bluuebunny/crossref_metadata_2025 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

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 >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

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

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

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

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

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

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 >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

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.
Abstract CT090: Neoadjuvant chemotherapy of FOLFIRI with or without radiotherapy in the treatment of marginally resectable recurrent rectal cancer exposed to oxaliplatin: A cohort study
Authors: Xiao Jian , Cai Zerong , Tan Yingxin , Chen Yufeng , Deng Yanhong , Zou Yifeng , Wu Xiaojian , Lan Ping
Published: August 2018

Background

FOLFIRI is the standard second-line chemotherapy for recurrent rectal cancer previously exposed to oxaliplatin. For resectable recurrent rectal cancer, the optimal sequence of chemotherapy and resection is still unknown. We carried out a cohort study to evaluate the efficacy and feasibility of neoadjuvant chemotherapy of FOLFIRI in this setting.

Patients and Methods

Patients aged from 18 to 80 year-old with histologically confirmed and resectable recurrent rectal adenocarcinoma previously exposed to oxaliplatin were recruited. Resectability was decided by three colorectal surgeons. Eligible patients received six preoperative and six more postoperative FOFIRI regimens (irinotecan 180mg/m2 , folinic acid 400mg/m2 and fluorouracil 2800mg/m2, repeated every 14 days). Tumor response was assessed after 3 and 6 cycles. The primary end point was R0 resection rate and the second end points were grade 3 or 4 toxicity and tumor regression grade (Ryan). All the patients signed written informed consent.

Result

65 eligible patients were enrolled in this trial. According to RECIST criteria, 22 ( 33.8%) cases had partial remission, 18 ( 27.7%) cases had stable disease, 24 ( 36.9%) cases had progression disease and 1 patient refused to evaluate and quit study. 21 ( 32.8%) patients achieved R0 resection with 5 cases of TRG 1, 11 cases of TRG 2 and 5 cases of TRG 3. 25 patients received concurrent radiotherapy. Grade 3 or 4 toxicity was seen in 4 (6%) patients. One patient had intestinal perforation and one had bowel obstruction during chemotherapy. No one died during treatment.

Conclusion

Neoadjuvant chemotherapy of FOLFIRI in resectable recurrent rectal cancer can be well tolerated. But more active regimen is still needed for this setting to accomplish better outcome.

Funding: This study was supported by 5010 Project of Clinical Research of Sun Yat-sen University (2010012)

Citation Format: Jian Xiao, Zerong Cai, Yingxin Tan, Yufeng Chen, Yanhong Deng, Yifeng Zou, Xiaojian Wu, Ping Lan. Neoadjuvant chemotherapy of FOLFIRI with or without radiotherapy in the treatment of marginally resectable recurrent rectal cancer exposed to oxaliplatin: A cohort 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 CT090.
Abstract CT092: Effect of tumor treating fields in children with recurrent or progressive high-grade glioma and ependymoma; Pediatric Brain Tumor Consortium PBTC048
Authors: Goldman Stewart , Onar-Thomas Arzu , Dunkel Ira , Hwang Eugene
Published: August 2018

Background: Current treatment regimens show poor prognosis in recurrent or progressive pediatric CNS tumors. Children with high-grade gliomas (HGG) after progression cannot be cured, with reported median survival <1-2 years. Overall survival (OS) of pediatric recurrent/progressive ependymoma is also poor. Tumor Treating Fields (TTFields) is an anti-mitotic cancer therapy for the treatment of recurrent (supratentorial) glioblastoma (GB). A phase 3 clinical trial in adults with newly-diagnosed GB was stopped early due to significant improvements of event-free (EFS) and OS in patients receiving TTFields in conjunction with temozolomide. A separate phase 3 trial comparing TTFields monotherapy with physician's choice chemotherapy in adults with recurrent GB demonstrated comparable OS and improved quality-of-life (QoL).

Methods: This multicenter feasibility trial [NCT03033992] will examine the feasibility and device-related toxicity of TTFields in children aged 5-21 years with supratentorial HGG and ependymoma. The secondary objectives include: response rate, event-free survival, compliance and QoL. To establish feasibility Optune device will need to be worn ≥18 hours/day for at least 23/28 days of cycle one. Patients will have a brain MRI with/without contrast performed prior to therapy, after cycles 2, 4, 6, 9, then every 3 cycles thereafter until time of progression or completion of treatment. Treatment may continue up to 26 cycles based on observed benefit and safety. A sample size of 20 patients is planned with an interim analysis after the first 11 patients. Kaplan-Meier estimates of EFS for all eligible patients will be provided separately for the HGG and ependymoma cohorts. The rates of confirmed sustained objective responses (CR+PR) observed during treatment will be estimated. All PROMIS and Neuro-QoL scores will be reported using T-score matrix (mean=50; SD=10). The projected accrual rate is 1.5-2.5 patients per month with a follow-up for 2 years. The study is currently accruing patients.

Citation Format: Stewart Goldman, Arzu Onar-Thomas, Ira Dunkel, Eugene Hwang. Effect of tumor treating fields in children with recurrent or progressive high-grade glioma and ependymoma; Pediatric Brain Tumor Consortium PBTC048 [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 CT092.
Abstract CT098: Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC)
Authors: Cohen Ezra , Bishnoi Sarwan , Laux Douglas E. , Wong Deborah , Amin Asim , Nabell Lisle , Schmidt Emmett V. , Xing Biao , Leung Abraham C. , Janssen Robert
Published: August 2018

Background and Objectives: SD-101 is a synthetic CpG-ODN agonist of TLR9 that stimulates dendritic cells to release IFN-alpha and mature into antigen presenting cells to activate T cell anti-tumor responses. Pembrolizumab is a PD-1 inhibitor that has demonstrated activity in HNSCC with ORR of 14%. Study DV3-MEL-01 (NCT02521870) assesses the safety and preliminary efficacy of SD-101 in combination with pembrolizumab in patients with recurrent or metastatic HNSCC.

Methods: In phase 2 expansion cohort for anti-PD-1 treatment naïve HNSCC patients, SD-101 was injected in a single tumor lesion (weekly x 4 doses then every 3 weeks x 7 doses) at 8 mg and pembrolizumab was administered intravenously at 200 mg every 3 weeks. Responses are assessed per investigator using RECIST v1.1/irRECIST.

Preliminary Data and Results: 16 anti-PD-1 treatment naïve HNSCC patients are enrolled to date: median age 65 y/o, male 94%, ECOG PS1 63%, median prior lines of therapy 1. SD-101 safety profile consists of flu-like symptoms and injection-site reactions. Grade≥3 treatment-related AEs observed to date included influenza-like symptoms, myalgia, headache, injection site pain and swelling, and fatigue with each of the toxicities occurring in 1 patient (6.7%). No increase in frequency of known pembrolizumab immune-related AEs has been observed to date. ORR in evaluable pts (n=10) was 40% (4 PRs; 1 SD, 5 PDs with 1 still on treatment). The duration of response will be characterized when follow-up data become more mature.

Conclusions: In anti-PD-1 treatment naïve HNSCC patients, SD-101 in combination with pembrolizumab showed a promising response rate and has been well tolerated. Full accrual of subjects in this cohort is ongoing.

Citation Format: Ezra Cohen, Sarwan Bishnoi, Douglas E. Laux, Deborah Wong, Asim Amin, Lisle Nabell, Emmett V. Schmidt, Biao Xing, Abraham C. Leung, Robert Janssen. Phase Ib/II, open label, multicenter study of intratumoral SD-101 in combination with pembrolizumab in anti-PD-1 treatment naïve patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) [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 CT098.
Abstract DDT01-05: ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor
Authors: Kati Warren
Published: August 2018

The BET family of proteins consists of BRD2, BRD3, BRD4 and BRDT, with each of these proteins containing two distinct bromodomains (BDI and BDII). ABBV-075, like other first generation BET family bromodomain inhibitors currently under clinical development, binds to each of the 8 bromodomains with similar affinity and inhibits the proliferation of cancer cells that represent a wide range of tumor types. We hypothesized that selectively targeting specific subsets of the BET bromodomain might abolish this broad spectrum profile such that only the tumor types that are highly addicted to the subtype specific BET bromodomain-mediated transcription would remain sensitive to these selective agents. The BDII bromdomains are highly conserved across BET family members (>70% identity), suggesting that the generation of compounds that are selective for the four BDII bromodomains relative to the four BDI bromodomains might be achievable. Structure-based design targeting the Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) helped to guide the identification of structural analogs of ABBV-075 demonstrating greater than 300X selectivity for BRD4 BDII over BRD4 BDI. Further elaboration ultimately resulted in the discovery of BDII-selective compounds with improved oral bioavailability and the identification of the clinical asset ABBV-744. In striking contrast to the broad range of cell growth inhibition effected by pan BET inhibitor ABBV-075, the anti-proliferative activity for BDII-selective ABBV-744 was largely but not exclusively restricted to AML and androgen receptor (AR) positive prostate cancer cell line models, including models of Enzalutamide resistance. In vivo, doses of ABBV-744 at fractions of its MTD induced tumor growth inhibition in AML and prostate cancer xenograft models that were comparable to those observed with ABBV-075 when dosed at its MTD. Together, these in vitro and in vivo results provide proof of concept that highly selective BDII BET family bromodomain inhibitors may have improved tolerability relative to pan-BET inhibitors while maintaining tumor growth inhibition in AML and AR positive prostate cancer. Disclosures: All authors are employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication.

Citation Format: Warren Kati. ABBV-744: A first-in-class highly BDII-selective BET bromodomain inhibitor [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 DDT01-05.
Abstract LB-003: Novel multi-functional chemoprobes for the characterization of the mechanism of action of histone lysine demethylases inhibitors in cancer
Authors: Lunardi Serena , Ciceri Filippo , Crusat Cristina Mascaró , Ruiz Raquel , Carceller Elena , Ortega Alberto , Sacilotto Natalia , Dessanti Paola , Salas Jordi , Lufino Michele , Maes Tamara
Published: August 2018

Histone Lysine demethylases (KDMs) are emerging clinical targets in cancer. However, a characterization of the mechanism of action of KDMs small molecule inhibitors is limited by the fact that these targets act at multiple levels, having several substrates, different scaffolding roles and regulating gene expression in a cell-specific manner. We developed biotinylated chemoprobes capable of binding to the active site of different KDMs and demonstrated their versatility in target engagement and chemoproteomics analysis. First, we synthetized a biotinylated chemoprobe capable of binding selectively and irreversibly to the active form of KDM1A. By coupling the chemoprobe to an immune-based assay, we can quantify the levels of free KDM1A relative to total levels of KDM1A in a dose-dependent manner in vitro and in vivo. Using this assay, we measured the KDM1A target engagement in models for AML and SCLC. These data were used to perform quantitative pharmacological modeling of SCLC xenograft models treated with ORY-1001 (see Medhi et al, AACR 2018 submitted abstract). The technique can be readily applied to clinical samples and has been used to characterize the pharmacokinetic / pharmacodynamic relationship of KDM1A inhibitors in Phase I trials. In addition, we show that the proteomic profile of the chemoprobe pulldown mirrors the binding partners of inhibited KDM1A. Our proteomic analysis using the KDM1A specific chemoprobe in AML cells identified several ZNF transcription factors but SNAG domain proteins, known to bind to the inhibitor binding site, were not retrieved, providing insight in the interaction changes induced by a KDM1A inhibitor. The strategy was also applied to other targets such as Jumonji C (JmjC) domain-containing proteins like the KDM5 demethylase family, reported to play a role in the emergence of drug tolerance. Overall, this study offers important insights and tools for investigating the role of KDM inhibitors in cancer and their further development into the clinical setting.

Citation Format: Serena Lunardi, Filippo Ciceri, Cristina Mascaró Crusat, Raquel Ruiz, Elena Carceller, Alberto Ortega, Natalia Sacilotto, Paola Dessanti, Jordi Salas, Michele Lufino, Tamara Maes. Novel multi-functional chemoprobes for the characterization of the mechanism of action of histone lysine demethylases inhibitors in 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-003.
Abstract LB-008: Intracellular delivery of SOCS3 suppresses hepatocelluar carcinoma progression
Authors: Shin Seulmee , Lee Kuysook , Hwang Yunseo , Choi Youngsil , Jo Daewoong
Published: August 2018

Background Practical methods to deliver proteins systemically in animals have been hampered by poor tissue penetration and inefficient cytoplasmic localization of internalized proteins. Therefore, we have developed novel cell-penetrating peptides (CPPs), named advanced macromolecule transduction domains (aMTDs), to deliver therapeutically active macromolecule including proteins systemically in vivo. The suppressor of cytokine signaling 3 (SOCS3) is negative feedback regulator of JAK/STAT signaling that plays a key role in inflammation, fibrosis and carcinogenesis in the liver. Furthermore, hypermethylation of CpG islands in the SOCS3 promoter is correlated with its transcriptional silencing in some cancers, including hepatocellular carcinoma (HCC). Objective The present study utilized aMTD sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutics against HCC. Methods Cell permeable SOCS3 proteins, with and without a 12-amino acid aMTD sequence, were expressed at high yields in E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers. Results iCP-SOCS3 fused to aMTD/SD suppressed cancer cell phenotypes (e.g., 84% inhibition of proliferation, arrested cell cycle progression, 86% inhibition of migration/invasion), apoptotic loss of cell viability (40 ~ 80% in HCC cell lines: Hep3B2.1-7, HepG2, Huh7 and SK-Hep1) and changes in apoptosis biomarker expression (e.g., Bcl-2 and cleaved caspase-3). In contrast, iCP-SOCS3 did not affect proliferation and apoptosis of non-cancer cells (Chang). In addition, iCP-SOCS3 also significantly suppressed the tumor growth (70% inhibition in Hep3B2.1-7; 67% inhibition in HepG2, respectively) in human-mouse xenograft models. The anti-tumor activity of iCP-SOCS3 was accompanied by changes in the expression of biomarkers linked to SOCS3 signaling including cyclin E, p21, Bax and VEGF. Furthermore, iCP-SOCS3 suppressed tumor growth equivalently to Cisplatin®, a well-established cytotoxic agent, but without observed toxicity or adverse effects. These results suggest that iCP-SOCS3 inhibits the growth of HCC tumor cells and tumor xenografts. Conclusions These results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of iCP-SOCS3 may provide a novel protein therapy against HCC.

Citation Format: Seulmee Shin, Kuysook Lee, Yunseo Hwang, Youngsil Choi, Daewoong Jo. Intracellular delivery of SOCS3 suppresses hepatocelluar carcinoma progression [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-008.
Abstract LB-010: Intracellular delivery of SOCS3 suppresses solid tumor progression
Authors: Choi Youngsil , Jung Minyong , Shin Seulmee , Lee Kuysook , Jo Daewoong
Published: August 2018

Introduction Suppressor of cytokine signaling 3 (SOCS3) functions as a negative-feedback regulator of JAK/STAT signaling that suppresses JAK kinase activity and promotes degradation of the activated cytokine receptor complex. Loss of SOCS3 enhances the growth and survival of some solid tumors; therefore, methods to replenish intracellular levels of the protein may provide an effective therapy against solid tumors dependent on JAK/STAT signaling for growth or survival.

Objective The present study utilized advanced macromolecule transduction domain (aMTD) sequences to develop improved cell-permeable (iCP-) SOCS3 as a protein-based biotherapeutic against solid tumors including gastric-, colorectal, lung-, breast-cancer and glioblastoma.

Methods Cell-permeable SOCS3 proteins, with (iCP-SOCS3) and without (Non-CP-SOCS3) a 12-amino acid aMTD sequence or containing an earlier generation of MTD based on the signal peptide of FGF4, termed membrane-translocating motif (MTM) were expressed and purified from E. coli. The proteins also contained a solubilization domain (SD) to enhance the solubility of the recombinant proteins in physiological buffers. The therapeutic potential of iCP-SOCS3 as anti-cancer agent for solid tumors was examined both in cultured cells and in human-mouse xenograft models.

Results Compared to CP-SOCS3, iCP-SOCS3 fused to aMTD exhibited higher solubility and yield (25- and 300-folds higher, respectively) that are sufficient to be developed for clinical use. Moreover, it exhibited cell-/tissue-permeability along with strong biological activity that was shown by significantly suppressed IFN-γ-induced phosphorylation of STAT1 and STAT3. In vitro study conducted with various cancer cell lines demonstrated that iCP-SOCS3 significantly suppresses cancer-associated phenotypes (e.g., >80% inhibition of proliferation in lung cancer and glioblastoma, >70% induction of apoptosis in gastric cancer, >65% inhibition of migration/invasion in gastric cancer) and induces changes in biomarker expression (e.g., p21, cleavage caspase-3 in breast cancer). In addition, iCP-SOCS3 also significantly suppressed the tumor growth of human solid tumor xenografts (65% inhibition in gastric-, 79% in colorectal-, 69% in lung-, 63% in breast-cancer and 78% in glioblastoma CDXs, respectively).

Conclusion Taken together, these results provide further evidence that SOCS3 can function as a tumor suppressor and intracellular delivery of SOCS3 with iCP-SOCS3 may provide novel protein therapy against solid tumors.

Citation Format: Youngsil Choi, Minyong Jung, Seulmee Shin, Kuysook Lee, Daewoong Jo. Intracellular delivery of SOCS3 suppresses solid tumor progression [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-010.
Abstract LB-017: HER2 overexpression induces sensitivity to moringa isothiocyanates in breast cancer cells
Authors: OLAYANJU JULIA B. , Xia Bing
Published: August 2018

Isothiocyanates (ITCs) are a class of natural products with promising anti-cancer activities and chemopreventive prospects. Moringa oleifera is a plant widely cultivated in the tropics and has been popularly used for centuries by locals to treat different diseases. Moringa leaves contain four unique sugar-modified aromatic glucosinolates, which can be converted to moringa isothiocyanates (MICs) by myrosinase also present in the leaves. In this study, we tested the efficacy of MIC-1 on 9 different breast cancer cell lines and found it to be a potent anti-cancer agent against them. Interestingly, the two cells lines most sensitive to MIC-1, BT474 and HCC1954, were both positive for HER2, which is amplified in up to 30% of breast cancer and correlates with poor prognosis. The correlation between HER2 overexpression and hypersensitivity to MIC was further confirmed using pairs of MCF-7 and MDA-MB-231 cells with and without HER2 overexpression. In studies to understand why the HER2+ breast cancer cells were more sensitive to MIC than HER2- lines, we observed higher basal intracellular ROS levels in HER2+ breast cancer cell lines compared to HER2- cells. Moreover, we observed that MIC regulates the abundance of KEAP1 and NRF2 across the different cell lines used in this study. In some cases, MIC-1 upregulated both KEAP1 and NRF2 at the same time, suggesting that it may directly or indirectly inactivate KEAP1 thereby stabilizing NRF2. More efforts are underway to elucidate the precise mechanisms of action. Our work shows that MICs may open new frontiers in breast cancer prevention and therapy, particularly for those with HER2 amplification.

Citation Format: JULIA B. OLAYANJU, Bing Xia. HER2 overexpression induces sensitivity to moringa isothiocyanates in breast cancer cells [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-017.
Abstract LB-039: PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary
Authors: Thaye Elien De , Vermeulen An , Ceelen Wim , Bocxlaer Jan Van , Wever Olivier De
Published: August 2018

Peritoneal spread is an indicator of poor prognosis in patients with micropapillary serous carcinoma of the ovary. In general, these patients are treated by surgical cytoreduction followed by intraperitoneal chemotherapy. Although this strategy has encouraging efficacy, personalized treatment regimens may potentially further improve efficacy of cancer management. To investigate such a personalized approach, patient-derived xenografts (PDX) and PDX-derived cell lines from peritoneal implants from micropapillary serous carcinoma of the ovary are developed and characterized. Freshly resected peritoneal implants from consenting donors were obtained. A cell suspension was made and immediately subperitoneally implanted in female immunocompromised mice and expanded as peritoneal metastasis (PM)-PDX. A transplantable PM-PDX was established from 1/1 donor. Histology confirmed the micropapillary and cribriform growth pattern, which was further characterized by intraluminal tumor budding. PM-PDX dissociated cells were maintained as a plastic-adherent cell culture up to 20 passages. The PM-PDX derived cell line is characterized by an epithelial morphotype with doubling time of 42 hours and shows a colony formation efficiency of 25-40% independent of estrogen signaling. The cell line is sensitive to the microtubule stabilizing agent paclitaxel (IC50 = 1.485 nM) and the allosteric MEK inhibitor trametinib (IC50 = 1.299 nM). Future work will provide insights on the mutational status of RAS and RAF, important indicators of potential MEK-targeted personalized medicine.

Citation Format: Elien De Thaye, An Vermeulen, Wim Ceelen, Jan Van Bocxlaer, Olivier De Wever. PDX and PDX-derived cell line development from peritoneal metastasis of micropapillary serous carcinoma of the ovary [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-039.
Abstract LB-049: Cancer stem cell-produced lysophosphatidic acid reprograms surrounding tumor cells to a stem-like state
Authors: Rakhshandehroo Taha , Tan Jiali , Grosshart Brandon , Cheresh David
Published: August 2018

Within a tumor, cancer stem cells (CSCs) represent a small yet highly aggressive, metastatic population that enhances the progression of the surrounding non-CSCs. Here we define lysophosphatidic acid (LPA) as a primary factor produced by pancreatic CSCs that converts non-CSCs to a stem-like fate. LPA promotes increased anchorage independence, drug resistance, self-renewal and stem gene expression including Oct4 and Nanog. Cancer stem cells were found to express high levels of the LPA producing enzyme cPLA2 explaining their production of LPA. Pancreatic cancer cells exposed to the drug Gemcitabine showed a dramatic upregulation of the LPA receptor 4 enabling the cells to become drug resistant and tolerant to a range of microenvironmental stresses.

These finding indicate that LPA is a bioactive lipid produced by CSCs that converts surround pancreatic tumor cells to a highly aggressive state. Therapeutic intervention and/or microenvironmental stress will induce non-CSCs to express LPA Receptor 4, thereby making them stress tolerant and drug resistant. Evidence is provided that targeting the LPA receptor pathway may reverse this paracrine effect and thereby reverse cancer progression and drug resistance.

Citation Format: Taha Rakhshandehroo, Jiali Tan, Brandon Grosshart, David Cheresh. Cancer stem cell-produced lysophosphatidic acid reprograms surrounding tumor cells to a stem-like state [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-049.