bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract CT164: A phase 1 study of abemaciclib in Chinese patients with advanced and/or metastatic cancers
Authors: Hu Xichun , Yang Nong , Zhang Jian , Zhou Chunhua , Ji Dongmei , Shen Weina , Li Wenhua , Han Rubing , Lu Yi , Chapman Sonya C. 
Published: September 2020

Abstract
Background: Abemaciclib, a cyclin-dependent kinase 4 & 6 inhibitor, is approved in combination with endocrine therapy or as a single agent for HR+/HER2- advanced breast cancer patients (pts) outside of China. The safety and PK profile has not been established in Chinese pts.
Patients and methods: In this multicenter, open-label, phase 1 trial, pts were randomized to receive abemaciclib 150 mg or 200 mg orally every 12 hours on a 28-day cycle. The primary objective was to evaluate the safety and tolerability of abemaciclib monotherapy in Chinese pts with advanced and/or metastatic cancers. The secondary objective was to assess PK and antitumor activity.
Results: A total of 25 pts were treated with abemaciclib: 12 in 150 mg cohort and 13 in 200 mg cohort. Pts had a median age of 54 years (range: 29-69) and a median of 4 prior systemic therapies (range: 1-7) for metastatic disease. In two dose cohorts, common (≥25%) treatment emergent adverse event (TEAE) related to study treatment included diarrhea, neutrophil count decreased, white blood cell count decreased, decreased appetite, blood creatinine increased, malaise, anemia, platelet count decreased, nausea, alanine aminotransferase increased and cough. The majority of TEAEs were Grade 1 or 2 in severity. Study treatment related Grade ≥3 TEAE (≥10%) included neutrophil count decreased (32%), platelet count decreased (24%), embolism (16%), diarrhea (12%) and white blood cell count decreased (12%). Four pts (16%) discontinued treatment due to AE. The PK characteristics of abemaciclib and its two major active metabolites (LSN2839567 and LSN3106726) were comparable to those observed in previous studies in non-Chinese populations. No CR was observed. Two pts (8%) achieved PR with one confirmed responder. The disease control rate (CR + PR + SD) was 68% (n=17).
Conclusion: Abemaciclib was well tolerated at both cohorts evaluated in Chinese pts with advanced and/or metastatic cancers. The safety profile and PK characteristics in Chinese pts were similar to those in previous studies in non-Chinese populations. Preliminary antitumor activity was observed and supported further development of abemaciclib in Chinese pts.
ClinicalTrials.gov no.: NCT02919696
Citation Format: Xichun Hu, Nong Yang, Jian Zhang, Chunhua Zhou, Dongmei Ji, Weina Shen, Wenhua Li, Rubing Han, Yi Lu, Sonya C. Chapman. A phase 1 study of abemaciclib in Chinese patients with advanced and/or metastatic 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 CT164.
Abstract CT183: CD5+ B-cell count is a favorable prognostic factor associated with progression-free survival in glioblastoma patients receiving chemoradiation and pembrolizumab
Authors: Claunch Cheryl J. , Diaz Claire , Roth-Carter Riley A. , Popp Lauren , Fu Rochelle , Huddleston Amy E. , Moussalli Dana L. , Peterson Julie , Uluc Kutluay , Szidonya Laszlo , Fan Guang , Pucci Ferdinando , Barajas Ramon F. , Muldoon Leslie L. , Neuwelt Edward A. , Ambady Prakash 
Published: September 2020

Abstract
The exploratory endpoint for our prospective single-arm study (NCT 03347617) evaluated longitudinal changes in immune cell sub-populations (B-cells, T-cells, NK cells, monocytes, and myeloid cells) in 25 newly diagnosed glioblastoma patients who received standard of care chemoradiation with concurrent pembrolizumab after maximal safe resection. Patient demographics included the following: 15 males, 10 females, age range 25-72 years old, mean age 52 years old, 8 MGMT unmethylated, 17 MGMT methylated, 7 IDH1 mutant, and 18 IDH1 wild-type. Flow cytometry was performed on blood collected at predetermined timepoints (pre-treatment, post-radiation, suspected progression, and confirmed progression) and immune cell sub-populations were evaluated as covariates in survival analysis using Cox proportional hazards regression in R. CD5+ CD19+ B-cell count was significantly associated with progression-free survival at pre-treatment (hazard ratio (HR)= 0.76; likelihood ratio test (LRT) p=0.029) and post-radiation (HR = 0.16; LRT p=0.004) timepoints. No association with progression-free survival was found in 25 other immune cell sub-populations evaluated. The study will continue to monitor for progression. Results of imaging, tissue histology, overall survival analysis and functional studies in animal models are pending. Investigations of the immunological mechanisms underlying the potential anti-tumor activity of CD5+ B-cells are ongoing and include detection and characterization of anti-tumor antibodies, T cell-dependence of the response, and whether it is triggered by pembrolizumab. Modulating CD5+ B-cells, or the antibodies they produce, may have therapeutic implications in improving checkpoint inhibition in glioblastoma.
Citation Format: Cheryl J. Claunch, Claire Diaz, Riley A. Roth-Carter, Lauren Popp, Rochelle Fu, Amy E. Huddleston, Dana L. Moussalli, Julie Peterson, Kutluay Uluc, Laszlo Szidonya, Guang Fan, Ferdinando Pucci, Ramon F. Barajas, Leslie L. Muldoon, Edward A. Neuwelt, Prakash Ambady. CD5+ B-cell count is a favorable prognostic factor associated with progression-free survival in glioblastoma patients receiving chemoradiation and pembrolizumab [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 CT183.
Abstract CT235: A phase 1b/2 study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC)
Authors: Barzi Afsaneh , Lenz Heinz-Josef , Samuëlsz Errin , Ridinger Maya , Erlander Mark , Bekaii-Saab Tanios S. , Ahn Daniel H. 
Published: September 2020

Abstract
Background: Chemotherapy in combination with targeted agents are standard-of-care options for patients for mCRC with response rates &gt;50% in first line. In the second line setting, efficacy of chemotherapy and targeted agents are much lower with response rates of 5% for FOLFIRI (5-fluorouracil, leucovorin, irinotecan) + bevacizumab (anti-VEGF). New treatment options are urgently needed in particular for the 50 % of patients harboring a KRAS mutation. Polo-like kinase 1 (PLK1) is a serine/threonine kinase, master regulator of the mitotic checkpoint and cell division. PLK1 is overexpressed in CRC and its overexpression is associated with poor prognostic. A genome wide RNAi screen identified PLK1 as a synthetic lethal target in KRAS mutant CRC cells, inducing cell cycle arrest and apoptosis upon inhibition. Onvansertib is an oral, highly selective PLK1 inhibitor that demonstrates single agent and synergistic activity with irinotecan in preclinical CRC models. Additionally, KRAS mutated vs wild-type cells showed higher sensitivity to onvansertib. PLK1 inhibition is a potential target in KRAS-mutated mCRC and onvansertib + FOLFIRI + bevacizumab may provide a new second-line treatment option.
Trial design: The primary objective of this single-arm Phase 1b/2 study is to assess the safety and preliminary efficacy of onvansertib in combination with FOLFIRI and bevacizumab in the second line setting for KRAS-mutated mCRC patients. For the Phase 1b segment, a standard 3 + 3 dose-escalation design is used to determine the maximum tolerated dose or recommended phase 2 dose (RP2D) of onvansertib. As of January 24th 2020, enrollment in the second dose level is ongoing. Efficacy will be determined by objective response rate (ORR) according to RECIST v1.1 (primary endpoint), progression-free survival and reduction in KRAS allelic burden in liquid biopsies (secondary endpoints). In the phase 2, based on a one-sided one sample log-rank test with 10% Type I error, there will be at least 90% power to detect an improvement in ORR from 5% to 20% with 26 patients. Exploratory endpoints include genomic studies of circulating tumor cells and ctDNA to evaluate altered pathways that correlate with patient response. Clinical trial identification NCT03829410.
Citation Format: Afsaneh Barzi, Heinz-Josef Lenz, Errin Samuëlsz, Maya Ridinger, Mark Erlander, Tanios S. Bekaii-Saab, Daniel H. Ahn. A phase 1b/2 study of onvansertib (PCM-075) in combination with FOLFIRI and bevacizumab for second line treatment of patients with KRAS-mutated metastatic colorectal cancer (mCRC) [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 CT235.
Abstract CT264: Clinical phase II study of SCO-101 - an inhibitor of SRPK1 and ABCG2 - restoring sensitivity to FOLFIRI in metastatic FOLFIRI resistant colorectal cancer patients
Authors: Vestlev Peter Michael , Roest Nicklas L. , Schou Jakob HV , Stenvang Jan , Brünner Nils 
Published: September 2020

Abstract
The purpose of the phase II study is to determine safety, tolerability, MTD and efficacy of SCO-101 in combination with FOLFIRI in patients with FOLFIRI resistant metastatic colorectal cancer. SCO-101 is a low molecular weight molecule (Acidic di-aryl urea). Preclinical studies have shown that it inhibits the SRPK1 kinase which phosphorylates and thereby activates proteins involved in the regulation of alternative splicing. It also degrades the ABCG2 drug efflux pump to which irinotecan (SN38) is a substrate. SCO-101 has successfully passed 4 clinical phase I studies in healthy volunteers and demonstrated to be a safe oral drug with very limited toxicity and good PK parameters. It reverses irinotecan- and several other types of anti-cancer drug resistance in in vitro and in vivo preclinical cancer models. The clinical phase II study: An open-label, non-randomized, prospective study, enrolling patients with acquired FOLFIRI resistant metastatic colorectal cancer. The study consists of two parts: -Part 1 is a dose escalation part based on a traditional 3+3 design. Increasing doses of SCO-101 are investigated in combination with a fixed, patient specific, dose of FOLFIRI. The primary objectives of part 1, is to determine the safety- and toxicity profile and the MTD of SCO-101. The MTD will be the recommended dose of SCO-101 for part 2 (RDP2); -Part 2 is the efficacy part, where up to 25 patients (Simons Two Stage Design) receive the SCO-101 RDP2 in combination with FOLFIRI. Primary objectives are to determine the safety- and toxicity profile and assess objective response rates. A number of potential biomarkers for SCO-101 efficacy will be evaluated. Approval for the study has been obtained and the study will start recruiting patients primo 2020. SCO-101 has two unique mechanisms of action. No other drugs have been presented that inhibits the SRPK1 kinase. Several published preclinical studies have associated high SRPK1 activity with progression of cancer including development of cancer drug resistance. SCO-101 is also the first drug described that degrades the ABCG2 drug efflux pump. If a positive signal is obtained in the clinical study, we will continue with a randomized clinical design allowing for time-dependent end-points, e.g. PFS and OS.
Citation Format: Peter Michael Vestlev, Nicklas L. Roest, Jakob HV Schou, Jan Stenvang, Nils Brünner. Clinical phase II study of SCO-101 - an inhibitor of SRPK1 and ABCG2 - restoring sensitivity to FOLFIRI in metastatic FOLFIRI resistant colorectal cancer patients [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 CT264.
Abstract DDT02-04: GDC-9545: Discovery of an oral estrogen receptor antagonist, degrader, and immobilizer for the treatment of ER+ breast cancer patients
Authors: Wang Xiaojing , Wang Xiaojing 
Published: September 2020

Abstract
GDC-9545: Discovery of an orally bioavailable pure antiestrogen for the treatment of ER+ breast cancer patients. Breast cancer affects one out of every eight women in their lifetime making it the most frequently occurring cancer among women. Mortality remains high with more than 40,000 of women expected to die of breast cancer in 2019 in the U.S alone. Approximately 70% of all breast cancer expresses estrogen receptor alpha (ERα), making it a prime target for the treatment of breast cancer. Despite effective endocrine therapies, many patients eventually relapse and become resistant to standard of care treatments. These endocrine resistant tumors often continue to depend on ERα for growth and survival, as evidenced by their sensitivity to the selective estrogen receptor antagonist and degrader, fulvestrant. However, fulvestrant is limited by its pharmaceutical and pharmacokinetic properties and its intramuscular route of administration to achieve sufficient target occupancy. Consequently, selective ERα ligands with desirable mechanisms of action and superior drug properties were sought after, allowing consistent and rapid achievement of therapeutic exposure. We have reported previously of our first and second generations of orally available ERα ligands, GDC-0810 and GDC-0927 respectively. Targeting a pure antiestrogen profile and guided by co-crystal structures, we identified a structurally distinct scaffold from these first two generations. Fine-tuning the physiochemical properties while balancing potency and efficacy culminated into a third generation development candidate GDC-9545. GDC-9545 immobilizes ERα to achieve full antagonism and degradation. It inhibits tumor growth or causes tumor regression in patient derived xenograft mouse models. It is orally bioavailable and has high safety margins in preclinical species. GDC-9545 is currently in active clinical testing.
Citation Format: Xiaojing Wang, Xiaojing Wang. GDC-9545: Discovery of an oral estrogen receptor antagonist, degrader, and immobilizer for the treatment of ER+ breast cancer patients [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 DDT02-04.
Abstract LB-008: Patient derived organoids: Bringing the "patient in the lab" for pre-clinical and clinical development
Authors: Mullenders Jasper , Buijs Annemarie , Van Maanen Inge , Piani Carol , Mardpour Soura , Clevers Hans , Vries Rob , Boj Sylvia 
Published: September 2020

Abstract
Pre-clinical disease models are essential for the development of novel therapies and help better understand the molecular processes. In recent years, a novel groundbreaking technology to generate patient specific in vitro cultures based on adult stem-cell organoids, has gained widespread interest for the development of new therapies and as a predictive diagnostic tool. ASC-organoids can be generated at high efficiency from both healthy and diseased tissue (resections as well as biopsies) including most carcinomas. These patient derived cultures can be expanded for prolonged periods of time while maintaining many properties of the tissue they were derived from. At HUB, we have created comprehensive ‘living biobanks' from tumors of different origin like colon, lung, breast, pancreas and ovary. These biobanks have been characterized at the genetic and transcriptional level. These analyses have shown that our ‘living biobanks' capture disease heterogeneity at the genetic and molecular level. Because organoids can be expanded long term, drug screening is feasible in these models. HUB has developed procedures for (high-throughput) compound screening in organoids including small molecules and biologics. In this setting, organoids have been used to identify novel targets, identify lead compounds and stratify potential responders based on their genetic or molecular profile. Recent advances in the field of immuno-oncology have revolutionized the treatment for cancer patients. Despite of the improvements and due to the complex and highly regulated nature of the immune system, treatment does not have a similar effect on all tumors. We have created a co-culture model of tumor derived organoids and immune cells. In these co-cultures, the cytotoxic effect of the immune cell on the tumor can be measured in a reproducible and quantitative manner. Currently we are expanding existing co-culture models to incorporate different immune cells and organoid tumor types. In addition, organoids can serve as a patient avatar in clinical development or diagnostics. In this setting, organoids could add a functional test for therapy response in a patient centered setting providing a unique tool for personalized medicine.
Citation Format: Jasper Mullenders, Annemarie Buijs, Inge Van Maanen, Carol Piani, Soura Mardpour, Hans Clevers, Rob Vries, Sylvia Boj. Patient derived organoids: Bringing the "patient in the lab" for pre-clinical and clinical development [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 LB-008.
Abstract LB-021: Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition
Authors: Zhang Baoyuan , Zhang Yan , Zhang Jiangwei , Liu Ping , Jiao Bo , Wang Zaiqi , Ren Ruibao 
Published: September 2020

Abstract
KRAS mutation is found in around 20-30% of human cancer. Previously, lack of targeting therapy limited the treatment outcomes. Recently, KRAS G12C inhibitors like AMG510, MRTX849, and MRTX1257 were developed and exhibited promising therapeutic outcomes targeting the mutation. However, a considerable amount of cases showed less sensitivity, indicating either intrinsic or adaptive resistance mechanisms. Other reports and our own data exhibited that Focal Adhesive Kinase (FAK) inhibition showed good treatment effects to KRAS mutant cancer. Interestingly, TCGA data analysis reveal that FAK mRNA expression level is significantly higher in KRAS mutant tumors. Considering that FAK is one predominant target for cancer treatment resistance, we hypothesize that FAK is one of mediator leading to resistance mechanism of KRAS G12C inhibition. To explore our hypothesis, we employed high potent FAK inhibitor IN10018, which is being tested in phase I clinical trial for different cancer types. First, we found that IN10018 is active in a series of KRAS mutated cancer xenograft models. The compound sharply decreased the level of phosphoFAK Y397, a direct marker for FAK activity. Then we investigated whether combination of IN10018 with KRAS G12C inhibitors can show synergic effects in vitro and in vivo. IN10018 in combination with either AMG510 or MRTX1257 showed better effects in killing KRAS G12C cancer cells than each single treatment. More importantly a significant synergy between IN10018 with KRAS G12C inhibitors against KRAS mutated cancer cell lines was observed in vivo. Further evidence showed that KRAS G12C inhibition can significantly increase the expression of phosphoFAK Y397, suggesting a possible underlying mechanism of resistance to KRAS G12C inhibitors. IN10018 significantly decreased the upregulated FAK Y397 phosphorylation in the combination treatments, underlying the mechanism of synergy between the two inhibitors. Our results indicate that KRAS G12C cancer patients can be better treated by the combination of IN10018 with KRAS G12C inhibitor.
Citation Format: Baoyuan Zhang, Yan Zhang, Jiangwei Zhang, Ping Liu, Bo Jiao, Zaiqi Wang, Ruibao Ren. Focal adhesive kinase inhibitor IN10018 sensitizes KRAS mutant cancer and overcomes drug resistance of KRAS G12C inhibition [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 LB-021.
Abstract LB-047: CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia
Authors: Umphred-Wilson Katharine , Adoro Stanley 
Published: September 2020

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a very aggressive hematologic malignancy that results from the transformation of immature T-cell progenitors. Aberrant cell growth and proliferation is sustained by strong oncogenic drivers, notably NOTCH1 and MYC, whose activation is present in more than half of all T-ALL cases. However, although it is known that post-translational modifications, such as ubiquitination by the E3-ligase FBXW7, regulate NOTCH1 and MYC protein stability and activity, regulatory proteins involved in their stability remain unestablished. The Charged multivesicular body protein 5 (CHMP5), an accessory protein of the ESCRT (endosomal sorting complex required for transport) pathway, has been shown to regulate the stability of client proteins in thymocytes through the recruitment of de-ubiquitinating enzymes. Here, we report that CHMP5 protein is not only highly expressed in T-ALL cells, but also promotes the stability of transactivating intracellular NOTCH1 (ICN1) and MYC. We found that depletion of CHMP5 significantly reduced the abundance of ICN1 and MYC, and the transcription of their target genes in vitro, as well as suppressed the development of T-ALL in vivo in a murine model of NOTCH1 driven T-ALL. Additionally, loss of CHMP5 restored T-ALL cell susceptibility to chemotherapeutic agents, including glucocorticoids and gamma secretase inhibitors, resistance to which contributes to disease relapse in patients. We further reveal CHMP5 as an adaptor protein required to orchestrate T-ALL client protein deubiquitination and stability. Altogether, our data suggest that CHMP5 is a non-oncogenic dependency of T-ALL and its depletion may be an effective therapeutic strategy for T-ALL.
Citation Format: Katharine Umphred-Wilson, Stanley Adoro. CHMP5 dependency is a therapeutic vulnerability of T cell acute lymphoblastic leukemia [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 LB-047.
Abstract LB-077: Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis
Authors: Lin Jeffrey H. , Vonderheide Robert H. 
Published: September 2020

Abstract
Dysfunction of type 1 conventional dendritic cells (cDC1s) - the dendritic cell subtype crucial for spontaneous anti-tumor T cell immunity - has long been hypothesized to develop secondarily to invasive cancer. Here, we reveal that cDC1 dysfunction instead develops in the earliest stages of cancer development upon formation of preinvasive pancreatic intraepithelial neoplasias (PanINs) in the KrasG12D Trp53R172H Pdx1-Cre-driven (KPC) mouse model of pancreatic ductal adenocarcinoma. This results in systemically increased cDC1 apoptosis and insufficient upregulation of T cell-polarizing cytokines during cDC1 maturation. CD8+ T cell activation following vaccination is subsequently impaired in PanIN- and tumor-bearing mice. Yet, combination therapy with CD40 agonist and Flt3 ligand in tumor-bearing mice returns cDC1 abundance to normal levels and induces an IFNg response signature, repairing cDC1 maturation and restoring full CD8+ T cell activation. This study therefore reveals the unexpectedly early and systemic onset of cDC1 dysregulation while elaborating therapeutically tractable strategies towards cDC1 repair.
Citation Format: Jeffrey H. Lin, Robert H. Vonderheide. Dendritic cell dysfunction precedes tumor formation during pancreatic oncogenesis [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 LB-077.