bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 917: Defects in multiple DNA damage repair pathways render endocrine treatment resistance in ER+ breast cancer patients
Authors: Anurag Meenakshi , Punturi Nindo , Hoog Jeremy , Bainbridge Matthew N. , Ellis Matthew J. , Haricharan Svasti 
Published: August 2018

Abstract
Endocrine therapy resistance results in the death of majority of women diagnosed with breast cancer in the USA every year. Although a few markers can predict endocrine treatment failure, comprehensive understanding of the underlying cause and early detection of resistant population remains biggest challenge in the field. Recently, deficient expression or mutation in MutL mismatch repair components was found to cause 20% of intrinsic resistance in primary ER+ HER2- breast cancers. The role of other DNA damage repair (DDR) defects in inducing endocrine resistance therefore requires exploration. To address this question, a systematic study of associations between DDR dysregulation at DNA and RNA level and response to endocrine therapy was conducted using aggregated data from patient tumors from several neoadjuvant aromatase inhibitor (NeoAI) clinical trials. METABRIC, TCGA and Loi et al. datasets were used as validation datasets. Statistically significant correlations between endocrine therapy resistance and mutations in two single strand break repair (SSBR) pathways, i.e. nucleotide excision repair (NER; p=0.04) and base excision repair (BER; p=0.03), and one double strand break repair (DSBR) pathway, i.e. non-homologous end joining (NHEJ; p=0.004) were identified. A second set of analyses identified loss of expression of three genes: CETN2 and ERCC1 from the NER pathway and NEIL2 from BER as specifically associating with poor outcome despite endocrine treatment, emphasizing potential connections between NER and BER defects and endocrine treatment response. The functional role of CETN2, NEIL2 and ERCC1 loss in inducing intrinsic endocrine therapy resistance was experimentally validated in two breast cancer cell lines, and in ER+ PDX models. Finally, a DDR signature score was devised from baseline expression levels of candidate genes and was able to predict endocrine treatment failure in &gt;30% of patients.In conclusion, this study describes a screening strategy for identifying novel predictive markers of endocrine therapy resistance in primary patient tumors. Three DDR pathways, NER, BER and NHEJ, were identified in clinical data as associating with endocrine resistance and validated using experimental model systems. Results reveal an understudied but impactful role for DDR pathways that may explain up to half of all endocrine therapy failure and open new avenues for early screening, predictive diagnostics and personalized medicine.
Citation Format: Meenakshi Anurag, Nindo Punturi, Jeremy Hoog, Matthew N. Bainbridge, Matthew J. Ellis, Svasti Haricharan. Defects in multiple DNA damage repair pathways render endocrine treatment resistance in ER+ breast cancer patients [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 917.
Abstract 930: Targeted delivery of cytotoxic NAMPT inhibitors using antibody-drug conjugates
Authors: Neumann Christopher S. , Olivas Kathleen C. , Waight Andrew B. , Meyer David , Loftus Luke V. , Zaval Margo , Anderson Martha E. , Jin Steven , Cochran Julia H. , Simmons Jessica K. , Pittman Paul G. , Lyon Robert P. , Senter Peter D. 
Published: August 2018

Abstract
Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme involved in the salvage biosynthetic pathway of NAD from nicotinamide. Small-molecule inhibitors of NAMPT lead to rapid depletion of NAD(H) and subsequent depletion of ATP as cellular energy metabolism is interrupted. While these inhibitors can be potently cytotoxic in vitro, their application as cancer chemotherapeutics is limited by toxicity upon systemic administration. We have developed NAMPT inhibitors that are suitable for targeted delivery to cancer cells using our antibody-drug conjugate (ADC) platform. The inhibitors retain impressive biochemical potency against purified NAMPT, as well as potent in vitro cytotoxicity. Cleavable drug linkers were constructed using an enzyme-labile glucuronic acid moiety as the trigger for drug release. The resulting linkers are relatively hydrophilic, allowing ADCs with eight drugs per antibody to be prepared with no aggregation and favorable pharmacokinetic profiles. In vitro, treatment of cells with ADCs leads to depletion of cellular NAD. This pharmacodynamic effect is also observed in xenografted L540cy tumors, where NAD(H) is not detected in excised tumors 4 days after dosing. Across multiple tumor xenograft models, treatment with NAMPT-based ADCs leads to tumor regression. Exploratory toxicology studies in rats show excellent single-dose tolerability, with recoverable anemia and lymphopenia noted. Importantly, retinal and cardiac toxicities associated with systemic administration of NAMPT inhibitors in rodents were not observed with NAMPT-based ADCs. These data demonstrate the ability of NAMPT inhibitors to serve as a novel payload class for ADCs, and the potential to reintroduce this unique mechanism of action to the clinic with improved therapeutic windows.
Citation Format: Christopher S. Neumann, Kathleen C. Olivas, Andrew B. Waight, David Meyer, Luke V. Loftus, Margo Zaval, Martha E. Anderson, Steven Jin, Julia H. Cochran, Jessica K. Simmons, Paul G. Pittman, Robert P. Lyon, Peter D. Senter. Targeted delivery of cytotoxic NAMPT inhibitors using antibody-drug conjugates [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 930.
Abstract 976: FOXA1 promotes a luminal growth program in prostate cancer
Authors: Adams Elizabeth J. , Hoover Elizabeth , Karthaus Wouter R. , Sawyers Charles L. 
Published: August 2018

Abstract
FOXA1 is an important pioneering transcription factor for androgen receptor (AR), a key driver of prostate cancer. FOXA1 has emerged as one of the most recurrently mutated genes in primary and metastatic castrate resistant prostate cancer, with alterations frequencies ranging from 4-15% in various cohorts. Given the well-established role of FOXA1 in modulating AR function, we hypothesize that FOXA1 mutations contribute to prostate oncogenesis by altering the chromatin landscape, resulting in changes in the AR cistrome and AR transcriptional output. Here we use prostate organoids to show that acute FOXA1WT overexpression promotes lumen formation and drives luminal differentiation. Consistent with this, CRISPR/Cas9-mediated deletion of FOXA1 slows proliferation and organoids lacking FOXA1 fail to form lumens. Assays to evaluate the functionality of recurrent FOXA1 mutations (measured by cell viability, lumen formation, and lumen size) along with RNA-sequencing suggest there are distinct classes of FOXA1 mutations. The first are the gain-of-function mutations (such as FOXA1FE254-255del), which promote growth and lumen formation to a larger extent than wild-type FOXA1. Interestingly, a FOXA1 luciferase reporter assay we developed in HEK293 cells indicates that the majority of mutants tested behave as gain of function. The only mutant to score as loss of function, FOXA1R219S, is found nearly exclusively in prostate cancer, and is enriched in neuroendocrine prostate cancer cohorts. Expression of FOXA1R219S suppresses lumen formation and promotes both basal and epithelial-mesenchymal transition transcriptional programs. However, this mutant also provides a growth advantage beyond what is conferred by FOXA1WT. Taken together, these data suggest that FOXA1R219S is not simply a loss of function allele and instead may drive disease progression through a different set of signaling pathways than the FOXA1 alleles that promote luminal differentiation. Further study of these classes of mutations and how they relate to patient outcome, along with analysis of the FOXA1mut/AR cistromes, is ongoing to determine the genome-wide implications of FOXA1 alterations and how they promote prostate cancer progression.
Citation Format: Elizabeth J. Adams, Elizabeth Hoover, Wouter R. Karthaus, Charles L. Sawyers. FOXA1 promotes a luminal growth program in prostate 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 976.
Abstract CT049: Long term outcome of EBV-associated lymphoma patients treated with post-remission therapy using EBV LMP1 and LMP2a specific CTLs
Authors: Kim Nayoun , Sohn Hyun-Jung , Im Keon-Il , Jeon Young-Woo , Nam Young-Sun , Song Yunejin , Lee Jun Seok , Kim Tai Gyu , Cho Seok-Goo 
Published: August 2018

Abstract
Background: Conventional therapeutic approaches, such as chemotherapy and radiotherapy, have been limited in successfully achieving durable response in Epstein Barr virus (EBV)-associated malignancies causing frequent relapse, low overall survival rate and poor prognosis. EBV-specific cytotoxic T lymphocytes (EBV-CTLs) have emerged as an alternative therapeutic approach to treat EBV associated lymphoma by enhancing EBV-specific immunity.
Methods: To evaluate the efficacy and safety of EBV latent membrane protein (LMP)-1 and LMP-2a specific CTLs (LMP1/2a CTLs) stimulated with LMP1/2a RNA-transferred dendritic cells, we treated ten EBV+ ENKTCL patients and two EBV+ PTLD patients who showed complete response to induction therapy. Patients who completed and responded to chemotherapy, radiotherapy, and/or high-dose therapy followed by stem cell transplantation were eligible to receive eight doses of 2 x107 LMP1/2a CTLs/m2.
Results: Following infusion, there were no immediate or delayed toxicities. The seven-year overall survival (OS) and progression-free survival (PFS) were 100%, and 90% (95% CI: 71·4% to 100%) for ENKTCL patients respectively with a median follow-up of 94 months. Similarly, PTLD patients showed long-term remission with a follow-up of up to 70 months. Overall, circulating IFN-γ secreting LMP1 and LMP2a-specific T cells within the peripheral blood corresponded with decline in plasma EBV DNA levels in patients.
Conclusion: Adoptive transfer of LMP1/2a CTLs in patients is a safe and effective post-remission therapeutic approach. Further randomized studies will be needed to define the role of EBV-CTLs in preventing relapse of EBV-associated lymphoma.
Citation Format: Nayoun Kim, Hyun-Jung Sohn, Keon-Il Im, Young-Woo Jeon, Young-Sun Nam, Yunejin Song, Jun Seok Lee, Tai Gyu Kim, Seok-Goo Cho. Long term outcome of EBV-associated lymphoma patients treated with post-remission therapy using EBV LMP1 and LMP2a specific CTLs [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 CT049.
Abstract CT063: BAT1706 demonstrates high similarity to Bevacizumab in comparative analysis with originator and phase I clinical trials in New Zealand and China
Authors: Yu Jin-Chen 
Published: August 2018

Abstract
Bevacizumab, a humanized monoclonal antibody against VEGF, has been approved by FDA to treat colon, lung, renal cancers and glioblastoma. We have developed BAT1706 as a biosimilar to Bevacizumab. Their evaluation was performed using several analytical assays and stress degradation studies. Both products BAT1706 shows similar binding affinity and biological function as Bevacizumab. In additionAdditionally, , several analytical assays and stress degradation studies have been conducted to compare multiple lots of BAT1706 and Bevacizumab. Tthe data indicate that BAT1706 is at least as pure as Bevacizumab and that the following attributes are consistent highly similar between both products: isoelectric point, peptide mapping profile, amino acid sequence, disulfide bond numbers and location, molecular weight and size, binding affinity towards the antigen and relevant immunologic receptors, isoform ratios, levels of impurities, glycosylation parameters, and secondary and tertiary structures. The degradation pathways and rates were evaluated using two different conditions (high temperature and strong light exposure) by means of several stability indicating methods. All Both products showed similar reactions during the incubating conditions and similar degradation rates. These data demonstrated that BAT1706 is highly similar to Bevacizumab, in structure, function, process impurities, and stability attributes.
We have also completed two phase I studies with BAT1706 in New Zealand and China. Data revealed that a single IV infusion of BAT1706 (1 mg/kg) is safe and well tolerated in healthy subjects. No death was reported during either study and there was only 1 SAE of fibula fracture, which was not considered as related to BAT1706 by the investigator. The key PK parameters of both Phase I studies also revealed that BAT1706 is a bioequivalent to Bevacizumab. No positive results of anti-drug antibodiesy werewas reported for any subject in either study. Currently, a global randomized, double blind phase III study is on-going, to compare the efficacy, and to evaluate the safety and immunogenicity of BAT1706 to EU Bevacizumab in patients with previously untreated advanced non-squamous NSCLC.
Citation Format: Jin-Chen Yu. BAT1706 demonstrates high similarity to Bevacizumab in comparative analysis with originator and phase I clinical trials in New Zealand and China [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 CT063.
Abstract CT070: Innovative design for a phase I trial with intra-patient dose escalation: The Crotoxin study
Authors: Medioni Jacques , Brizard Mara , Elaidi Reza , Reid Paul F. , Khadija Benlhassan5 , Bray Dorothy 
Published: August 2018

Abstract
INTRODUCTION. Crotoxin is a bipartite South America rattle snake neurotoxin. It has broad spectrum antitumor activity in vivo in addition to exerting analgesic effects. Prior clinical reports using i.m. injections resulted in local immune reactions with erythema, itching or pain, in addition to anaphylaxis though encouraging responses were recorded. A clinical study was designed incorporating i.v. administration, dose escalation and pre-treatment antihistamine use, aimed at improving dose limiting toxicity (DLT) and local tolerance.
METHOD. This trial was performed in patients with stage IV cancer with the primary endpoints to assess safety and tolerability, measured by Dose-Limiting Toxicity (DLT) and to define the Maximum Tolerated Dose (MTD). The secondary objectives were to document anti-tumor efficacy, evaluated according to radiological RECIST criteria 1.0 and analgesia. Baseline pain assessments were completed for each patient. Cohort I included 6 patients with advanced solid tumors (no further therapy options), with dose escalation from 0.04 to 0.32 mg/m2/day administered IV by saline drip over 2h daily (Mon to Fri) over 54 days.
RESULTS.One male and 5 females (pts) with prior heavily-treated advanced tumors were enrolled: colorectal adenocarcinoma, epithelioid mesothelioma, non-small-cell lung cancer, carcinoma of unknown primary site, invasive breast ductal carcinoma and ovarian papillary adenocarcinoma. Three patients reached the highest target dose level. DLT or MTD were not attained. In Cohort I grade 1 to 2 drug-related events occurred in 3/6 patients: anorexia, diplopia and nystagmus. There were no drug-related serious adverse events. Tumor assessment was performed after 8 weeks of dose escalation (day 54) and all subjects were determined to have progressive disease. At baseline, pain was reported for 5/6 subjects, surveys revealed a diminution of analgesic scores.
CONCLUSION: Crotoxin i.v. dose escalation protocol allowed administering 0.32 mg/m2/day without unexpected toxicity. Lack of anti-cancer benefit might be related to the long period of 6-8 weeks to reach this dose. A redesign of the protocol to escalate faster and to higher doses, without weekend breaks, is required.
Citation Format: Jacques Medioni, Mara Brizard, Reza Elaidi, Paul F. Reid, Benlhassan5 Khadija, Dorothy Bray. Innovative design for a phase I trial with intra-patient dose escalation: The Crotoxin 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 CT070.
Abstract CT071: Continuous i.v. Crotoxin in advanced cancer: Intra-patient dose escalation
Authors: Delgado Marian Gil , Paul Gougis , Bray Dorothy H. , DELGADO Francois M. , SPANO Jean P. , Idbaih Ahmed , Reid Paul F. , Benlhassan Khadija , Diaw Cheikh , Khayat David 
Published: August 2018

Abstract
Introduction: Crotoxin (CRTX), a potent neurotoxin from the venom of Crotalus durissus terrificus, rattlesnake, upon intramuscular administration has been shown to have broad anti-tumor activity accompanied with significant toxicity. Preclinical animal data suggested that in intra-patient dose escalation protocol the administration of high doses and efficacy can be achieved without toxicity.
Methods: We followed the design of Medioni et al (Contemp. Clinical Trials Comm. 7, 2017: 186-168) in intra-patient dose escalation study to administer CRTX in heavily pre-treated patients (5 males and 1 female) with advanced solid tumors: 1 nasal squamous cell carcinoma, 2 glioblastomas, 1 endometrial adenocarcinoma, 1 NSCLC and 1 prostatic carcinoma. Lightweight RythmicTM pump capable of continuous delivery (no weekend breaks) allowed patients to stay at home. Over 35 days, CRTX dose escalation from 0.08 to 0.64 mg/m2/day was carried on Mondays, Wednesdays and Fridays, followed each time by 2h observation at the clinic. Dose limiting toxicity (DLT) and maximum tolerated dose (MTD) were defined as the inability of dose escalation twice due to toxicity and the dose at which no further dose escalation can be safely achieved for &gt;33% of the pts in the study, respectively.
Results: 2/6 patients developed possibly drug-related G1 diplopia and 1/6 pts increased ASAT/ALAT. One patient recruited with pre-existent diarrhoea syndrome with uncontrolled G2 hypomagnesaemia, G3 hypokalaemia and G2 anaemia, developed complete arrhythmia with asymptomatic atrial fibrillation that resolved with amiodarone. Patient was hospitalised for observation and the event was classified as a possible study drug-related SAE as well as related to the digestive syndrome and tubulopathy resulting from previous chemotherapy (nivolumab and platinum salts). Stable disease was observed in 2/6 patients.
Conclusion: No DLT or MTD have been reached. CRTX dose escalation is safe but too slow, doses achieved too low and too late for advanced patients. In a new cohort, CRTX regimen will be continued starting from higher dose with faster dose escalation.
Citation Format: Marian Gil Delgado, Gougis Paul, Dorothy H. Bray, Francois M. DELGADO, Jean P. SPANO, Ahmed Idbaih, Paul F. Reid, Khadija Benlhassan, Cheikh Diaw, David Khayat. Continuous i.v. Crotoxin in advanced cancer: Intra-patient dose escalation [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 CT071.
Abstract CT081: Tumor treating fields in combination with Bevacizumab in recurrent or progressive meningioma in a phase II study
Authors: Kumthekar Priya , Kruser Timothy , Sachev Sean , Raizer Jeffrey , Grimm Sean , Dixit Karan 
Published: August 2018

Abstract
Meningioma is the most common primary brain tumor with a prevalence of about 170,000 in the United States. For patients with WHO grade II meningioma, the two-year and five-year overall survival was 93% and 73%, respectively. Patients with malignant meningioma (grade III) had significantly worse outcomes, with two-year and five-year overall survival rates of 57% and 42%. The recurrence rate remains high and in the case of grade 3 meningioma overall survival is as low as 3 years after diagnosis. The current treatment for high grade and recurrent meningioma includes maximal safe surgical resection and radiation. Tumor treating fields (TTFields) and Bevacizumab (BEV) have been reported to show activity in recurrent and high-grade meningioma. The combination of TTFields and BEV may provide a viable treatment option for patients with recurrent and high grade meningioma.
This Phase 2 Simon two-staged, non-randomized, open-label, phase II, single arm clinical trial [NCT02847559] will investigate the combination of TTFields and BEV in recurrent or progressive meningioma. The primary endpoint will be progression free survival (PFS) at 6 months (PFS-6). Secondary endpoints will include overall survival (OS); Tumor Response Rate (TRR), Objective Response Rate (ORR); and Quality of Life (QOL) using FACT-Br questionnaire. Patients (N=27), including those who have failed prior BEV therapy, will receive BEV IV 10 mg/kg over 30-90 minutes on days 1 and 15 of courses 1-4. Beginning on day 1 of course 5, patients may choose to receive bevacizumab IV 15 mg/kg every 3 weeks or remain on the every 2-week schedule. Patients will receive TTFields 200 KHz (1-3 V/cm) daily via the Optune device for at least 18 hours/day. This study is powered to detect a true PFS-6 rate of 20% with 80% probability (80% power) and to detect a true PFS-6 rate of 5% with 90% probability (alpha=0.10). We planned for 27 patients in total to have 24 evaluable patients. For patients who are unable to obtain commercial BEV, the study has been amended to include a monotherapy arm of TTFields alone to increase the pool of eligible patients.
Citation Format: Priya Kumthekar, Timothy Kruser, Sean Sachev, Jeffrey Raizer, Sean Grimm, Karan Dixit. Tumor treating fields in combination with Bevacizumab in recurrent or progressive meningioma in a phase II 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 CT081.