bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5226: The PI3K inhibitor Paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models of atypical teratoid/rhabdoid tumors
Authors: Malebranche Kristen , Findlay Tyler , Eberhart Charles , Raabe Eric , Rubens Jeffrey 
Published: June 2022

Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are aggressive pediatric brain tumors and the most common malignant brain tumors of infancy. The four-year event-free survival rate is only 37%. For patients with relapsed AT/RT, there are limited treatment options, but novel precision therapies may help improve survival for patients with this deadly disease. We have previously identified strong activation of the PI3K-AKT-mTOR (mTOR) signaling pathways in AT/RT. Paxalisib is a highly brain-penetrant PI3K inhibitor acting upstream of mTOR. We find that Paxalisib slows tumor growth in orthotopic xenograft models of AT/RT and extends median survival from 40 to 54 days (p=0.001, log-rank test). RNASeq after mTOR pathway inhibition identifies reflexive activation of the MAPK pathway as a possible mechanism of therapy resistance (KEGG pathway analysis). TAK580 (DAY 101) is a highly brain penetrant, pan-RAF kinase inhibitor, currently in clinical trials in pediatric low grade gliomas (NCT03429803, NCT04775485). Paxalisib combines synergistically with TAK580 to reduce AT/RT growth and viability (Bliss synergy score 24.22). A pilot study suggests combination therapy is well tolerated in mice bearing AT/RT orthotopic xenografts and slows tumor growth compared to Paxalisib alone and vehicle controls. This novel combination of precision therapies can translate into a clinical trial aimed at improving survival in this deadly disease.
Citation Format: Kristen Malebranche, Tyler Findlay, Charles Eberhart, Eric Raabe, Jeffrey Rubens. The PI3K inhibitor Paxalisib combines synergistically with the pan-Raf inhibitor TAK580 (DAY 101) to extend survival in orthotopic xenograft models of atypical teratoid/rhabdoid 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 5226.
Abstract 5227: Combination therapy activating the integrated stress response synergistically suppresses proliferation and induces apoptosis in diffuse intrinsic pontine glioma
Authors: Novak Orlandi V. , Arnold Antje , Eberhart Charles , Raabe Eric H. 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor. Radiation, the standard of care, extends life for 6-18 months but has never cured a patient. Therefore, the discovery of novel treatments is imperative. DIPG tumors have elevated baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that allows cells to tolerate various forms of stress. Increased expression of activating transcription factor 4 (ATF4) indicates activation of the ISR. Low levels of ATF4 protect cells from stress, while sustained high-levels of ATF4 result in cell death. Because DIPG has a high baseline level of ATF4, we hypothesized that the ISR activators Sal003 and ONC201 would synergize and kill DIPG cells. After determining the IC25 of Sal003 and ONC201, we treated three patient-derived cell lines: JHH-DIPG1, SF-7761, and JHH-DIPG16A with low micromolar doses. To measure proliferation, we performed immunofluorescence staining for bromodeoxyuridine (BrdU) incorporation. The combination treatment significantly reduced BrdU incorporation (JHH-DIPG1 p=0.0026, SF-7761 p=0.0002, JHH-DIPG16A p&lt;0.0001 by ANOVA and Dunnett’s multiple comparisons test compared to DMSO control). In all three cell lines, the combination also significantly reduced proliferation compared to monotherapy. We next measured apoptosis by staining for cleaved caspase-3 (CC3) and performing western blots for cleaved PARP. The combination of Sal003 and ONC201 significantly increased apoptosis as measured by CC3 immunofluorescence in comparison to DMSO (JHH-DIPG1 p&lt;0.0001, SF-7761 p&lt;0.0001, JHH-DIPG16A p&lt;0.0001 by ANOVA and Dunnett’s multiple comparisons test compared to DMSO control). In all cell lines, combination therapy significantly increased CC3 positivity compared to single treatment. Western blots for cleaved PARP expression detected induction of apoptosis in all three cell lines treated with the combination over DMSO and monotherapy treated cells. In JHH-DIPG1 and SF-7761, the combination increased ATF4 expression. Since Sal003 is not yet available for clinical testing in humans, we will next investigate treatment with ONC201 and the well-tolerated ATF4 inducer fenretinide. The combination of ONC201 with another ISR activating agent has the potential to serve as a therapy for DIPG.
Citation Format: Orlandi V. Novak, Antje Arnold, Charles Eberhart, Eric H. Raabe. Combination therapy activating the integrated stress response synergistically suppresses proliferation and induces apoptosis in diffuse intrinsic pontine glioma [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 5227.
Abstract 5249: Efficacy and safety of apatinib in treatment of unresectablehepatocellular carcinoma: A real-world study
Authors: Liu Jun , Li Guangbing , He Qiang , Sun Shijun , Zhao Chuanlin , Sun Chuandong , Zhang Bo , Cui Yi , Ye Yongqiang , Zhi Xuting , Li Shiping , Li Shiping , Pan Guozheng , Ma Changlin , Hu Jinhua , Li Jun , Wang Suling , Qiao Yuangang , Ren Wanhua , Meng Qi 
Published: June 2022

Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in China. Apatinib is a small molecule TKI inhibitor. Its efficacy and safety for unresectable HCC patients have been demonstrated in randomized controlled clinical studies. However, the efficacy and safety of apatinib in real world is lacking. We are aiming to evaluate the efficacy and safety of apatinib in real world.MethodsPatients of older than 18 years with unresectable HCC confirmed by IHC (Immunohistochemistry) or CT and MR Imaging were enrolled in the study. All patients received apatinib monotherapy or combined with other treatments including TACE and chemotherapy. The enrolled patients were treated until disease progression, death, or severe intolerable toxicity, etc. The primary endpoint was overall response rate (ORR), and secondary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The adverse events (AEs) were also recorded.ResultsFrom February, 2019 to May, 2020, a total of 233 patients were enrolled. Among them, 66 (28.33%) patients received apatinib monotherapy and 167 (71.67%) patients received combination therapy. Patients with a history of hepatitis accounted for 70%. 8 patients achieved complete response (CR), 64 patients achieved partial response (PR), 120 patients achieved stable disease (SD), and 41 patients had progressive disease (PD), illustrating an ORR of 30.90% and a DCR of 82.40%. Median PFS and OS were 6.93 months (95% CI, 6.19-7.68 months) and 11.36 months (95% CI, 9.96-12.77 months), respectively. The safety profile indicated that the most common drug-related adverse events were hypertension (37.90%), hand-foot-skin reaction (27.39%), fatigue (19.11%), thrombocytopenia (16.02%). Grade 3/4 treatment related AEs included thrombocytopenia (4.30%), hypertension (3.82%), neutropenia (2.73%). After symptomatic treatment, all the adverse events were treated properly, and no unexpected adverse events were observed. Conclusions In current study, apatininb showed good tolerance with acceptable toxicity and high tumor response rate that translated into promising PFS and OS in unresectable HCC patients. ChiCTR1900021822
Citation Format: Jun Liu, Guangbing Li, Qiang He, Shijun Sun, Chuanlin Zhao, Chuandong Sun, Bo Zhang, Yi Cui, Yongqiang Ye, Xuting Zhi, Shiping Li, Shiping Li, Guozheng Pan, Changlin Ma, Jinhua Hu, Jun Li, Suling Wang, Yuangang Qiao, Wanhua Ren, Qi Meng. Efficacy and safety of apatinib in treatment of unresectablehepatocellular carcinoma: A real-world study [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 5249.
Abstract 5254: Association of USP6 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors
Authors: Long De , Fan Dandan , Chen Yaoxu , Huang Mengli 
Published: June 2022

Abstract
Background: Melanoma is a serious skin cancer. Immune checkpoint inhibitors (ICIs) including pembrolizumab, nivolumab, ipilimumab have been approved by FDA. However, ICIs demonstrate antitumor effects only in a fraction of patients and research exploring the association between gene mutation and clinical benefit is limited. USP6 (Ubiquitin-specific protease 6) mutation rate is high in melanoma. Studies have shown that USP6 functions as a tumor suppressor in Ewing Sarcoma through the activation of NK cells and macrophages, which indicates that USP6 activity may create a "hot" tumor microenvironment in immunotherapy. The association between USP6 mutation and survival in melanoma is unknown.
Methods: The association between USP6 mutation with TMB and survival data was analyzed in melanoma patients from the public immunotherapy-treated cohort called Melanoma.Allen2015.WES.110, which worked as training cohort while another cohort called Melanoma.Hugo2016.WES.38 worked as validation cohort. Wilcoxon test was used for the comparison of TMB. OS (Overall survival) analysis were conducted in the public cohort using Kaplan-Meier curves and log-rank tests. In addition, the genomic and immune cell infiltration data of 466 patients with Skin Cutaneous Melanoma was obtained from TCGA and the correlation analysis was further analyzed by CIBERSORT. Statistical significance was set at p=0.05.
Results: In the training cohort, 10.9% (12/110) melanoma patients harbored USP6 mutation. USP6 mutation is associated with higher TMB (p=0.0007) and results in significantly longer OS (21.3 vs 8.1 months; HR, 0.44; p=0.049).Meanwhile, the validation cohort shows that USP6 mutation results in higher TMB without significant difference (p=0.08) and significantly longer OS (31.5 vs 14.4 months; HR, 0.14; p=0.0026).Furthermore, the correlation analysis between immune infiltration and USP6 mutation status in melanoma shows that both M1 macrophages and follicular helper T cells increased significantly (p=0.02, p=0.033), while differential neutrophil decreased significantly (p=0.048).
Conclusions: This study shows that USP6 mutation may serve as a potential positive biomarker of ICIs in melanoma since it correlated with higher TMB, the up regulation of M1 macrophages, follicular helper T cells and the down regulation of differential neutrophil.
Citation Format: De Long, Dandan Fan, Yaoxu Chen, Mengli Huang. Association of USP6 mutation with tumor mutation burden and survival in melanoma patients treated with immune checkpoint inhibitors [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 5254.
Abstract 5266: Prognostic role of molecular subclassification based on mutational profiling and tumor-associated neutrophil status in stage III colon cancer
Authors: Chan CY , Lo AWI , Lam KO , Ng HY , Chen CC , Lung ML , Ko JMY 
Published: June 2022

Abstract
The traditional prognostic prediction of colon cancer (CC) is based on the tumor-node-metastasis (TNM) system. This, however, is not adequate for clinical decision making due to the existence of inter-patient variations and heterogeneity of underlying molecular pathways. We aim to investigate the prognostic value of molecular subclassification utilizing i) tumor-associated neutrophil (TAN) status by immunohistochemical (IHC) staining; ii) microsatellite instability (MSI) and elevated microsatellite alteration at selected tetranucleotide repeats (EMAST) status by PCR-based microsatellite typing; and iii) next-generation sequencing (NGS) mutational profiling by deep sequencing of a 77-gene oncology panel. In the discovery phase, 130 pairs of archived normal and tumor formalin-fixed paraffin-embedded (FFPE) specimens of stage III CC patients were retrospectively recruited from Queen Mary Hospital. CC patients will be categorized into different molecular subclasses (MSCs) based on the status of TAN/MSI/EMAST/NGS mutational profiling molecular biomarkers. Kaplan-Meier analysis, log rank test, univariate and multivariate Cox proportional hazards regression analysis will be used for estimation of progression-free survival (PFS) and overall survival (OS) between the two groups of CC patients. We expect our data to provide useful information for improved stratification of stage III CC patients into high or low risk of recurrence and survival.
Acknowledgement: The Health and Medical Research Fund (07181536) to JMYK.
Citation Format: CY Chan, AWI Lo, KO Lam, HY Ng, CC Chen, ML Lung, JMY Ko. Prognostic role of molecular subclassification based on mutational profiling and tumor-associated neutrophil status in stage III colon 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 5266.
Abstract 5311: Auranofin sensitizes paclitaxel induced apoptotic cell death through oxidative mechanism in breast cancer cells
Authors: Prasad N. Rajendra , Natarajan Deepika 
Published: June 2022

Abstract
Breast cancer cells exhibit several basal redox systems, thus poorly responding to oxidative cell death. These intrinsic redox statuses capitalize on the efficacy of chemotherapeutic drugs. Auranofin, an FDA-approved gold compound documented with effective pharmacokinetics and safety profiles in humans, has recently been repurposed for anticancer activity. This study examined the paclitaxel sensitizing effect of auranofin by targeting redox balance in the MDA-MB-231 and MCF-7 breast cancer cell lines. We observed that auranofin inhibits thioredoxin reductase activity (TrxR) in these breast cancer cells and collapses the cellular antioxidants status, including the reduced activities of superoxide dismutase, catalase, and glutathione peroxidase. Furthermore, it has been noticed that auranofin augmented paclitaxel mediated cytotoxicity in a concentration dependant manner in both the MDA-MB-231 and MCF-7 cell lines. Furthermore, auranofin increased intracellular ROS levels (DCFH-DA staining) and altered mitochondrial membrane potential (Rhodamine-123 staining) in these breast cancer cell lines. The proapoptotic markers such as p53, Bax, and caspase-3 and caspase-9 expressions were higher in auranofin plus paclitaxel treated breast cancer cells when compared to paclitaxel alone treatment. Thus, the present results illustrate the chemosensitizing property of auranofin in MDA-MB-231 and MCF-7 breast cancer cell lines.
Citation Format: N. Rajendra Prasad, Deepika Natarajan. Auranofin sensitizes paclitaxel induced apoptotic cell death through oxidative mechanism in breast cancer cells [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 5311.
Abstract 5314: Selinexor, a selective inhibitor of nuclear export (SINE) compound, enhances the anti-tumor activity of Eribulin in leiomyosarcoma
Authors: Mittal Sonam , Pulikkal Ishaque , Chang Hua , Landesman Yosef , Charlson John , Pradeep Sunila 
Published: June 2022

Abstract
Leiomyosarcoma (LMS) is a rare soft tissue sarcoma (STS) that begins in smooth muscle tissue and most often initiates in the abdomen or uterus. Compared with other uterine cancers, uterine LMS is an aggressive tumor associated with poor prognosis and has a high risk of recurrence and death, regardless of stage at presentation. Selinexor is a first-in-class selective inhibitor of nuclear export (SINE) compound that binds covalently to exportin 1, thereby reactivating tumor suppressor proteins and downregulating the expression of oncogenes and DNA damage repair (DDR) proteins. Selinexor has demonstrated preclinical activity in various cancer types, including STS, and is currently in Phase I and II clinical trials for advanced cancers (Marretta et al. 2021). In this study, we evaluated the effects of Selinexor in combination with Dacarbazine, Gemcitabine, Doxorubicin, Pazopanib, Eribulin, and Trabectedin in LMS cell lines. The effects on cell viability were evaluated by treating the LMS cell lines SK-UT1 (p53-mut) and SK-UT1-B (p53 WT) with Selinexor and different chemotherapy combinations. Treatment with these drugs significantly decreased the cell proliferation and survival of SK-UT1 and SK-UT1-B cell lines tested in vitro. However, this effect was enhanced in SK-UT1 cells following treatment in the combination of Selinexor with Eribulin and Doxorubicin. The effects of treatment were also evaluated in mouse xenograft models generated with SK-UT1 cell lines. Treatment with Selinexor combined with Eribulin showed synergistic effects on tumor growth inhibition in SK-UT1 derived xenografts which warrant further investigation of these combinations at the clinical level.
Citation Format: Sonam Mittal, Ishaque Pulikkal, Hua Chang, Yosef Landesman, John Charlson, Sunila Pradeep. Selinexor, a selective inhibitor of nuclear export (SINE) compound, enhances the anti-tumor activity of Eribulin in leiomyosarcoma [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 5314.
Abstract 5325: Image-based functional precision medicine for repurposing neuroactive drugs in glioblastoma
Authors: Lee Sohyon , Weiss Tobias , Bühler Marcel , Wegmann Rebekka , Mena Julien , Bihl Michel , Goetze Sandra , van Drogen Audrey , Rushing Elisabeth J. , Wollscheid Bernd , Weller Michael , Snijder Berend 
Published: June 2022

Abstract
Treatment of glioblastoma multiforme (GBM), the most aggressive form of primary brain cancer, has essentially not advanced over the past few decades. Numerous challenges hinder the successful development of new therapies, including drug delivery across the blood-brain barrier (BBB), the complexity of the tumor microenvironment (TME), and the lack of clinically predictive cancer models. Here, we present the results of an image-based ex vivo drug-testing platform that addresses these therapeutic roadblocks. To demonstrate the clinical utility of our platform, in a retrospective cohort of 14 GBM patients, we show that ex vivo sensitivity to Temozolomide (TMZ, 1st-line GBM chemotherapy), is associated with longer progression free survival (PFS) and overall survival (OS). Next, by screening 150 clinically approved drugs across 27 GBM surgical patient samples, we identify a set of BBB-permeable neuroactive drugs with anti-glioma activity. These neurological drugs display remarkably consistent on-target killing of cancer cells with minimal toxicity to non-malignant TME cells across both primary and recurrent GBM samples. Single-cell transcriptional profiling of GBM patient samples and functional genetics reveals novel glioma-dependencies on neurological drug-target expression. Furthermore, a drug-target network enrichment analysis uncovers an AP1/BTG/TP53 gene signature associated with the anti-glioma activity of neurological drugs. In silico screening of over 1 million compounds for this common gene signature identified additional drug hits that could be validated in patient samples with 90% accuracy. Multiplexed transcriptomics revealed AP-1 transcription factor family activation to be the common underlying feature of neurological drugs with anti-glioma activity. Among the most promising candidate drugs, we identify the atypical antidepressant Vortioxetine as the strongest inducer of this gene signature, and confirm its efficacy in vivo across multiple mouse models. Vortioxetine in combination with Temozolomide or Lomustine further increased median survival in vivo compared to single agents alone. This study thus provides a clinically predictive and personalized drug-testing platform that identifies new treatment opportunities for GBM, warranting further investigation.
Citation Format: Sohyon Lee, Tobias Weiss, Marcel Bühler, Rebekka Wegmann, Julien Mena, Michel Bihl, Sandra Goetze, Audrey van Drogen, Elisabeth J. Rushing, Bernd Wollscheid, Michael Weller, Berend Snijder. Image-based functional precision medicine for repurposing neuroactive drugs in glioblastoma [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 5325.
Abstract 533: A study of sequencing circulating cell free DNA from lung cancer patients
Authors: Kang Zhigang , Cao Liang 
Published: June 2022

Abstract
Precision oncology requires accurate cancer molecular information. While widely used to characterize tumors, tissue biopsy is limited in patient follow-up due to its invasive nature and the lack representation of the entire tumor bulk. To develop the method of circulating cell free DNA (cfDNA) for obtaining clinically valuable sequence information, we isolated cfDNA from the plasma samples of 10 advanced metastatic lung cancer patients and performed next generation sequencing (NGS) using a unique molecular marker (UMI) integrated 275-gene-target-panel at the average depth of 4,000 X coverage. We were able to identify common mutants of lung cancer driver genes, e.g. EGFR, KRAS, DNMT3 and TP53 with high confidence. In one example, the TKI resistant EGFR mutant T790M was found coexisting with EGFR 746-750del and TP53 splice variant in a baseline sample of a patient progressed from a first-generation EGFR inhibitor. And the dynamic changes of the allele frequency of EGFR and TP53 mutants were consistent with total cfDNA levels of the patients. Interestingly, an osimertinib resistance EGFR mutant C797S emerged at Day 355 post-treatment and followed by disease progression in 4 months. In addition to EGFR gene mutations, we further found increasing EGFR copy number associated with drug resistance and cancer progression of this patient. Our study demonstrated that it is feasible using cfDNA for patient follow-up to understand cancer resistance or disease progression through characterization of cancer mutations.
Citation Format: Zhigang Kang, Liang Cao. A study of sequencing circulating cell free DNA from lung cancer patients [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 533.