a necessary function of nuclear proteasome in generating a free DNA break from abortive topoisomerase cleavage complexes that will eventually lead to DSBs.
Citation Format: Jessica Marinello, Maria Delcuratolo, Yves Pommier, Monica Binaschi, Andrea Pellacani, Giovanni Capranico. DNA topoisomerase-mediated transcription-replication conflicts cause DNA damage by a transient increase of R loops and proteasome activity [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B188.
Abstract B195: Immune microenvironment change after acquiring resistance to EGFR TKI therapy in EGFR mutant non-small cell lung cancer
Authors: Kim Tae-Jung , Kang Jin-Hyoung , Hong Sook-hee 
Published: August 2018

Abstract
Introduction: The efficacy of anti-programmed death-1 therapy in EGFR mutant NSCLC is limited. We hypothesized that immune microenvironment was different before and after developing acquired resistance to EGFR-TKI (tyrosine kinase inhibitor) therapy. We evaluated the change of the tumor proportion score (TPS) of programmed death-ligand 1 (PD-L1) and intratumoral CD8+ tumor-infiltrating lymphocyte (TIL) in EGFR mutant NSCLC. Materials and Methods: We identified 44 patients with sufficient paired tumor tissues before and after EGFR-TKI therapy available for analysis. PD-L1 expression on tumor cells was defined by immunohistochemical (IHC) stain with 22C3 pharmDx assay. Intratumoral CD8+ TIL score was also defined by IHC stain. Results: According to paired pre- and post-TKI biopsies comparison, the degree of PD-L1 expression was consistent in both biopsies in 26 (59.1%) patients, but varied upon the development of resistance in 18 (40.9%), with 10 showing higher levels of PD-L1 expression in the resistant biopsy. The score of CD8+ TIL was consistent in both biopsies in 15 (34.1%) patients, but varied upon the development of resistance in 29 (65.9%), with 11 (25%) showing higher levels CD8+ TIL score in the resistant biopsy. Regarding exon 20T790M acquired mutation, only 2 (14.2%) of 14 specimens observed higher TPS of PD-L1 in post-TKI biopsies. We defined high post-TKI TPS of PD-L1 group who observed high TPS of PD-L1 in post-TKI compared to paired pre-TKI biopsies or post- TKI TPS of PD-L1 ≥50%. The post-TKI high TPS of PD-L1 group tended to decrease CD8+ TIL score . 8 observed post-TKI TPS of PD-L1 ≥50% and 7 of 8 observed low CD8+ TIL score. The median progression-free survival of first-generation EGFR-TKI in these 7 patients was statistically significantly lower than the others (6.6 months vs 14.0 months, respectively; P=0.0105). Conclusions: The TPS of PD-L1 and CD8+ TIL score changed after EGFR-TKI therapy. High TPS of PD-L1 and low CD8+ TIL in post-TKI EGFR mutant NSCLC could be related to EGFR-TKI resistance. Before considering anti-PD-1 therapy, reevaluation of PD-L1 should be considered.
Citation Format: Tae-Jung Kim, Jin-Hyoung Kang, Sook-hee Hong. Immune microenvironment change after acquiring resistance to EGFR TKI therapy in EGFR mutant non-small cell lung cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B195.
Abstract CN05-03: Precision therapeutics with DNA-damaging agents
Authors: Pommier Yves G. , Reinhold William C. , Murai Junko , Thomas Anish 
Published: August 2018

Abstract
Precision therapeutics can be defined as the ability to prescribe effective (curative) therapies only to those patients who will respond, while limiting toxicity to normal tissues and minimizing side effects. The paradigm for precision therapeutics is the BCR-ABL inhibitor imatinib (Gleevec) approved in 2001 for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). As DNA-damaging agents have been approved before the era of precision medicine, their use remains empirical. Some patients respond remarkably well while others only suffer from the drug side effects. The possibility of using DNA-damaging agents in the context of precision medicine changed with the approval of the poly(ADPribose) polymerase (PARP) inhibitors, which have been approved for patients with BRCA deficiencies and prior response to platinum drugs, and act as DNA-damaging agents by trapping PARP1 and PARP2 on DNA lesions. We will review the use of cancer cell line genomics to discover novel determinants of response to DNA-targeted agents, and to elaborate molecular signatures of response. We will also discuss the broad implications of the discovery of Schlafen 11 (SLFN11) as a novel determinant of response to PARP inhibitors, platinum derivatives, topoisomerase inhibitors, gemcitabine, hydroxyurea, and cytosine arabinoside. We will demonstrate the use of our novel crossdatabase (cdb) web-based tools to mine genomics and pharmacologic determinants of response and genomic signatures for anticancer drugs (https://discover.nci.nih.gov/cellminercdb).
Citation Format: Yves G. Pommier, William C. Reinhold, Junko Murai, Anish Thomas. Precision therapeutics with DNA-damaging agents [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN05-03.
Abstract CN07-01: Cellular plasticity in cancer: Driving force and therapeutic target
Authors: Brabletz Thomas 
Published: August 2018

Abstract
We have shown that in particular tumor cells at the invasive front undergo a partial epithelial-mesenchymal transition (EMT) and aberrantly express EMT-associated transcription factors (EMT-TFs). The amount of such cancer cells strongly correlates with metastasis formation and poor clinical outcome in human cancers. Strikingly, metastases show a mesenchymal-epithelial retransition (MET) with a redifferentiated phenotype, indicating high cancer cell plasticity and supporting a regulatory role of the tumor environment. We described that the EMT-TF ZEB1 is a crucial determinant of cellular plasticity. At the molecular level, ZEB1 is linked in a double-negative feedback loop with the miR-200 family and miR-203, which are strong inducers of epithelial differentiation. Thus, aberrant ZEB1 expression stabilizes EMT and stemness, thereby promoting dissemination, metastasis, and drug resistance of cancer cells. We have validated the findings by showing that a depletion of ZEB1 in the KPC-mouse model of pancreatic cancer counteracts tumor cell plasticity and metastasis. Moreover, we detected that ZEB1 controls the Notch pathway and directly cooperates with the Hippo-pathway effector YAP in driving aggressive cancer types. We determined epigenetic modifications conferred by ZEB1, and screened for epigenetic drug to restore expression of its silenced target genes and to subsequently overcome therapy resistance. Despite their potent tumor-promoting effects, EMT-TFs are rarely mutated in cancer. This likely is due to the necessity for a transient expression and the associated plasticity of cancer cells, underscoring the important role of nonmutated genes in cancer progression.
Citation Format: Thomas Brabletz. Cellular plasticity in cancer: Driving force and therapeutic target [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr CN07-01.
Abstract LB-A11: Targeting DNA-PK and the DNA damage response via small molecule Ku inhibitors
Authors: Turchi John J. , Gavande Navnath , VanderVere-Carozza Pamela S. , Vernon Tyler , Pawelczak Katherine S. 
Published: August 2018

Abstract
The DNA dependent protein kinase (DNA-PK) is a validated target for cancer therapeutics that drives the DNA damage response (DDR) and plays a critical role as a primary sensor in the non-homologous end joining (NHEJ) DNA double strand break (DSB) repair pathway. Various anti-cancer therapeutic strategies mediate their cytotoxic effects by inducing DSBs, including ionizing radiation (IR), and clinical outcomes are directly related to the repair of DNA damage. Modulating the pathway responsible for repairing DSBs will have a profound impact on the efficacy of DNA damaging agents in the clinic. To date, development of inhibitors for DNA-PK has focused on targeting the active site with ATP mimetics. We have taken the novel and innovative approach to inhibiting DNA-PK via blocking the Ku 70/80 heterodimer interaction with DNA, a necessary step in DNA-PK activation. Exploiting this unique mechanism of kinase activation, we have identified a series of highly potent and specific DNA-PK inhibitors that impart their inhibitory activity via disruption of the binding of Ku protein to DNA ends. This novel approach affords significant advantages to current approaches in kinase inhibition. Novel derivatives of our initial hit inhibit DNA-PK catalytic activity at nanomolar concentrations and potentiate cellular sensitivity to DSB-inducing agents like etoposide and bleomycin. Data demonstrate that the cellular effects observed are a function of Ku inhibition and that this novel class of DNA-PK inhibitors can be further developed as anti-cancer therapeutics that can be used as an adjuvant to, or concomitant with radiotherapy and other cancer therapies that induce DNA damage.
Citation Format: John J. Turchi, Navnath Gavande, Pamela S. VanderVere-Carozza, Tyler Vernon, Katherine S. Pawelczak. Targeting DNA-PK and the DNA damage response via small molecule Ku inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A11.