bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 99: Phenotypic characterization of knockdown of CDKs in the intestinal epithelial cells
Authors: Lu Shuyan , Hu Wenyue , Sung Tae , Hirakawa Brad , Amaro Marina , Jessen Bart 
Published: September 2020

Abstract
Cyclin-dependent kinases (CDKs) are serine/threonine kinases that bind to cyclins and together act as regulators of cell cycle progression. CDK inhibitors have various therapeutic potentials including cancer (e.g. CDK4/6 inhibitors). Intestinal epithelial cells are highly proliferative; however, the impact of individual CDK inhibition on intestinal cell proliferation has not been well studied. The IEC6 cell line, a non-transformed rat small intestinal epithelial cell line with characteristics of crypt epithelial cells, was utilized in the current study to understand the role of CDKs in the proliferation and survival of intestinal cells. In the initial experiment CDK4/6 inhibitor palbociclib treatment demonstrated a lack of potent toxicity in the IEC6 in comparison with MCF7 (breast cancer cell line), indicating the absence of intestinal cell reliance on CDK4 or CDK6 for cell cycle progression. To further illustrate the role of CDKs in intestinal cells, targeted gene knockdown experiments using CDK1, 2, 4, and 6 siRNA and lipofectamine-mediated transfection were conducted. Surprisingly, only CDK1 knockdown causes profound cell death. CDK2, 4, or 6 knockdowns, whether single, double or triple combinations, did not have significant impact on IEC6 cells, as measured by multiple endpoints including impedance, ATP viability, and caspase activity. To further understand the role of CDK1 in cell cycle, various seeding densities of IEC6 cells were used with CDK1 siRNA. Although the impact of CDK1 knockdown on IEC6 cells decreased at the initial proliferation phase with the higher seeding density, there was still a decrease of viability observed at the later time point (when cells reached proliferation plateau), indicating a non-canonical role of CDK1 that is not related to cell cycle. This research supports the concept that CDK1, but not CDKs 2, 4, or 6, is essential for intestinal cell cycle progression and explains the lack of GI toxicity observed with palbociclib.
Citation Format: Shuyan Lu, Wenyue Hu, Tae Sung, Brad Hirakawa, Marina Amaro, Bart Jessen. Phenotypic characterization of knockdown of CDKs in the intestinal epithelial cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 99.
Abstract 992: IL-6/STAT3-mediated inflammatory signaling results in dysregulated fibroblast growth factor receptor activation and tumor cell signaling in human pancreatic adenocarcinoma
Authors: Nawalaniec Karol , Wang Yuxiang , Moench Romana , Cao Minghua , Luo Yueming , Hsiao Li-Li , Waaga-Gasser Ana Maria 
Published: September 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by delayed diagnosis and the lowest five-year survival amongst all cancer sites. PDAC development and progression are attributed to chronic inflammation and associated tissue repair mechanisms which contribute to high density tumor formation and chemoresistance. PDAC-associated inflammation is, in part, owed to high levels of interleukin 6 (IL-6) and its activated pathways including JAK/STAT3. In Addition, Fibroblast growth factor (FGF) signaling pathways are known to be dysregulated in cancer and have been implicated in various malignancies including PDAC. As such, we sought to explore the association between IL-6-induced inflammatory signaling and FGF signaling activation. To observe this effect as it pertains to carcinogenesis and cancer progression we used four human cell lines ranging from healthy pancreatic ductal epithelial (HPDE) cells to various grade (G) PDAC cells. Cells were treated with IL-6 at a concentration of 100 ng/mL for 24 hours. The results showed increased phosphorylation of STAT3 in BxPC-3 (G2) and PANC-1 (G3) cells with no change noted in HPDE and SW1990 (G2, metastatic) cells. IL-6 stimulation likewise resulted in markedly increased phosphorylation of the fibroblast growth factor receptor substrate 2-alpha (FRS2-α) and its downstream component Erk1/2 in BxPC3 cells, indicating activation of FGF signaling through the MAPK/Erk pathway in our low grade PDAC cell model. In conclusion, the results demonstrate a potential link between IL-6 induced inflammatory signaling and dysregulation of FGF signaling in human PDAC. Activated STAT3 signaling seems to be involved in this process. Existing cancer therapies aimed at controlling growth factor signaling broadly target vascular endothelial or epithelial growth factor receptors (VEGF/EGFR) with marginal efficacy and adverse side effects in PDAC. Identifying the pivotal link between inflammatory signaling and dysregulation of fibroblast growth factor signaling will allow for the development of more precisely targeted and effective cancer therapy in pancreatic cancer. This may minimize clinically observed exaggerated fibrotic events within the tumor and may hence result in higher vulnerability for established chemotoxic therapies in the tumor cells.
Citation Format: Karol Nawalaniec, Yuxiang Wang, Romana Moench, Minghua Cao, Yueming Luo, Li-Li Hsiao, Ana Maria Waaga-Gasser. IL-6/STAT3-mediated inflammatory signaling results in dysregulated fibroblast growth factor receptor activation and tumor cell signaling in human pancreatic adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 992.
Abstract CT074: Pre-existing ESR1 mutations in early-stage primary breast cancer predict failure of endocrine therapy and poor survival
Authors: Dahlgren Malin , George Anthony M. , Brueffer Christian , Gladchuk Sergii , Chen Yilun , Vallon-Christersson Johan , Hegardt Cecilia , Häkkinen Jari , Rydén Lisa , Malmberg Martin , Larsson Christer , Gruvberger-Saal Sofia K. , Ehinger Anna , Loman Niklas , Borg Åke , Saal Lao H. 
Published: September 2020

Abstract
Background: More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy. Although mutation in ESR1 is known as an acquired mechanism of resistance to endocrine therapy (ET), found in 12-55% of metastatic breast cancers treated previously with ET, the impact of ESR1 mutation on therapy response in primary breast cancer is unclear. Patients and methods: In this study we analyzed 3217 real-world and population-based early-stage primary breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096). Tissues were sampled from initial diagnosis prior to any treatment and analyzed for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by SAGAsafe droplet digital PCR. Results: We identified ESR1 resistance mutations in 30 cases (0.9%), of which 29 were ER-positive (1.1%). In ER-positive disease, presence of ESR1 mutation was significantly associated to poor relapse-free survival (RFS) and overall survival (OS) (p=0.011 and p=0.019, respectively), and moreover predicted poor RFS and OS within the patient group that received ET (p=0.007 and p=0.010, respectively). Conclusions: These results indicate that ESR1 mutations at diagnosis of untreated primary breast cancer are rare, however we confirm for the first time that such early mutations predict eventual resistance to standard hormone therapy in the adjuvant setting. If replicated, tumor ESR1 screening may be considered in ER-positive primary breast cancer and, in mutated cases, ER-degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
Citation Format: Malin Dahlgren, Anthony M. George, Christian Brueffer, Sergii Gladchuk, Yilun Chen, Johan Vallon-Christersson, Cecilia Hegardt, Jari Häkkinen, Lisa Rydén, Martin Malmberg, Christer Larsson, Sofia K. Gruvberger-Saal, Anna Ehinger, Niklas Loman, Åke Borg, Lao H. Saal. Pre-existing ESR1 mutations in early-stage primary breast cancer predict failure of endocrine therapy and poor survival [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT074.
Abstract CT152: First in human study with EOS100850, a novel potent A2A antagonist, shows excellent tolerance and clinical benefit in immune resistant advanced cancers
Authors: Buisseret Laurence , Rottey Sylvie , de Bono Johann , Mossakowski Manon , Delafontaine Brant , Manickavasagar Thubeena , Kotecki Nuria , Martinoli Chiara , Schneider Manfred , De Henau Olivier , Chevron Patricia , Lager Joanne , Machiels Jean-Pascal 
Published: September 2020

Abstract
Adenosine is a strong immunosuppressive mediator often found at high extracellular levels in the microenvironment of most tumors. Blocking A2A receptors, predominantly expressed on tumor-infiltrating immune cells, is aimed at reversing the immunosuppressive effect of adenosine. EOS100850 is a potent and highly selective small molecule antagonist of the A2A receptor that remains active even at the high adenosine concentration found in tumors and that does not cross the blood-brain barrier. This multicenter FIH Phase I clinical trial (NCT02740985) assessed the safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary clinical activity of EOS100850 monotherapy in subjects with refractory solid tumors. Pharmacodynamic assessments were performed in peripheral blood and tumor biopsies with simultaneous determination of plasma PK. Twenty-one adult participants with advanced malignancies were treated with EOS100850 monotherapy. Cohorts of 3 participants each were evaluated at 20 and 40 mg QD or 40 mg BID administration. Six participants were subsequently tested at doses of 80 mg BID and at the maximum administered dose of 160 mg BID. All subjects had at least 1 prior regimen (median 3). PK analysis indicated dose-proportional increase of EOS100850 plasma exposures up to 80 mg BID while PD evaluations revealed prolonged and maintained A2AR inhibition over the dosing interval. The most common adverse events (&gt;15%) attributed to the investigational treatment included Grade 1-2 nausea, fatigue, vomiting, and liver enzyme abnormalities. No drug-related Grade 3-4 AEs and no dose-limiting toxicities were observed. As of the data cut off (15JAN20), stable disease was observed in 6 participants who remain on therapy, including head & neck cancers, endometrial cancers, and checkpoint inhibitor-refractory melanoma. Further evaluation is ongoing as monotherapy and in combination with pembrolizumab or chemotherapy in both immune checkpoint-naïve and -refractory patients.
Citation Format: Laurence Buisseret, Sylvie Rottey, Johann de Bono, Manon Mossakowski, Brant Delafontaine, Thubeena Manickavasagar, Nuria Kotecki, Chiara Martinoli, Manfred Schneider, Olivier De Henau, Patricia Chevron, Joanne Lager, Jean-Pascal Machiels. First in human study with EOS100850, a novel potent A2A antagonist, shows excellent tolerance and clinical benefit in immune resistant advanced cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT152.
Abstract CT186: HEPANOVA: Interim safety analysis from a phase 2 study of Tumor Treating Fields (TTFields, 150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma (HCC)
Authors: Gkika Eleni , Brunner Thomas , Thimme Robert , Grosu Anca-Ligia 
Published: September 2020

Abstract
Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. TTFields are approved by the FDA for the treatment of glioblastoma and malignant pleural mesothelioma. In vitro and invivoTTFields at 150 kHz reduced the proliferative potential of hepatocelluar carcinoma (HCC) cell lines. Most HCC patients are not amenable to curative therapies and are treated with systemic chemotherapy following failure of local treatment options. The HEPANOVA Phase II trial (NCT03606590) is a prospective, single-arm study investigating the safety and efficacy of TTFields as a treatment option for advanced HCC concomitant with sorafenib in 25 patients. We present the interim saftey data of the HEPANOVA trial.
Methods: Incidence and severity of adverse events of the first nine patients who have been enrolled in the HEPANOVA Phase II trial were analyzed based on the MedDRA body system (system organ class) and preferred terms.
Results: The median age was 70 (range 63-85), all the patients were male, 3 (33.3%) patients had an ECOG score of 0. The median number of prior treatments was 2 (0-6) and median time from diagnosis was 9 (0-56) months. Five (55.6%) patients had Barcelona Clinic Liver Cancer (BCLC) stage B disease. The median treatment duration was 2 months for sorafenib and 3 months for TTFields. The total TTFields treatment duration for all nine patients was 29.1 months. Six (66.7%) patients had severe AEs (grade 3-4) and 3 (33.3%) had serious adverse events (SAE), none of which were related to TTFields. Mild-moderate skin toxicity was the only TTFields-related AE, reported in seven (78%) patients.
Conclusions: No unanticipated serious adverse device effects have been reported to date in the HEPANOVA study. The majority of AEs reported to date were expected and associated with the disease or chemotherapy. The most common adverse event reported was the expected TTFields-related dermatitis. In summary, these results emphasize the tolerably and safety of TTFields (150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma.
Citation Format: Eleni Gkika, Thomas Brunner, Robert Thimme, Anca-Ligia Grosu. HEPANOVA: Interim safety analysis from a phase 2 study of Tumor Treating Fields (TTFields, 150 kHz) concomitant with sorafenib in advanced hepatocellular carcinoma (HCC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT186.
Abstract CT187: Pembrolizumab and nanoparticle albumin bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC)
Authors: Giannatempo Patrizia , Raggi Daniele , Farè Elena , Marandino Laura , Bandini Marco , Colecchia Maurizio , Pederzoli Filippo , Calareso Giuseppina , Madison Russell , Monopoli Francesco , Russo Giusy , Ferrara Roberto , De Braud Filippo , Montorsi Francesco , Necchi Andrea 
Published: September 2020

Abstract
Methods: In an open-label, single-arm, phase 2 trial, pts receive pembro 200 mg intravenously (IV) on D1 and 125 mg/m2 IV nPtx on D1 and D8, every 3 weeks, until disease progression (PD) or onset of unacceptable toxicity. Key inclusion criteria are: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response is evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers include PD-L1 expression with the combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint of the study is the progression-free survival (PFS). The target is to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 12/2019, PEANUT study enrolled 63 pts evaluable for the study endpoint: 24% female, median age 69 y (IQR 61-73); 75% had failed 1 prior systemic therapy vs 25% 2 prior therapies; 35% had ECOG-performance status 1; 33% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up of 5 months, 33 pts have relapsed (52%). The median PFS was 5 months (95%CI: 4-not achieved). The confirmed objective response-rate (ORR) was 44.4% (95%CI: 0.34 to 0.55): 19 partial responses and 9 complete responses (14.4%). Grade 3-4 treatment-related adverse events (TRAE) were seen in 14 pts (22%). Most common any-grade TRAE included alopecia (76%), neutropenia (33.3%), and asthenia (33%). Permanent interruption of treatment (nPtx only) was seen in 9 pts (14.2%) due to toxicity. Neither TMB nor CPS were significantly associated with PFS on univariable analyses.
Conclusions: Preliminary results from PEANUT study demonstrated a promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. Updated data, including mature OS, duration of response and biomarkers will be presented.
Citation Format: Patrizia Giannatempo, Daniele Raggi, Elena Farè, Laura Marandino, Marco Bandini, Maurizio Colecchia, Filippo Pederzoli, Giuseppina Calareso, Russell Madison, Francesco Monopoli, Giusy Russo, Roberto Ferrara, Filippo De Braud, Francesco Montorsi, Andrea Necchi. Pembrolizumab and nanoparticle albumin bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT187.
Abstract CT219: Efficacy of TTFields in elderly patients with newly diagnosed glioblastoma (GBM): Sub-group analysis of the EF-14 trial
Authors: Ram Zvi , Zhu Jay-Jiguang 
Published: September 2020

Abstract
Background: Tumor Treating Fields (TTFields) are an anti-mitotic, regional treatment modality, utilizing low intensity alternating electric fields delivered non-invasively to the tumor using a portable medical device. In the EF-14 phase 3 study leading to FDA approval, TTFields significantly extended survival in newly diagnosed GBM when added to maintenance temozolomide (TMZ). Elderly GBM patients usually have worse prognosis and often receive only partial treatment for the disease. The aim of the following post-hoc analysis was to examine the effects of TTFields in the elderly population (≥65 years of age) enrolled in the EF-14 study. Method: All 134 elderly patients (≥65 years of age) from the EF-14's intent-to-treat population were included in the analysis, Overall survival (OS) and progression-free survival (PFS), as well as adverse event frequency and severity were compared between the TMZ + TTFields arm and the TMZ alone arm. Result: The median age was 69 (range: 65-83), 69% were male. Median PFS from randomization was 6.5 months versus 3.9 months in the TTFields + TMZ Vs. TMZ alone arms, respectively (hazard ratio [HR], 0.47 [95%CI 0.30, 0.74] P&lt;0.0236). Median OS was 17.4 months versus 13.7 months in the TTFields + TMZ versus TMZ alone arm, respectively (HR 0.51 [CI 0.33, 0.77] P&lt;0.020). Serious adverse events (SAEs) were reported in 39% of patients treated with TTFields + TMZ and in 33% of patients treated with TMZ alone. None of the SAEs were considered related to TTFields. SAEs were considered related to TMZ or to the underlying disease. Grades 1-2 skin AEs were observed in 51% of patients. Conclusion: Consistent with the overall outcome of the EF-14 study, elderly patients treated with TMZ + TTFields showed significantly better OS compared to patients on TMZ alone, and without increase in grade 3-4 toxicity.
Citation Format: Zvi Ram, Jay-Jiguang Zhu. Efficacy of TTFields in elderly patients with newly diagnosed glioblastoma (GBM): Sub-group analysis of the EF-14 trial [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT219.
Abstract CT222: Colon cancer in elderly patients: Retrospective analysis of targeted therapy era
Authors: KIM JIN YOUNG , Shin Sojin , Heo Mi Hwa , Lee Kang Kook 
Published: September 2020

Abstract
Purpose: This study was conducted in order to evaluate the response rate, progression free survival (PFS), safety and prognostic factors of targeted combination chemotherapy in colon cancer patients older than 65 years. Methods: This retrospective study included 69 elderly patients (≥ 65 years) with metastatic Colon cancer who have not received palliative chemotherapy before. All patients were histologically confirmed colon cancer at Keimyung university Dongsan medical center from Jan 2007 to July 2017. All recruited patients received either cetuximab or bevacizumab every 2 weeks. Results: The median age was 73.35 (65-87) and 33 were right side, 32 were left, 2 were transverse and rest of 2 patients were multiple primary sites. Bevecizumab was administerd to 42 patients (60.9%) and cetuximab was administered to 27 patients (39.1%). Complete response was 9 patients (13%), partial response was 23 (33.3%) and progression disease was 9 (13.0%). Overall response rate was 31 (46.4%) and disease control rate was 42 (62.3%). Progression free survival was 12.038 ±1.565 months (95% CI: 8.97~12.12). The most common hematologic side effects was anemia with grade 3/4 in 14 (20.3%). Systemic chemotherapy with targeted agents were moderately tolerated with grade 3/4 neutropenia 40 (57.9%). Conclusion: In elderly patients with colon cancer, clinical outcomes showed similar results compared with prior clinical trials. Preventing such complications may improve survival.
Citation Format: JIN YOUNG KIM, Sojin Shin, Mi Hwa Heo, Kang Kook Lee. Colon cancer in elderly patients: Retrospective analysis of targeted therapy era [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT222.