bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 287: A novel class III receptor tyrosine kinase inhibitor synergizes with olaparib by inhibition of DNA repair-related genes in non-small cell lung cancer cells
Authors: Ryu Hwani , Song Jie-young , Hwang Sang-Gu , Ahn Jiyeon 
Published: August 2019

Abstract
The platelet-derived growth factor receptors (PDGFRs), which are classified with class III receptor tyrosine kinase (RTK) family, play critical roles in cell proliferation, differentiation, and malignancy in various types of human cancers. To develop novel class III RTK inhibitors, dozen novel oxazole amine derivatives were designed and synthesized. Among the synthesized compounds, KM201 showed inhibitory activities of pan-class III RTK by an in vitro kinase activity assay and potent anti-proliferative activities in variety of cancer cell lines including leukemia and solid cancer cells. Genome-wide RNAseq profiling revealed a significant decrease of DNA repair-related genes in non-small cell lung cancer A549 cells treated with KM201. Moreover, KM201-induced DNA damage was detected by H2AX phosphorylation, which led to cell cycle arrest in the G2/M phase. We hypothesized that KM201 in combination with a PARP inhibitor may exhibit synergistic effect on inhibition of proliferation since PARP inhibitors are primarily effective against cancers with loss-of-function mutations in BRCA1 and BRCA2. Combination of KM201 and olaparib (a PARP inhibitor) markedly more effective in anti-proliferation and apoptotic cell death in A549 and H1299 cells harboring wild type BRCA1/2, compared with either drug alone. Our results show that the novel class III RTK inhibitor KM201 inhibits proliferation of leukemia and solid tumor cells by potentiating DNA damage and exerts synergistic cytotoxicity in combination with olaparib. Further detailed studies could help to investigate the full potential of KM201 as a class III RTK inhibitor and a combination adjuvant of PARP inhibitors.
Citation Format: Hwani Ryu, Jie-young Song, Sang-Gu Hwang, Jiyeon Ahn. A novel class III receptor tyrosine kinase inhibitor synergizes with olaparib by inhibition of DNA repair-related genes in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 287.
Abstract 2870: Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia
Authors: McNeer Nicole , Philip John , Geiger Heather , Ries Rhonda E. , Lavallee Vincent-Philippe , Walsh Michael , Shah Minita , Arora Kanika , Emde Anne-Katrin , Robine Nicolas , Alonzo Todd A. , Kolb E. Anders , Gamis Alan S. , Smith Malcom , Gerhard Daniela Se , Guidry-Auvil Jaime , Meshinchi Soheil , Kentsis Alex 
Published: August 2019

Abstract
Survival for children with acute myeloid leukemia (AML) remains low, with a primary induction remission failure rate of 10-15%. Although some mutations have been identified that are associated with increased relapse risk, the genomic landscape of pediatric AML resistant to primary chemotherapy is not well characterized. As part of the TARGET initiative (Therapeutically Applicable Research To Generate Effective Treatments), we assembled a cohort of 28 pediatric AML patients with primary chemotherapy resistance and failure of induction chemotherapy, uniformly treated as part of the COG AAML0531 study. We analyzed whole-genome DNA, mRNA, and miRNA sequence data obtained at diagnosis and after induction chemotherapy. At least three genetically distinct groups were apparent in this cohort, including those with NUP98 rearrangements, somatic mutations of WT1 in the absence of NUP98 variants, and additional recurrent variants including those in KMT2C and MLLT10. Comparisons of mutations before and after chemotherapy revealed both common and distinct gene expression programs. On chemotherapy exposure, these leukemias exhibited diverse forms of clonal evolution. We observed selection for mutant alleles of FRMD8, DHX32, PIK3R1, SHANK3, MKLN1, as well as persistence of WT1 and TP53 mutant clones, and elimination or contraction of FLT3, PTPN11, and NRAS mutant clones. These findings suggest diverse genetic mechanisms for primary chemotherapy resistance in pediatric AML, which should guide new approaches for its diagnosis and therapy.
Citation Format: Nicole McNeer, John Philip, Heather Geiger, Rhonda E. Ries, Vincent-Philippe Lavallee, Michael Walsh, Minita Shah, Kanika Arora, Anne-Katrin Emde, Nicolas Robine, Todd A. Alonzo, E. Anders Kolb, Alan S. Gamis, Malcom Smith, Daniela Se Gerhard, Jaime Guidry-Auvil, Soheil Meshinchi, Alex Kentsis. Genetic mechanisms of primary chemotherapy resistance in pediatric acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2870.
Abstract 2892: Genetic inhibition of STAT3 increases medulloblastoma chemosensitivity
Authors: Ray Sutapa , Coulter Donald , Wilder Phillip , Sughroue Jason , Chaturvedi Nagendra , Mcguire Timothy , Joshi Santharam , Sharp Graham , Bhakat Kishor , Rizzino Angie 
Published: August 2019

Abstract
Medulloblastoma (MB) is the most common malignant brain tumor in children that arises from cerebellar neuronal progenitor cells. Post-surgical radiotherapy in combination with adjuvant chemotherapy are considered as standard treatment of care for MB. However, this long-term treatment often leads to harmful neurologic effects to the developing brain in children. Therefore, identification of novel therapeutic target to increase efficacy and reduce toxicity in MB represent an unmet clinical need. Signal transducers and activators of transcription-3 (STAT3) is constitutively activated in MB, where it functions as an oncoprotein, mediating cancer cell proliferation. Here, to evaluate the biological consequences of specific targeting of STAT3 in detail, we engineered MYC expressing Group 3 MB cells to stably express STAT3 shRNA under a doxycycline (Dox) inducible promoter and assessed the its effect on STAT3 function. Treatment of MB cells with Dox leads to growth inhibition and cell cycle arrest. Dox treatment downregulated expression of STAT3 and its target genes/proteins including MYC and delayed migration of MB cells. Expression of STAT3 shRNA decreased association of STAT3, BRD4, phospho-RNA Pol II to the proximal promoter of MYC and CCND1. It further downregulated occupancy of acetylated histone H3 K27 to the MYC and CCND1 promoter indicating gene repression. Moreover, we showed that combination Dox and cisplatin significantly decreased highly aggressive MYC-amplified MB cell growth and induced apoptosis by downregulating STAT3 regulated proliferation and anti-apoptotic gene expression. Together, our results revealed an important role of STAT3 in regulating MB pathogenesis. Disruption of this pathway with STAT3 inhibitor, therefore, may serves as a promising candidate for targeted MB therapy by enhancing chemo-sensitivity of MB cells, potentially improving outcomes in high-risk patients.
Citation Format: Sutapa Ray, Donald Coulter, Phillip Wilder, Jason Sughroue, Nagendra Chaturvedi, Timothy Mcguire, Santharam Joshi, Graham Sharp, Kishor Bhakat, Angie Rizzino. Genetic inhibition of STAT3 increases medulloblastoma chemosensitivity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2892.
Abstract 2893: ALK amplification and rearrangements are recurrent targetable events in glioblastoma
Authors: Blandin Anne-Florence 
Published: August 2019

Abstract
Anaplastic Lymphoma Kinase (ALK) expression, rearrangements, and single nucleotide variants have been reported in several brain tumor types, but the significance and function of each aberration in adults and children have not been clearly established. To determine the degree to which ALK represents a relevant therapeutic target in gliomas, we first examined ALK expression using immunohistochemistry (IHC) in a panel of 148 adult GBM and 49 pediatric GBM/high grade gliomas. We identified high ALK expression was most frequent in pediatric gliomas (32%, 16/49, IHC score 2+ or 3+). Copy arrays/sequencing and FISH for the ALK locus revealed high levelALK amplification in 31% of ALK-expressing cases (5/16) but was a rare event in gliomas overall. Whole-genome sequencing and RNA sequencing identified novel and recurrent PPP1CB-ALKfusions in 43% of ALK-expressing pediatric GBM (7/16), suggesting IHC may be an efficient means of screening for ALK aberrations as in the identification of EML4-ALK lung cancer. All ALK- amplified cases harbored PPP1CB-ALK fusion but 2 PPP1CB-ALK cases were copy neutral. The phosphatase PPP1CB was fused in-frame to ALK at exon 20 with preservation of the ALK kinase domain and predicted to activate via the same mechanism as other ALK rearranged cancers. ALKfusion proteins promoted cell proliferation and constitutive kinase activity and upregulated STAT and AKT signaling pathways. However, expression of novel ALK missense mutations in NSCs did not promote proliferation. Administration of ALK inhibitor Crizotinib reduced tumor growth in a PDX GBM from a patient with a novel ALK fusion. This work validates amplification and rearrangement of ALK as a highly recurrent driver event and therapeutic target in GBM, particularly in young children where it may be the sole driver event.
Note: This abstract was not presented at the meeting.
Citation Format: Anne-Florence Blandin. ALK amplification and rearrangements are recurrent targetable events in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2893.
Abstract 290: Formulation of tolerable protocols for combination regimens to control triple-negative breast cancer cell-derived xenograft tumor development in animals
Authors: Pattarawat Pawat , Wallace Shelby , Odoi Agricola , Pfisterer Bianca , Wang Hwa-Chain R. 
Published: August 2019

Abstract
Cumulative research and clinical results suggest an advantage to use a multiple drug combination over a single drug to control tumor growth and metastasis. In general, combination therapy may result in lower treatment failure rates, lower case fatality ratios, slower development of resistance, and fewer side effects than monotherapy, as well as reducing cost. Triple-negative breast cancer (TNBC) is aggressive, lethal, and heterogeneous. The molecular heterogeneity may account for the differential responses of TNBC to chemotherapies. TNBC is sensitive to conventional chemotherapies with initially high response rates; however, the prognosis is not optimal due to cancer recurrence and metastasis. Although recent advancements in drug development of targeted therapeutics and immunotherapy were somewhat effective in treating TNBC, these therapeutics still need extensive study. Although combination regimens are thought to have better therapeutic outcomes than single drug treatments, drug combinations may also come with overlapped toxicities. Thus, it is important to identify combination regimens that are safe and effectively treat cancers. Based on our in vitro results of combination regiments effective in the synergistic induction of TNBC cell death, we systemically investigated the toxicity and efficacy of combined triple and double agents at various doses and administration protocols to assess the treatment of mice bearing TNBC cell-derived xenograft tumors. We analyzed the adverse effects of combination regimens on the bone marrows, livers, and kidneys, as well as the blood cell profiles in immune-competent and -deficient mice. Our studies successfully identified tolerable protocols for triple and double combination regimens of gemcitabine, romidepsin, and cisplatin, which are FDA-approved anticancer agents, as well as the efficacy of these combination regimens in controlling TNBC xenograft tumors in immune-deficient mice. Our results indicated that the triple combination of gemcitabine plus romidepsin and cisplatin regimen was more effective than double combination regimens in the control of TNBC tumor development in vivo. In conclusion, our studies suggested that the triple combination regimens should be promptly considered as an advanced treatment of TNBC over the conventional gemcitabine and cisplatin regimen or the clinical trial romidepsin plus cisplatin regimen.
Citation Format: Pawat Pattarawat, Shelby Wallace, Agricola Odoi, Bianca Pfisterer, Hwa-Chain R. Wang. Formulation of tolerable protocols for combination regimens to control triple-negative breast cancer cell-derived xenograft tumor development in animals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 290.
Abstract 2904: Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer cell fate and behavior
Authors: Li Mingchuan , Nopparat Jongdee , Zhang Jiao , Aguilar Byron J. , Chen Yan-Hua , Du Jie , Ai Xin , Luo Yong , Jiang Yongguang , Boykin Christi , Lu Qun 
Published: August 2019

Abstract
Only a small number of genes are bona fide oncogenes and tumor suppressors such as Ras, Myc, p53 and PTEN. However, targeting these cancer drivers frequently fail to demonstrate sustained cancer remission. Tumor heterogeneity and evolution contribute to cancer resistance and pose challenges for cancer therapy due to differential gene expression profiles driving distinct tumor responses to treatments. Here we report that intratumor heterogeneity of Wnt/β-catenin/armadillo modulator δ-catenin controls individual cell behavior to promote cancer. The differential intratumor subcellular localization of δ-catenin mirrors its compartmentalization in prostate cancer xenograft cultures as a result of mutation-rendered δ-catenin truncations. Wildtype and δ-catenin mutants displayed non-overlapping protein interactomes that highlight rewiring of signal networks. Localization specific δ-catenin mutants influenced p120ctn-dependent Rho GTPase phosphorylation and shifted cells towards bFGF-responsive growth, a known signal to bypass androgen receptor dependence. Mutant δ-catenin promoted Myc-induced prostate tumorigenesis by increasing proliferation over apoptosis as well as β-catenin stabilization and HIF-1α expression. Therefore, intratumor δ-catenin heterogeneity by genetic remodeling promotes prostate cancer expansion towards androgen independence, supporting a neomorphism model paradigm for targeting tumor progression.
Citation Format: Mingchuan Li, Jongdee Nopparat, Jiao Zhang, Byron J. Aguilar, Yan-Hua Chen, Jie Du, Xin Ai, Yong Luo, Yongguang Jiang, Christi Boykin, Qun Lu. Intratumor δ-catenin heterogeneity driven by genomic rearrangement dictates growth factor dependent prostate cancer cell fate and behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2904.
Abstract 2912A: Intratumoral heterogeneity and immune checkpoint inhibitor response in the KPC pancreatic cancer model
Authors: Roth Sarah Martinez 
Published: August 2019

Abstract
Cancer cells are subjected to evolutionary selection and adaptation of clonal populations by changes in the tumor and metastatic microenvironment as well as their response to drug treatment. We wished to evaluate how this tumor heterogeneity impacts the efficacy and responses to immune checkpoint blockade. To understand the contribution of clonal subpopulations to the malignant progression and to the response to drugs, we established a model of tumor heterogeneity from six syngeneic, clonal primary cancer cells isolated from a p48-CRE X LSLmutKras X LSLmutP53 mouse pancreatic cancer (KPC). The clonal cell lines were characterized for genomic mutations, gene expression and tumor allografts reconstituted in syngeneic host mice from mixes of the clonal cell lines. Each of the clonal cells formed invasive and metastatic lesions when grafted into hosts. The original tumor and clonal cell lines harbored common mutations in 99 genes demonstrating their common ancestry. Additional unique mutations in the clonal lines were used to identify and quantitate clones in heterogeneous cell pools. The clones showed different levels of MAP kinase signaling, unique morphologies, different growth rates in vitro and tumor growth rates in immune competent mice. Moreover, the sensitivity to ~200 anticancer drugs revealed an up to 25-fold varying in vitro sensitivity of the clones to signal transduction inhibitors and cytotoxic drugs. Drug sensitivity of individual clones when included in a heterogeneous cell population was strikingly different from their drug sensitivity when growing on their own including the sensitivity of different clones to MEK or PI3K inhibition. Furthermore, the sensitivity of clones to an anti-PD1 checkpoint inhibitor was distinct across the clonal cells growing in the heterogeneous mixture: Some clones were resistant and others highly sensitive to the checkpoint blockade. We will discuss pathways and drivers of resistance as well as sensitivity in the different subpopulations. We conclude that malignant progression and selection of checkpoint inhibitor sensitive cancer cell subpopulations is impacted by the crosstalk between clonal cell populations present in heterogeneous tumors and the host environment.
Citation Format: Sarah Martinez Roth. Intratumoral heterogeneity and immune checkpoint inhibitor response in the KPC pancreatic cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2912A.
Abstract 292: PTC596 combination therapy for sarcoma
Authors: Weetall Marla , Branstrom Art , Baird John , Cao Liang , Sheedy Josephine , O'Keefe Kylie , Ingham Matthew , Schwartz Gary K. , Spiegel Robert , O'Mara Edward 
Published: August 2019

Abstract
Sarcomas are rare cancers derived from mesenchymal tissues. Although rare, there are approximately 15,000 new cases of sarcoma diagnosed each year in the United States. Certain soft tissue sarcomas are treated with doxorubicin and olaratumabas first line, gemcitabine as second line, and often dacarbazine (DTIC) as third line. PTC596 is a first-in-class, oral investigational new drug that reduces levels of BMI1, a protein required for cancer stem cell survival. PTC596 acts by binding to tubulin causing a G2M cell cycle arrest. PTC596 lowers levels of BMI1 in preclinical tumor models and is generally well tolerated as a monotherapy at doses that result in preclinical target plasma concentrations. Efficacy of PTC596 was evaluated in a series of preclinical models. PTC596 delayed tumor growth as monotherapy and significantly enhanced, in combination, the activity of standard chemotherapeutics including gemcitabine, doxorubicin/ doxil, dacarbazine (DTIC), and other tubulin binding agents. Based on these results, a Ph1b clinical trial in patients with relapsed refractory leiomyosarcoma is to be initiated. It is a dose escalation study of a combination regimen of dacarbazine and PTC596 with the dose-limiting toxicity (DLT) to be determined using a continuous reassessment methodology. Previously, a Phase I multi-center dose escalation study was conducted in patients with advanced solid tumors. PTC596 was administered as an oral monotherapy in 4-week cycles using bodyweight-adjusted twice-per-week (biw) dosing. A maximum tolerated dose (MTD) was not determined though a well-tolerated recommended Phase 2 dose of 7mg/kg biw was identified. The most relevant toxicities observed were neutropenia, nausea, and vomiting which were generally mild to moderate, manageable and reversible.
Citation Format: Marla Weetall, Art Branstrom, John Baird, Liang Cao, Josephine Sheedy, Kylie O'Keefe, Matthew Ingham, Gary K. Schwartz, Robert Spiegel, Edward O'Mara. PTC596 combination therapy for sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 292.
Abstract 2930: Baicalein attenuates radiation-induced enteritis by improving endothelial dysfunction
Authors: Jang Hyosun , Park Sunhoo , Shim Sehwan , Myung Jae Kyung 
Published: August 2019

Abstract
Background: Radiation-induced intestinal injury is frequently observed following clinical application of radiation for abdominal and pelvic cancers or occurs secondary to radiation exposure following a nuclear accident. Radiation-induced enteritis may be considered an ideal model of gastrointestinal inflammation. The endothelium is a crucial component of inflammation, and the endothelial dysfunction following radiation exposure induces the intestinal proinflammatory response and progression of radiation enteritis. Baicalein (5,6,7-trihydroxyflavonoid) is a flavonoid from Scutellaria baicalensis used in oriental herbal medicine. Baicalein has been found to have multiple beneficial properties including antioxidant, anti-inflammatory, anti-allergic, and anti-cancer activities. Here, we investigated the therapeutic effects of baicalein on endothelial dysfunction in radiation-induced intestinal inflammation. Methods: We performed histological analysis, bacterial translocation assays, and intestinal permeability assays, and also assessed infiltration of leukocytes and inflammatory cytokine expression using a radiation-induced enteritis model. In addition, to investigate the effect of baicalein in endothelial dysfunction, we analyzed endothelial-derived adherent molecules in human umbilical vein endothelial cells and irradiated intestinal tissue. Results: Histological damage such as shortening of villi length and impaired intestinal crypt function was observed in the radiation-induced enteritis model. However, intestinal damage was attenuated in baicalein-treated groups with improvement of intestinal barrier function. Baicalein inhibited the expression of radiation-induced adherent molecules in the endothelial cells and increased leukocyte infiltration in the irradiated intestine. We also determined that baicalein could accelerate crypt regeneration via recovery of endothelial damage. Conclusions: Baicalein has a therapeutic effect on radiation-induced intestinal inflammation by attenuating endothelial damage. &lt;!–EndFragment–&gt;
Citation Format: Hyosun Jang, Sunhoo Park, Sehwan Shim, Jae Kyung Myung. Baicalein attenuates radiation-induced enteritis by improving endothelial dysfunction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2930.