bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2924: Evaluation of the pan-FGFR inhibitor AZD4547 with radiation in non-small cell lung cancer
Authors: Miller Margot , Fisher Michael , Senthilkumar Gopika , Kaushik Saakshi , Able Lindsey , Brennan Sean , Iyer Gopal , Kimple Randall , Baschnagel Andrew M. 
Published: August 2019

Abstract
Objective: The fibroblast growth factor receptors (FGFR) are commonly altered in non-small cell lung cancer (NSCLC), including high level of amplification of FGFR1 in lung squamous cell carcinoma. FGFR signaling may play a role in the response to radiation. We investigated the radiosensitizing effects of the selective tyrosine kinase inhibitor AZD4547 in a NSCLC model using cell lines and tumor xenografts.
Methods: A panel of six NSCLC cell lines were screened for FGFR1/2 DNA amplification, RNA expression, and protein expression. All cells were assessed for in vitro response to AZD4547. Immunoblots were used to examine the effect of AZD4547 on downstream signaling proteins. Apoptosis was measured by Annexin V staining and autophagy with acridine orange assay. Radiation clonogenic survival assays and xenograft growth delays experiments were performed to investigate radiosensitization. In vivo mechanistic studies were conducted using immunohistochemistry.
Results: Cell lines demonstrated varying degree of FGFR1/2 RNA and protein expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time dependent manner. In vitro clonogenic survival assays showed robust radiosensitivity with AZD4547 in three out of six NSCLC cell lines. All three cell lines overexpressed FGFR1 and two of the cells had high FGFR1 copy number. There was no radiosensitization seen in an immortalized normal human bronchial epithelial cell line. A significant increase in autophagy and apoptosis was observed with combined radiation and AZD4547. Significant tumor growth delay was observed with the administration of radiation and AZD4547 compared to radiation or drug alone in two NSCLC xenograft tumor models. IHC analysis revealed modulation of FGFR-downstream signaling (p-Erk and p-S6) and proliferative (Ki67) and apoptotic markers (Cleaved Caspace 3).
Conclusion: These findings suggest that AZD4547 can augment the response of radiation in NSCLC model systems. FGFR1 and FGFR2 expression may be a potential targets for radiosensitization in NSCLC. Additional studies are underway to understand the mechanism of radiosensitization.
Citation Format: Margot Miller, Michael Fisher, Gopika Senthilkumar, Saakshi Kaushik, Lindsey Able, Sean Brennan, Gopal Iyer, Randall Kimple, Andrew M. Baschnagel. Evaluation of the pan-FGFR inhibitor AZD4547 with radiation in non-small cell lung cancer [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 2924.
Abstract 2934: AKT mutant allele-specific activation dictates pharmacologic sensitivities
Authors: Bhattarai Tripti Shrestha , Shamu Tambudzai , Patel Swati , Gorelick Alexander , Chang Matthew T. , Gavrila Elena I. , Gao JianJong , Donoghue Mark T. , Gao Paul S. , Soumerai Tara , Abida Wassim , Smyth Lilian M. , Hyman David M. , Solit David B. , Taylor Barry S. 
Published: August 2019

Abstract
The objective of this study is to explore the biochemical characteristics and therapeutic sensitivity profiles of novel, non-E17K, less frequent AKT1 mutations, and thereby expand the biomarker of sensitivity to AKT inhibition in molecularly defined cancer patients. AKT is a critical signaling node that translates phosphoinositide 3-kinase (PI3K) pathway stimulation into diverse cellular effects. Gain of function AKT1 mutations arise in diverse human cancers, of which E17K is the most common. Presence of AKT1 E17K mutation renders these tumors susceptible to AKT inhibition. Nevertheless, the long tail of potentially activating mutations in AKT is largely uncharacterized, thereby limiting our ability to act clinically in prospectively sequenced advanced cancer patients. We performed a population-scale candidate driver mutation discovery analysis in AKT1, AKT2 and AKT3 in a cohort of 41,075 retrospectively and prospectively sequenced primary and metastatic cancers, and explored both their functional and biological impact as well as their therapeutic sensitivity. Our results demonstrated that some, but not all of the identified AKT missense mutations activated PI3K signaling in a growth factor-independent manner, and sensitized tumor cells to diverse AKT inhibitors. By contrast, we discovered a different class of small in-frame paralogous AKT duplication mutants that induced distinctive structural changes, leading to a far greater degree of membrane affinity, AKT activation, pathway dependence, and hyper-sensitivity to ATP-competitive AKT inhibitors, while conferring resistance to allosteric AKT inhibitors. Leveraging a co-clinical trial framework, we are now enrolling patients on the basis of these mutations in a basket study involving AKT alterations. One such case was that of a castration-resistant metastatic prostate cancer patient who harbored AKT2 duplication mutant, and subsequently responded to AKT inhibition. Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.
Citation Format: Tripti Shrestha Bhattarai, Tambudzai Shamu, Swati Patel, Alexander Gorelick, Matthew T. Chang, Elena I. Gavrila, JianJong Gao, Mark T. Donoghue, Paul S. Gao, Tara Soumerai, Wassim Abida, Lilian M. Smyth, David M. Hyman, David B. Solit, Barry S. Taylor. AKT mutant allele-specific activation dictates pharmacologic sensitivities [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 2934.
Abstract 2943: Severe hepatotoxicity of mithramycin therapy caused by altering expression of hepatocellular bile transporters
Authors: Sissung Tristan M. , Huang Phoebe A. , Hauke Ralph , McCrea Edel , Peer Cody J. , Barbier Roberto H. , Strope Jonathan D. , Ley Ariel M. , Zhang Mary , Hong Julie A. , Venzon David , Jackson Jonathan P. , Brouwer Kenneth R. , Grohar Patrick , Glod John , Widemann Brigitte C. , Heller Theo , Schrump David S. , Figg William D. 
Published: August 2019

Abstract
Mithramycin has shown significant preclinical anticancer activity, but its therapeutic dose is limited by the development of hepatotoxicity that remains poorly characterized. A pharmacogenomics characterization of mithramycin-induced transaminitis revealed that hepatotoxicity is associated with inter-individual variation in genes involved in bile disposition: ABCB4(MDR3) rs2302387 and ABCB11(BSEP) rs4668115 variants reduce transporter expression (P&lt;0.05) and were associated with ≥Grade 3 liver function test (LFT) elevations developing 24 hours after the third infusion of mithramycin (25mcg/kg, 6hr/infusion, qdx7, every 28 days;P&lt;0.0040). A similar relationship was observed in a pediatric cohort genotyped for ABCB11. We therefore undertook to characterize the mechanism of mithramycin-induced acute transaminitis. As mithramycin affects cellular response to bile acid treatment by altering the expression of multiple bile transporters (e.g., ABCB4, ABCB11, NTCP, OSTα/β) in several cell lines (Huh7, HepaRG, HepaRG BSEP (-/-)) and primary human hepatocytes, we hypothesized that mithramycin inhibited bile-mediated activation of the farnesoid X receptor (FXR). FXR was downregulated in all hepatocyte cell lines and primary human hepatocytes (P&lt;0.0001), and mithramycin inhibited CDCA- and GW4046-induced FXR-GAL4 luciferase reporter activity (P&lt;0.001). Mithramycin promoted GCDC-induced cytotoxicity in cells lacking the BSEP transporter and increased the overall intracellular concentration of bile acids in primary human hepatocytes grown in sandwich culture (P&lt;0.01). Mithramycin is an FXR expression and FXR transactivation inhibitor that inhibits bile flow and potentiates bile-induced cellular toxicity, particularly in cells with low BSEP function. These results suggest that mithramycin causes hepatotoxicity through derangement of bile acid disposition; results also suggest that pharmacogenomic markers may be useful to identify patients who may tolerate higher mithramycin doses.
Citation Format: Tristan M. Sissung, Phoebe A. Huang, Ralph Hauke, Edel McCrea, Cody J. Peer, Roberto H. Barbier, Jonathan D. Strope, Ariel M. Ley, Mary Zhang, Julie A. Hong, David Venzon, Jonathan P. Jackson, Kenneth R. Brouwer, Patrick Grohar, John Glod, Brigitte C. Widemann, Theo Heller, David S. Schrump, William D. Figg. Severe hepatotoxicity of mithramycin therapy caused by altering expression of hepatocellular bile transporters [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 2943.
Abstract 2967: Activity of G-quadruplex stabilizing small molecule that downregulates MYC and synergizes with Navitoclax in acute myeloid leukemia cells
Authors: Montoya Justin J. , Turnidge Megan A. , Wai Daniel H. , Lee David W. , Patel Apruvi , Gokhale Vijay , Hurley Laurence J. , Azorsa David O. 
Published: August 2019

Abstract
Acute Myeloid Leukemia (AML) is a malignancy of myeloid precursor cells that can occur when genomic changes alter expression of key genes, causing cells to resume an undifferentiated state and proliferate. Ongoing efforts have focused on developing therapies that specifically target the protein products of aberrantly expressed genes. However, many of the identified proteins are difficult to target because of structural challenges, protein overexpression, or mutations that confer resistance to therapy. A type of therapy that circumvents these issues is the use of small molecules that stabilize DNA secondary structures called G-quadruplexes, which are present in the promoters of many potential oncogenes, and have regulatory roles in their transcription. This study analyzes the activity of G-quadruplex stabilizing small molecule GQC-05 that has been shown to down-regulate MYC, which is commonly misregulated in AML. Treatment of MYC-expressing AML cell lines KG-1a, CMK and TF-1 with GQC-05 resulted in decreased expression of MYC mRNA and protein, with the effect more pronounced in KG-1a cells. GQC-05 treatment of the AML cells decreased cell viability, while increasing apoptosis and DNA damage. Combinational drug screening was performed to identify compounds that potentiated the anti-proliferative effects of GQC-05. Results from the screen identified the BCL-2 inhibitor Navitoclax as a compound that potentiated GQC-05 activity. Co-treatment with GQC-05 and Navitoclax showed synergistic effect on cell viability of AML cells as determined by Chou-Talalay analysis. Furthermore, co-treatment with Navitoclax did not affect the downregulation of MYC by GQC-05, but did increase apoptosis and DNA damage leading to rapid cytotoxicity. These results indicate that the G-quadruplex stabilizing small molecule GQC-05 may function more as a DNA damaging agent in AML cells and that combining GQC-05 with a Bcl-2/Bcl-XLinhibitor such as Navitoclax can result in increased cytotoxic activity.
Citation Format: Justin J. Montoya, Megan A. Turnidge, Daniel H. Wai, David W. Lee, Apruvi Patel, Vijay Gokhale, Laurence J. Hurley, David O. Azorsa. Activity of G-quadruplex stabilizing small molecule that downregulates MYC and synergizes with Navitoclax in acute myeloid leukemia 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 2967.
Abstract 2980: The role of USP7 and USP7 inhibitor in HER2+ breast cancer treatment
Authors: Yu Jia , Qin Bo , Boughey Judy , Goetz Matthew , Wang Liewei 
Published: August 2019

Abstract
INTRODUCTION: Breast cancer is the most common invasive cancer and the second leading cause of cancer death in women. Approximately 20% of breast cancer tumors overexpress human epidermal growth factor receptor 2 (HER2), which is associated with an aggressive clinical phenotype and with a poorer prognosis. The development of trastuzumab, an immunoglobulin G monoclonal antibody directed against HER2, has changed the treatment paradigm for this disease. However, approximately 15-20% still does not respond to anti-HER2 therapy. Furthermore, despite advances in the management of metastatic HER2-positive breast cancer, response rate varies greatly, with most patients eventually succumbing to their disease. It is crucial to develop additional therapeutic strategies to improve outcomes for HER2 positive patients, especially those with tumors that do not respond to anti-HER2 therapy.
METHODS and RESULTS: Using HER2+ breast cancer cell lines, we found that an USP7 inhibitor, P5091, dramatically sensitized cancer cells to HER2 inhibitor, trastuzumab treatment. To confirm it in vivo, we tested the drug combination in BT474 xenografts and found P5091 and trastuzumab synergistically suppressed tumor growth. Furthermore, using trastuzumab resistant HER2+ breast cancer cell line, we found that USP7 inhibitor, P5091, can dramatically re-sensitize trastuzumab-resistant BT474 cell line to trastuzumab treatment both in vitro and in vivo. More importantly, using patient derived xenograft (PDX) HER2+ models, we confirmed the synergistic combination effect of P5091 and trastuzumab. Mechanistically, USP7 inhibitor, P5091 led to significantly increased degradation of all four HER family members (HER1-4). When we knocked down USP7 by RNA interference or small hairpin RNA (shRNA), we observed similar substantial decrease in HER family member proteins.
CONCLUSIONS: We have demonstrated the feasibility of using USP7 inhibitor P5091 to sensitize HER2+ breast cancers to trastuzumab treatment. These results provide a rationale for the use of combination therapy of USP7 inhibitors and HER2 inhibitors to treat HER2+ breast cancer. This combination therapy might also be effective in other cancers with upregulated HER signaling, such as GI cancer, lung cancer or ovarian cancer.
Citation Format: Jia Yu, Bo Qin, Judy Boughey, Matthew Goetz, Liewei Wang. The role of USP7 and USP7 inhibitor in HER2+ breast cancer treatment [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 2980.
Abstract 2983: LpMab-23: an anti-podoplanin cancer-specific antibody for a prognostic marker of oral cancer
Authors: Miwa Takashi , Yamada Shinji , Kaneko Mika K. , Furusawa Yoshikazu , Fukui Masato , Kato Yukinari 
Published: August 2019

Abstract
Background
Podoplanin (PDPN) is a specific ligand of C-type lectin-like recepotor-2 (CLEC-2), and is involved in cancer metastasis. The physiological PDPN function has been discussed in many normal tissues, including lymphatic endothelial cells, pulmonary type I alveolar cells, and renal podocytes. Herein, we aimed to produce cancer-specific anti-PDPN monoclonal antibodies (mAbs). Furthermore, we investigated whether the reactivity of cancer-specific anti-PDPN mAbs might be a prognostic marker of oral cancer.
Materials and methods
We immunized mice with LN229/PDPN cells, and screened mAbs, which react with PDPN-expressing cancer cell lines, such as glioblastoma cell lines and lung squamous cell carcinoma cell lines and do not react with PDPN-expressing normal cells, including primary lymphatic endothelial cells and renal epithelial cell lines in flow cytometry. Furthermore, we investigated the reactivity of anti-PDPN mAbs by immunohistochemistry against oral cancers. Anti-tumor activities by mouse-human chimeric LpMab-23 (chLpMab-23) were examined using mouse xenograft models of oral cancer cells. Finally, we analyzed the association between the reactivity of anti-PDPN mAbs and clinical/pathological features of oral cancers.
Results
We established LpMab-23, a cancer-specific anti-PDPN mAb. LpMab-23 reacted with PDPN-expressing cancer cell lines in flow cytometry. In contrast, LpMab-23 recognized PDPN-expressing normal cells very weakly. LpMab-23 reacted only with PDPN-expressing cancer cells, not with lymphatic endothelial cells in oral cancer tissues by immunohistochemistry. The epitope mapping of anti-PDPN mAbs revealed that LpMab-23 recognized a cancer-specific glycopeptide including Thr55/Ser56. chLpMab-23 revealed high ADCC and anti-tumor activities against oral cancers. The Kaplan-Meier curves of the five-year new metastasis-free survival rate (nMFS) were significantly lower in LpMab-23-positive patients than in the patients with LpMab-23-negative ones.
Conclusions
A cancer-specific anti-PDPN mAb (LpMab-23) and its mouse-human chimeric mAb (chLpMab-23) were successfully established. LpMab-23 is advantageous in anti-tumor activities. LpMab-23-positive cases could be a useful predictor of poor prognosis for oral cancer.
Citation Format: Takashi Miwa, Shinji Yamada, Mika K. Kaneko, Yoshikazu Furusawa, Masato Fukui, Yukinari Kato. LpMab-23: an anti-podoplanin cancer-specific antibody for a prognostic marker of oral cancer [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 2983.
Abstract 2997: 15-hydroxyprostaglandin dehydrogenase induced differentiation in colon cancer cells is regulated via Gli1
Authors: Satapathy Shakti R. , Mehdawi Lubna M. , Olsson Roger , Sjolander Anita 
Published: August 2019

Abstract
Prostaglandin E2 (PGE2) is a crucial regulator of colon cancer (CC), an inflammation associated cancer. Tumor suppressor 15-hydroxyprostglandin dehydrogenase (15-PGDH) is a PGE2 degrading enzyme but is often downregulated in CC. Interestingly, CC-patients with high levels of Cysteinyl leukotriene receptor 2 (CysLT2R) exhibit good prognoses. Previously, we have reported differentiation promoting role of 15-PGDH in CC cells when induced by LTC4, the CysLT2R ligand. However the mechanism is unclear. Hedgehog (Hh) signalling is involved in embryogenesis and development but hyper activated in colon carcinogenesis. LTC4-induced activation of 15-PGDH downregulated both mRNA and protein expression of GLI1 in HT-29 and Caco-2 colon cancer cells. Moreover, absence of Gli1 significantly reduced the differentiation promoting ability of 15-PGDH, with no change in the differentiation markers Sucrase isomaltase, Mucin-2 and Protocadherin-24. In addition, no noticeable change in the mRNA expression of WNT-specific target AXIN-2 coupled with restoration of the proliferation marker cMYC was observed. In HT-29-derived colonospheres depletion of mRNA expression of CC-CSC markers ALDH1A1 and DCLK1 remained regulated by Gli1. Elevation in Mucin-2 expression in zebrafish xenograft with HT-29 was also noted to be Gli1 dependent. GLI1 and MUCIN-2 mRNA expression in normal mucosa and matched tumor in colon cancer patient also exhibited higher co-relation along with concomitant elevation in DCLK1 expression in tumor in compared to normal mucosa. Tumor microarray (TMA) with low expression of CysLT2R and 15-PGDH exhibited higher Gli1 expression with no trace of Mucin-2. Therefore, restoring the expression of 15-PGDH in CC through activation of CysLT2R signalling and targeting Hh-Gli signalling would open new therapeutic possibilities with minimal collateral damage to the normal tissue.
Citation Format: Shakti R. Satapathy, Lubna M. Mehdawi, Roger Olsson, Anita Sjolander. 15-hydroxyprostaglandin dehydrogenase induced differentiation in colon cancer cells is regulated via Gli1 [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 2997.
Abstract 2998: Co-targeting bulk tumor and CSCs in clinically translatable TNBC patient-derived xenografts via combination nanotherapy
Authors: Sulaiman Andrew , El-Sahli Sara , McGarry Sarah , Wang Lisheng , Gadde Suresh 
Published: August 2019

Abstract
Triple negative breast cancer (TNBC) accounts disproportionally for the majority of breast cancer related deaths throughout the world. This is largely attributed to lack of a specific therapy capable of targeting both bulk tumor mass and cancer stem cells (CSC) as well as appropriate tumor animal models to accurately evaluate treatment efficacy for the clinical translation. Thus, development of effective and clinically translatable targeted therapies for TNBC is an unmet medical need. In this report, we developed a hybrid nanoparticles-based co-delivery platform containing both paclitaxel and verteporfin (PV-NPs) to target TNBC patient-derived xenograft (PDX) tumor and CSCs. MRI and IVIS imaging were performed on mice containing PDX tumors to assess tumor vascularity and selective accumulation of NPs. NF-kB, Wnt and YAP activities were measured by reporter assays. Mice bearing TNBC PDX tumor were treated with PV-NPs and controls; and tumors progression and CSC subpopulations were analyzed. Our MRI imaging studies indicated high vascularization of PDX tumors. IVIS imaging showed selective accumulation of NPs in PDX tumors. In comparison to control NPs and free-drug combination, PV-NPs significantly retarded tumor growth of TNBC PDX. PV-NPs simultaneously repressed NF-kB, Wnt and YAP that have been shown to be crucial for cancer growth, CSC development and tumorigenesis. In conclusion, NPs containing two clinically used drugs concurrently inhibited NF-kB, Wnt and YAP pathways and exhibited synergic effects on killing TNBC bulk tumor and CSCs. This combination nanotherapy evaluated with a PDX model may lead to an effective treatment of TNBC patients.
Note: This abstract was not presented at the meeting.
Citation Format: Andrew Sulaiman, Sara El-Sahli, Sarah McGarry, Lisheng Wang, Suresh Gadde. Co-targeting bulk tumor and CSCs in clinically translatable TNBC patient-derived xenografts via combination nanotherapy [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 2998.
Abstract 3001: Isolation of large and diverse monoclonal antibody panels against difficult targets in oncology
Authors: Rucker Joseph 
Published: August 2019

Abstract
Although monoclonal antibodies (MAbs) are a well-established treatment approach in oncology, multipass membrane proteins are largely inaccessible as targets for MAb discovery due to their poor expression, membrane-dependent structure, small extracellular regions, and high sequence conservation between humans and rodents. We have developed a platform, MPS Antibody Discovery, that specifically addresses these challenges. We will present case studies of our successful isolation of large and diverse panels of MAbs, including functional (agonist/antagonist) MAbs, against oncology targets, including claudins, GLUT4, CXCR5, CCR7, and other chemokine receptors. Several key features of our MPS platform enabled our ability to isolate MAb panels against these targets. Antigen engineering allowed us to increase the expression levels of the target protein. Immunizing divergent animal species with a combination of DNA and Lipoparticles (high-concentration membrane proteins) allowed us to obtain high-titer immune responses against the native form of the membrane protein. Performing phage display with Lipoparticles allowed us to isolate diverse panels of MAbs with a success rate &gt;95%. Our technology offers the potential for discovering MAbs against difficult targets in cancer, including neoantigens.
Citation Format: Joseph Rucker. Isolation of large and diverse monoclonal antibody panels against difficult targets in oncology [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 3001.