bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4023: Low nutrient availability drives increased macropinocytosis and MEK inhibitor resistance in KRASG12R-mutant pancreatic ductal adenocarcinoma
Authors: Linke Amanda , Burge Rachel , Hobbs Aaron 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the third most deadly human cancer with a dismal five-year survival rate of 10%. KRAS is mutated in over 95% of PDAC tumors and is a key driver of PDAC tumorigenesis. Mutant KRAS is constitutively active and drives proliferation through the upregulation of numerous signaling and metabolic pathways to support tumor proliferation. Despite the promise of targeted inhibitors of the RAF-MEK-ERK MAPK signaling pathway, arguably the most critical RAS-mediated proliferative signaling pathway, clinical trials targeting oncogenic MEK/ERK signaling as a single-agent therapy have been unsuccessful. The PDAC tumor microenvironment has been shown to be depleted of glutamine and free amino acids, suggesting that PDAC relies heavily on nontraditional metabolic processes for proliferation such as macropinocytosis, the nonselective uptake of proteins and molecules from extracellular spaces, and autophagy, a mode of cellular recycling. Macropinocytosis has been shown to be elevated in PDAC cell lines and human tumors. Despite recent findings describing the limited nutrient availability in the tumor microenvironment, cell culture studies supporting the use of MEK/ERK inhibitors are predominately performed in a high glutamine medium. By utilizing a minimal glutamine medium supplemented with bovine serum albumin, a large protein that is absorbed via macropinocytosis, we show that this growth medium drives resistance to MEK MAPK inhibition. To evaluate whether PDAC cells proliferating in a low glutamine medium can be sensitized to MEK inhibition, we have performed a CRISPR/Cas9 loss-of-function screen targeting the druggable genome to determine effective therapeutic combinations under these conditions. To follow up on our in vitro screen, we will evaluate the therapeutic efficacy of our findings with 2D and 3D PDAC proliferation assays. These studies will describe novel treatment strategies for PDAC patients with elevated macropinocytosis.
Citation Format: Amanda Linke, Rachel Burge, Aaron Hobbs. Low nutrient availability drives increased macropinocytosis and MEK inhibitor resistance in KRASG12R-mutant pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4023.
Abstract 4052: Evaluation of anti-tumor activity of SB-216, a novel potent tubulin inhibitor, in pancreatic cancer
Authors: Wang Rui , Pochampally Satyanarayana , Hamilton David , Miller Duane D. , Li Wei 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high mortality. It is the 4th leading cause of cancer-related death in the U.S. and has the lowest 5-year survival rate among all cancer types. One of the main hurdles for the treatment is limited effective chemotherapy and rapidly acquired resistance against it. Advanced PDAC research and various treatment options only showed minimal enhancement to the overall survival outcomes. Hence more effective drugs and therapies are in need for improving overall therapeutic outcomes for PDAC patients. Recently, we reported the discovery of a new generation of tubulin inhibitors (SB-216) that targets the colchicine binding site and serves as a potent anti-cancer agent for various cancer types. Here, we evaluated the in vitro effects of SB-216 on the PDAC cell lines in comparison with one of the first-line treatment paclitaxel. We also established luciferase labeled Mia PaCa-2 cell line, Mia PaCa-2-Luc, for live monitoring tumor progression and evaluating the anti-tumor effect in subcutaneous mouse models. The results showed that SB-216 effectively inhibited cell proliferation, colony formation, and cell migration dose-dependently at low nanomolar concentrations. Immunoblotting also confirmed SB-216 induced cell apoptosis in a dose-dependent manner. Cell cycle arrest assay confirmed that SB-216 can arrest cells in the G2/M phase. In vivo study suggested that SB-216 inhibited tumor growth significantly in Mia PaCa-2-Luc subcutaneous xenograft model with low toxicity. Our preclinical data demonstrated the potential of SB-216 to inhibit proliferation and induce apoptosis in PDAC cells, indicating a promising chemotherapy agent in treating PDAC. However, further evaluations are warranted in orthotopic and PDX tumor models for clinical significance.
Citation Format: Rui Wang, Satyanarayana Pochampally, David Hamilton, Duane D. Miller, Wei Li. Evaluation of anti-tumor activity of SB-216, a novel potent tubulin inhibitor, in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4052.
Abstract 4056: ONC201 in combination with carboplatin and etoposide as a novel triple drug treatment for small cell lung cancer (SCLC)
Authors: Lee Young S. , Zhou Lanlan , Azzoli Christopher , El-Deiry Wafik S. 
Published: June 2022

Abstract
Lung cancer is the leading cause of cancer death in both men and women according to the American Cancer Society, with more deaths than colon, breast, and prostate cancer combined. Small cell lung cancer (SCLC) comprises about 10 to 15 percent of all lung cancer diagnoses. Frequent loss of RB1 and mutations in p53 in SCLC make it rather difficult to develop targeted therapies. Many current therapies rely on toxic chemotherapy or immunotherapy to combat the aggressive nature of SCLC; however, even with the advent of new therapies, the median survival rate has remained relatively low at 12 to 16 months. SCLC is also characterized by a high mutation rate, resulting in patients becoming increasingly resistant to treatments. This calls for a novel combination to extend patient life expectancy. ONC201 is an imipridone that is currently in clinical trials for its proapoptotic effects in several cancer types. We propose that combining ONC201 with standard first-line chemotherapeutic agents etoposide and carboplatin will result in a synergistic effect and serve as a novel treatment plan for SCLC patients. SCLC cell lines H1048 and H1105 were treated with the novel triple drug combination ONC201, etoposide, and carboplatin. Cell-Titer Glo cell viability assays were conducted for 72 hours to see the additive and/or synergistic effect of novel triple drug treatment. Western blots were also run to evaluate the expression of proapoptotic protein cleaved PARP or expression of cellular metabolic stress protein ATF4 to explore the synergistic effect of triple drug treatments in SCLC cell lines. Cell viability after the triple drug treatment in both cell lines H1048 and H1105 may indicate a potential synergistic effect. Preliminary western results indicate that the triple drug treatment results in an increase in cPARP or ATF4 expression relative to the vehicle, suggesting a synergistic effect of the triple drug treatment. We are currently exploring the novel combination and potential underlying mechanisms behind the synergistic effects of the triple drug treatment. Future studies will evaluate this triple drug combination treatment in mouse models of SCLC.
Citation Format: Young S. Lee, Lanlan Zhou, Christopher Azzoli, Wafik S. El-Deiry. ONC201 in combination with carboplatin and etoposide as a novel triple drug treatment for small cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4056.
Abstract 4093: COSMIC Actionability: Supporting precision oncology through Identification of actionable mutations from clinical trials databases and publications
Authors: Jupe Steven C. , Bindal Nidhi , Sondka Zbyslaw , Wang Shicai , Nair Sumodh , Ponting Laura , Sondheimer Doron , Hathaway Charlie , Forbes Simon A. 
Published: June 2022

Abstract
The availability of drugs that are effective in cancer patients with specific somatic mutations is rapidly evolving. Finding the most recent information is not straightforward; clinical progress and drug approvals are recorded in clinical trial repositories, files from drug regulatory agencies, publications and conference abstracts. Often there is a delay between trials reaching their outcomes, publication and deposition of results in clinical trial databases. COSMIC Actionability is a new addition to COSMIC’s (Catalogue Of Somatic Mutations In Cancer) portfolio of navigational databases for precision oncology. It indicates the availability of drugs that target mutations and tracks the progress of novel drugs through clinical development. All stages of drug development are represented, through safety and clinical efficacy to market approval, with additional data from case studies expanding mutation coverage. For each mutation-cancer type combination, a simple tiered system indicates whether marketed drugs are available and if not, indicates the progress of drug development efforts. Trial records available in databases such as Clinical Trials.gov and EudraCT are supplemented with trials identified in publications. Trial progression and outcomes are recorded; details are sourced from clinical trial databases, publications, conference abstracts, corporate announcements and regulatory authorities such as the FDA. Curation identifies results for approximately 40% more trials than are available in clinical trial databases alone.
Like other COSMIC resources, Actionability is manually curated by Ph.D. level experts. The current version of COSMIC Actionability (October 2021) has 49 fully curated genes with a further 237 having some clinical information. Details of 6244 drug-cancer type combinations are available, of which 2224 have clinical results. 963 drugs are represented, in 2224 treatment combinations. 149 point mutations and 520 further mutations or fusions are represented. This dataset will be made freely available in 2022 then released quarterly, with extended gene coverage and updates of previous content.
Citation Format: Steven C. Jupe, Nidhi Bindal, Zbyslaw Sondka, Shicai Wang, Sumodh Nair, Laura Ponting, Doron Sondheimer, Charlie Hathaway, Simon A. Forbes. COSMIC Actionability: Supporting precision oncology through Identification of actionable mutations from clinical trials databases and publications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4093.
Abstract 4097: Clinicopathologic descriptors of subcutaneous panniculitis-like T-cell lymphoma (SPTCL): Analysis of a pooled database of a rare entity
Authors: Haddad Philip A. , Ganey Nowell 
Published: June 2022

Abstract
Introduction: SPTCL is a rare primary cutaneous T-cell lymphoma. SPTCL was initially described as an aggressive cutaneous T-cell lymphoma frequently associated with hemophagocytic syndrome (HPS) and requiring aggressive multiagent chemotherapy. In 2005, this entity was restricted to SPTCL with αβ phenotype, a less aggressive entity compared to its γδ counterpart, currently known as primary cutaneous γδ T-cell lymphoma. We conducted this analysis to explore the clinicopathologic characteristics of this little-known primary cutaneous T-cell entity.
Methods: In order to study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 214 cases. Descriptive statistics were calculated. Cox proportional-hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS).
Results: A total of 214 patients with confirmed SPTCL diagnosis were identified. The median age was 34 years with a peak incidence between ages 13 and 26. There was a female predominance with F:M ratio of 1.7. Upon presentation, 12% had lymphadenopathy, 12% had hepatosplenomegaly, and 27% had bone marrow involvement. No extra-nodal or extra-cutaneous involvement were reported. Cases expressed CD2 (8%), CD3 (85%), CD4(10%), CD5(10%), CD7 (9%), CD8 (77%), CD56 (6%), Granzyme-B (33%), and TIA-1 (34%). None of the cases expressed CD30. The most common clinical presentations were nodular skin changes (87%) followed by constitutional symptoms (57%). Fifteen and ten percent of SPTCL patients had history of immune-deregulatory disorders and immunosuppressive therapies, respectively. HPS occurred in 24% of the cases. Karyorrhexis, fat necrosis, and dermal involvement were noted in 15%, 9%, and 17%. The median duration of symptoms prior to diagnosis was 4 months. Median OS of the whole group was not reached while the mean OS was 73 months. OS was not impacted by sex, constitutional symptoms, immunocompromising factors, presence of lymphadenopathy, hepatosplenomegaly, or bone marrow involvement. OS was not impacted by histological or immunohistochemical features either. While older age and the occurrence of HPS negatively impacted OS, attaining complete remission positively impacted OS.
Conclusions: This study presents a comprehensive clinicopathologic data from a pooled cohort of patients with SPTCL. It describes the clinicopathologic features of SPTCL and identifies major determinants of OS in this rare disease.
Citation Format: Philip A. Haddad, Nowell Ganey. Clinicopathologic descriptors of subcutaneous panniculitis-like T-cell lymphoma (SPTCL): Analysis of a pooled database of a rare entity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4097.
Abstract 4100: Developmental deconvolution for classification of cancer origin
Authors: Moiso Enrico , Farahani Alexander , Marble Hetal , Hendricks Austin , Mildrum Samuel , Levine Stuart , Lennerz Jochen , Garg Salil 
Published: June 2022

Abstract
Cancer is a disease manifesting in abrogation of developmental programs, and malignancies are namedbased on their cell or tissue of origin. However, a systematic atlas of tumor origins is lacking. Here we map the single cell organogenesis of 56 developmental trajectories to the transcriptomes of over 10,000 tumors across 33 cancer types. We use this map to deconvolute individual tumors into their constituent developmental components. Based on these deconvoluted developmental programs, we construct a Developmental Machine Learning Perceptron (D-MLP) classifier that outputs cancer origin. The D-MLP classifier (ROC-AUC: 0.974 for top prediction) outperforms classification based on expression of either oncogenes or highly variable genes. We analyze tumors from patients with cancer of unknown primary (CUP), selecting the most difficult cases where extensive multimodal workup yielded no definitive tumor type. D-MLP revealed insights into developmental origins and diagnosis for most patient tumors. Our results provide a map of tumor developmental origins, provide a tool for diagnostic pathology, and suggest developmental classification may be a useful approach for otherwise unclassified patient tumors.
Citation Format: Enrico Moiso, Alexander Farahani, Hetal Marble, Austin Hendricks, Samuel Mildrum, Stuart Levine, Jochen Lennerz, Salil Garg. Developmental deconvolution for classification of cancer origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4100.
Abstract 4147: CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors
Authors: Sullivan Kathleen M. , Miao Shichang , Yue Huibin , Zhao Niky , Li Chris , Tai Ezra , Ebsworth Karen , Rico Gonzalo Tapia , De Souza Paul , Schall Tom , Zhang Penglie 
Published: June 2022

Abstract
Background: The small molecule CCX559 is a novel, highly potent inhibitor of human PD-L1 being developed as an oral treatment for cancer patients. We have previously demonstrated that CCX559 has nanomolar potency and high selectivity for PD-L1; that it enhances primary T cell activation and has anti-tumor efficacy, including the ability to induce complete responses, using in vivo models1.
Results: Safety pharmacology studies in preclinical animal species demonstrated pharmacokinetics and an acceptable safety profile for CCX559, which supported the initiation of human trials in patients with advanced tumors. Prior findings from toxicology studies were consistent with immune modulation, including consumptive coagulopathy, increased white blood cell counts, and changes in IL-6 plasma levels. A Phase 1, first in patient, multicenter, open-label, dose-escalation study was initiated, with a starting dose of once-daily (QD) oral dosing at 30 mg. The primary objectives are safety/tolerability, as well pharmacokinetic (PK) assessments aimed at determining a future phase 2 dose. Secondary objectives include pharmacodynamic (PD) assessments of immune cell activation in patient peripheral blood samples, as well as anti-tumor effects. For PK, intensive blood sampling is done on day 1 and day 21 of the first cycle of dosing; additional samples are collected on select days throughout the 21-day treatment cycles. PD analyses are done on selected blood draws as well. The first patient dosed (30 mg QD) showed that the drug was well tolerated with no adverse events reported. Preliminary PK results from this patient revealed CCX559 exposure levels consistent with preclinical predictions. Moreover, PD samples showed elevations in T cell proliferation and activation within the first 15 days, when compared to the predose sample. In conclusion, the preclinical data support clinical development of CCX559. CCX559 shows encouraging initial PK and PD results, and patient enrollment is ongoing in the trial (ACTRN12621001342808).
References: 1Chris Li, et al. CCX559 is a potent orally-administered small molecule PD-L1 inhibitor that induces anti-tumor immunity. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1274.
Citation Format: Kathleen M. Sullivan, Shichang Miao, Huibin Yue, Niky Zhao, Chris Li, Ezra Tai, Karen Ebsworth, Gonzalo Tapia Rico, Paul De Souza, Tom Schall, Penglie Zhang. CCX559, an orally administered small molecule PD-L1 inhibitor for the treatment of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4147.
Abstract 4149: Knock-down of Neuropilin-1 by locked nucleic acid antisense oligonucleotides facilitates cancer immune control
Authors: Maaske Andre , Kirchhammer Nicole , Festag Julia , Rodriguez Laura Fernandez , Buchi Mélanie , Schell Monika , Raith Stefanie , Michel Sven , Klar Richard , Zippelius Alfred , Jaschinski Frank 
Published: June 2022

Abstract
Immune checkpoint inhibitors have become an important tool for the treatment of cancer. However, the majority of patients does not respond to the currently employed antibody-based treatments, indicating a need for additional targets and new treatment modalities. The invention of 3rd generation chemistries like locked nucleic acids (LNAs) has allowed the development of highly specific and efficacious antisense oligonucleotides (ASOs) that allow target knockdown in vivo without the need for complex delivery formulations.
The membrane-bound protein neuropilin-1 (NRP1) was initially identified as a factor involved in cell migration, -survival, and neoangiogenesis making it an attractive target for cancer therapy. It was subsequently shown that it has additional immune-mediated pro-tumorigenic roles. It can suppress anti-tumor immune activity via regulation of trafficking of tumor-associated macrophages, phenotypic stability of Tregs, and exhaustion of effector T cells. Considering that these effects are mediated by multiple domains of NRP1, there is a conceptual advantage to down-regulate the expression of the whole protein over the functional or steric blockade of individual domains.
We used our in-house Oligofyer™ bioinformatics system to design both human NRP1 specific LNAplus™ ASOs, as well as murine surrogates, which both achieved target knock-down of more than 85% in vitro. Furthermore, the murine surrogate down regulated NRP1 in tumor mouse models. Systemic application of mouse-specific ASOs without additional carriers or adjuvants has led to a strong delay of tumor growth or complete eradication in syngeneic mouse models. This effect was almost completely abrogated in immune-compromised NSG mice. Furthermore, re-challenge of immune-competent mice after tumor eradication did not result in new tumor growth, suggesting induction of a long-lasting immunity by LNAplus™ ASO-mediated knockdown of NRP1. Taken together, these encouraging results indicate that the ASO-mediated down-regulation of NRP1 has the potential to become a promising treatment option for patients in need. We are currently performing further experiments to fully elucidate the mechanisms that underlie the observed anti-tumor efficacy.
Citation Format: Andre Maaske, Nicole Kirchhammer, Julia Festag, Laura Fernandez Rodriguez, Mélanie Buchi, Monika Schell, Stefanie Raith, Sven Michel, Richard Klar, Alfred Zippelius, Frank Jaschinski. Knock-down of Neuropilin-1 by locked nucleic acid antisense oligonucleotides facilitates cancer immune control [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4149.