bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3046: Targeting N-myristoylation in B cell lymphomas as a therapeutic strategy
Authors: Mackey John R. , Beauchamp Erwan , Yap Megan C. , Iyer Aishwarya , Perinpanayagam Maneka A. , Vincent Krista M. , Al-Momany Abass M. , Heit Ryan J. , Sim Jacky Y. , Lai Raymond , Dong Wei-feng , Lakshmanan Manikandan , Raju Anandhkumar , Tergaonkar Vinay , Tan Soo Yong , Lim Soon Thye , Postovit Lynne M. , Read Kevin D. , Gray David W. , Wyatt Paul G. , Berthiaume Luc G. 
Published: August 2019

Abstract
Treatment of aggressive lymphoma is toxic, expensive, and a substantial proportion of patients relapse and die. There is an urgent need for more effective treatments. Myristoylation is required for biological activity of &gt;200 intracellular proteins. N-myristoyltransferases (NMTs) transfer the fatty acid myristate to N-terminal glycine residue; there are two isoforms, NMT1 and 2. Since they are critical to intracellular signaling, NMTs are potential anti-cancer targets. We tested a novel potent pan-NMT inhibitor, PCLX-001, in B cell lymphoma cell lines. In vitro assays included cell viability, immunoblotting, and metabolic labeling of lymphoma cell lines. Immunohistochemistry was performed on formalin fixed paraffin embedded lymphoma specimens from patients. In vivo experiments included cell line derived murine xenografts and a patient derived mouse xenograft treated with increasing concentrations of PCLX-001. PCLX-001 selectively killed lymphoma cells, while sparing normal cells in vitro and in 3 mouse xenograft models, eradicating tumors in two of these models including a patient-derived xenograft from a R-CHOP refractory lymphoma patient. While NMT2 is overexpressed in some cancers, loss of NMT2 expression is common in numerous cancers and occurs at the highest prevalence in lymphomas, where it is independently linked to a worse prognosis. This NMT2 suppression occurred through epigenetic mechanisms and may account for lymphoma sensitivity to NMT inhibition. The global myristoylation of lymphoma cell proteins, including that of the protein tyrosine kinase oncogene Src, is profoundly inhibited by PCLX-001. Loss of Src myristoylation is accompanied by loss of Src activity and may account for loss of prosurvival signals causing lymphoma cell death. Targeting NMT2 deficient B cell lymphoma with a pan-NMT inhibitor suppresses the residual NMT1 function provides a novel, selective, and effective therapeutic strategy.
Citation Format: John R. Mackey, Erwan Beauchamp, Megan C. Yap, Aishwarya Iyer, Maneka A. Perinpanayagam, Krista M. Vincent, Abass M. Al-Momany, Ryan J. Heit, Jacky Y. Sim, Raymond Lai, Wei-feng Dong, Manikandan Lakshmanan, Anandhkumar Raju, Vinay Tergaonkar, Soo Yong Tan, Soon Thye Lim, Lynne M. Postovit, Kevin D. Read, David W. Gray, Paul G. Wyatt, Luc G. Berthiaume. Targeting N-myristoylation in B cell lymphomas as a therapeutic strategy [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 3046.
Abstract 3047: Connective tissue growth factor: Novel therapeutic target for non-small cell lung cancer
Authors: Chaudhary Priyanka , Labat Marie-Liesse , Wang Guangfang , Onaitis Mark 
Published: August 2019

Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC), which accounts for 85% of all lung cancer cases, includes adenocarcinoma, squamous cell lung carcinoma and large-cell lung carcinoma. Despite recent advances in targeted therapies for adenocarcinoma, they are effective in only a small percentage of patients while there are no targeted therapies available for squamous cell lung cancer. Therefore, it is critical to identify novel intervention strategies against NSCLC. In the present study, we have identified connective tissue growth factor (CTGF) as a possible therapeutic target for NSCLC. CTGF is an extracellular-matrix (ECM) associated protein, which is involved in cellular processes like cell adhesion, migration, proliferation, differentiation, survival, apoptosis and senescence. CTGF has been associated with both oncogenic as well as tumor suppressive activities in context of different cancer types. The function of CTGF in lung cancer pathogenesis remains controversial. We performed immunohistochemistry on tissue microarray containing 60 cases, which clearly suggested that CTGF expression increases in lung carcinoma. More specifically, among other subtypes, squamous cell lung cancer cases expressed more CTGF compared to their matched normal tissues. To determine the functional role of CTGF in NSCLC, we employed both genetic and pharmacologic approaches to inhibit CTGF activity. Our results clearly demonstrated that CTGF inhibition by both lentiviral knockdown as well as monoclonal antibody against CTGF (FG-3019) caused marked inhibition in cell proliferation, colony formation and xenograft growth in immunodeficient mice. We have also found that CTGF knockdown causes cell cycle arrest and apoptosis. Furthermore, we tested the efficacy of FG-3019 along with drugs like cisplatin and gemcitabine in patient-derived xenograft (PDX) model of squamous cell lung cancer. Our results demonstrated that CTGF inhibition enhances the effects of gemcitabine chemotherapy in PDX model of squamous cell lung carcinoma. These results clearly suggested that CTGF has a profound effect on lung tumorigenesis, as its inhibition not only causes attenuation in tumor growth but also potentiates the chemotherapeutic sensitivity of commonly used drugs for NSCLC. We have also elucidated that tumor hypoxia and Yap signaling are responsible for CTGF up-regulation in lung carcinoma. Overall, our study underscores the significance of CTGF inhibition in non-small cell lung carcinoma and offers the potential use of FG-3019 for its treatment.
Citation Format: Priyanka Chaudhary, Marie-Liesse Labat, Guangfang Wang, Mark Onaitis. Connective tissue growth factor: Novel therapeutic target for 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 3047.
Abstract 3051: Targeting cdk12/13 re-sensitizes trastuzumab resistant her2+ breast cancers
Authors: Vena Francesca , Aceti Max , Bayle Simon , Quereda Victor , Monastyrskyi Andrii , Roush William , Duckett Derek 
Published: August 2019

Abstract
Overexpression or amplification of the human epidermal growth factor receptor 2 (erbB2), which encodes for a receptor tyrosine kinase often referred to as HER2, occurs in about 20% breast cancer patients and is associated with aggressive disease and poor clinical outcome. The anti-HER2 therapy trastuzumab (a monoclonal antibody targeting HER2) has proven highly effective, increasing relapse free and overall survival for HER2 positive breast cancer patients. Nevertheless, acquisition of therapeutic resistance occurs frequently in advance disease. Recent studies have demonstrated that HER2 co-amplified genes may play a role in mechanisms of disease resistance. Cyclin dependent kinase 12 (CDK12) is among the genes that have been reported to be amplified in addition to HER2, and thus we aimed to investigate whether targeting CDK12 could be exploited as a therapeutic target and enhance and/or restore sensitivity in HER2 positive inhibitor resistant models of breast cancer.
We have developed an in-house, highly selective, potent, and orally bioavailable CDK12/13 inhibitor, which effectively blocks proliferation and induces apoptosis in a panel of breast cancer cell lines and acts in synergy with trastuzumab in HER2 treatment resistant cell lines. Furthermore, our lead compound significantly slows tumor growth in trastuzumab resistant patient derived xenograft (PDX) models (as a single agent) and importantly, provokes greater efficacy in combination with trastuzumab. We are beginning to identify the signaling pathways underlying HER2 positive treatment resistance and how inhibition of CDK12/13 thwarts these resistance mechanisms. Accordingly, we anticipate that the development of CDK12/13 inhibitors holds promise as an anti-breast cancer strategy and future treatment option for HER2 positive breast cancer patients with recurrent disease.
Citation Format: Francesca Vena, Max Aceti, Simon Bayle, Victor Quereda, Andrii Monastyrskyi, William Roush, Derek Duckett. Targeting cdk12/13 re-sensitizes trastuzumab resistant her2+ breast cancers [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 3051.
Abstract 3052: MGMT inhibition is associated with MAPK pathway inhibition and enhances Raf, MEK, ERK inhibitors and restores meaningful Temozolomide activity in melanoma
Authors: Bobustuc George C. , Kassam Amin B. , Bosenko Dmitry , Donohoe Deborah L. , Rovin Richard A. , Konduri Santhi D. 
Published: August 2019

Abstract
Braf and MEK inhibition leads to limited survival gains in melanoma. In this research we show that, in vitro, MGMT controls all MAPK pathway effectors. We show that triple lock - upstream and downstream, along the MAPK pathway - effectively restores durable Braf and MEK inhibitor activity and significantly sensitizes melanoma to Temozolomide. The advantage of a multiple lock approach on the MAPK pathway is substantiated by the lack of signaling cross talk. We briefly discuss how this simple MGMT based regulatory paradigm could be immediately exploited in the care of melanoma patients. We also show how this strategy was exploited in two, surviving, metastatic (to include CNS disease) melanoma patients who had failed Braf and MEK inhibition (2 and 5 years ago) who now show stable or negligible residual disease burden while continuing on an intermittent, low treatment density, combination regimen
Citation Format: George C. Bobustuc, Amin B. Kassam, Dmitry Bosenko, Deborah L. Donohoe, Richard A. Rovin, Santhi D. Konduri. MGMT inhibition is associated with MAPK pathway inhibition and enhances Raf, MEK, ERK inhibitors and restores meaningful Temozolomide activity in melanoma [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 3052.
Abstract 3056: Development of an integrated CRISPR interference system targeting ΔNp63 to treat lung and esophageal squamous cell carcinoma
Authors: Yoshida Masakazu , Yokota Etsuko , Sakuma Tetsushi , Takigawa Nagio , Ushijima Toshikazu , Yamamoto Takashi , Naomoto Yoshio , Fukazawa Takuya , Yamatsuji Tomoki 
Published: August 2019

Abstract
TP63 encodes two different transcripts that have opposite functions in transcriptional control. One transcript encodes TAp63 that is functionally similar to the tumor suppressor TP53. The other transcript, ΔNp63, lacks the transcription-activating domain of TAp63 and has been proposed to function as a potent oncogene in squamous cell carcinomas. In this study, we have developed an integrated CRISPR interference system to selectively suppress ΔNp63 and we have termed this system CRISPRiΔNp63. We engineered the CRISPRi using tandemized guide RNA expression cassettes to target the 50 to 100 bp downstream region of the transcription start site of ΔNp63 and we used inactivated Cas9 linked to the transcription repression module Krüppel-associated box repressor domain. The plasmid vector harboring CRISPRiΔNp63 repressed ΔNp63 transcriptional activity in lung and esophageal squamous cell carcinoma cells that express ΔNp63. Moreover, an all-in-one adenoviral vector containing tandemized gRNAs and the dCas9/KRAB expression cassette, Ad-CRISPRiΔNp63, suppressed ΔNp63 expression in squamous cell carcinomas cells. Ad-CRISPRiΔNp63 effectively decreased cell proliferation and colony formation and induced apoptosis in lung and esophageal squamous cell carcinoma cells in vitro. Moreover, the all-in-one vector significantly inhibited tumor growth in a lung squamous cell carcinoma xenograft mouse model in vivo. These results indicate that ΔNp63 suppression by CRISPRiΔNp63 might be an effective strategy for the treatment of lung and esophageal squamous cell carcinoma.
Citation Format: Masakazu Yoshida, Etsuko Yokota, Tetsushi Sakuma, Nagio Takigawa, Toshikazu Ushijima, Takashi Yamamoto, Yoshio Naomoto, Takuya Fukazawa, Tomoki Yamatsuji. Development of an integrated CRISPR interference system targeting ΔNp63 to treat lung and esophageal squamous cell carcinoma [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 3056.
Abstract 3060: YAP1 induces STAT3 phosphorylation & combined blockade enhances chemotherapeutic efficacy
Authors: Shibata Masahiro , Ooki Akira , Inokawa Yoshikuni , Izumchenko Evgeny , Munari Enrico , Bogina Giuseppe , Gabrielson Edward , Singh Anju , Hoque Mohammad Obaidul 
Published: August 2019

Abstract
Recent studies have identified transcriptions factors YAP1 and STAT3, as therapeutic targets in cancer, but efforts targeting either YAP1 or STAT3 pathway have met with limited success. Our study is focused on understanding the cross-talk between YAP1 and STAT3 signaling, impact of this cross-talk on lung tumorigenesis, drug resistance and blocking this pathway as a potential therapeutic strategy in lung adenocarcinoma (LUAD). Mechanistically, we demonstrate that YAP1 promotes the phosphorylation of STAT3 through IL-6 upregulation. In clinical LUAD samples, a positive correlation between YAP1 and phosphorylated STAT3 protein as well as an association between YAP1 and IL-6 mRNA was observed. Pre-clinically, genetic and pharmacologic dual inhibitions of YAP1 and STAT3 showed decreased cell growth and increased sensitivity to chemotherapy through the attenuation of cancer-stemness like features. Although verteporfin and S3I-201 were employed as YAP1 and STAT3 inhibitors respectively, verteporfin was found to suppress not only YAP1 but also STAT3, and their combination induced synergistic cytotoxic effects. Furthermore, addition of verteporfin and S3I-201 to standard-of-care chemotherapy regimen significantly inhibited tumor growth in patient-derived xenograft mouse models and attenuated in vivo expansion of malignant stemness. These findings provide the conceptual framework for combined targeting of YAP1 and STAT3 in LUAD.
Citation Format: Masahiro Shibata, Akira Ooki, Yoshikuni Inokawa, Evgeny Izumchenko, Enrico Munari, Giuseppe Bogina, Edward Gabrielson, Anju Singh, Mohammad Obaidul Hoque. YAP1 induces STAT3 phosphorylation & combined blockade enhances chemotherapeutic efficacy [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 3060.
Abstract 3061: Role of ID4 (inhibitor of DNA binding protein 4) in FKBP52-AR pathway
Authors: Komaragiri Shravan Kumar 
Published: August 2019

Abstract
Introduction: Inhibitor of DNA binding/differentiation protein 4 (ID4), acts as a dominant negative regulator of basic helix loop helix (bHLH) family of transcription factors. In normal prostate epithelial cells, ID4 collaborates with androgen receptor (AR) and p53 to exert its tumor suppressor activity. Previous studies have shown that ID4 promotes tumor suppressive function of AR whereas loss of ID4 results in tumor promoter activity of AR through selective interaction with FKBP52. Pharmacological inhibition of FKBP52, by MJC13, attenuated the tumor growth, weight, and volume of LNCaP cells lacking ID4(L(-)ID4) xenografts. The L(-)ID4 cells also gains CRPC phenotype through FKBP52-mediated AR signaling. In this study we investigated the role of ID4 in pharmacological inhibition of FKBP52 with GMC1 (Initial hit molecule by in-silico screening with the most potent inhibition of FKBP52) in regulating the AR pathway.
Experimental procedures: GMC1 drug treatments in LNCaP(-)ID4 and CW22RV1 generated xenograft tumors were further analyzed for tumor volume and tumor weight. We also performed immunohistochemistry on GMC1 treated xenografts to determine AR, PSA, FKBP51 and FKBP52 protein expression. Our in vivo studies with GMC1 drug treatments in castrated male SCID mice injected with LNCaP-ID4 and CW22RV1 cells showed decreased tumor size and volume when compared to untreated mice tumors.
Results: IHC results on GMC1 treated LNCaP(-)ID4 and CW22RV1 generated xenograft tumors showed no change in ID4 expression with decrease expression of AR, PSA, FKBP51, FKBP52 and KI67 when compared to untreated xenograft tumors. These results suggest that inhibition of FKBP52-regulated AR activity (via GMC1) demonstrated a significant reduction in the tumor volume of subcutaneous xenografts in vivo. Overall, ID4 appears as a potential tumor suppressor gene that selectively regulates AR activity through direct interaction with FKBP52, and its loss, promotes CRPC through FKBP52-mediated AR signaling.
Conclusions: In conclusion, we demonstrate that loss of ID4 in LNCaP cells elevates FKBP52 levels, transcriptionally potentiates AR activity which in turn then leads to progression of androgen-independent prostate cancer. GMC1 is a novel inhibitor that inhibits the binding of FKBP52 to AR thereby prevents the AR transcriptional hyperactivity in PCa
Acknowledgement: These studies were supported by DOD, Grant # W81XWH-17-1-0437
Citation Format: Shravan Kumar Komaragiri. Role of ID4 (inhibitor of DNA binding protein 4) in FKBP52-AR pathway [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 3061.
Abstract 3062: PLK1: a new therapeutic target in mucinous ovarian carcinoma
Authors: Affatato Roberta , Chilà Rosaria , Lupi Monica , Restelli Valentina , Erlander Mark , Carrassa Laura , Damia Giovanna 
Published: August 2019

Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynaecological cancer. Amongst the five histotypes (high-grade serous, clear-cell, endometrioid, mucinous, and low-grade serous), mucinous epithelial ovarian cancer (mEOC) is a rare subset and represents approximately 3% of EOC. Beside these different histotypes are unique clinical entities with a different prognosis and response to therapy, they are still treated as a homogeneous group with a similar chemotherapeutic approach (platinum-paclitaxel combination), to which however mEOC is generally poor responsive. New specific and active therapeutic strategies are needed for mEOC.
To find new therapeutic options for mEOC, we have performed a high-throughput screening using a siRNA library directed against 719 human protein kinases in the mEOC MCAS cell line. After two independent screenings and validation experiments with specific esiRNAs, Polo-like kinase1 (PLK1), a mitotic serine/threonine kinase, was identified as the most significant kinase whose downregulation interfered with both cell proliferation and survival. Both PLK1 siRNA and nanomolar concentrations of commercially available inhibitors against PLK1 (onvansertib (NMS-P937) and volasertib) inhibited cell growth in other two additional mEOC cell lines (EFO-27 and JHOM-1). In addition, in the mEOC cell lines PLK1 inhibition was able to induce apoptosis and to block cells in the G2-M phase of the cell cycle. We then evaluated in vitro combinations between the PLK1 inhibitors and different chemotherapeutic drugs used in mEOC, including cisplatin and paclitaxel used in front line therapy in all the available mEOC cell lines. No synergism could be found in any of the cell lines, when both PLK1 inhibitors were combined with cisplatin. On the contrary, strong synergism could be observed in two out the three mEOC cell lines investigated when onvansertib and volasertib were combined with both paclitaxel and eribulin. On the basis of the strong in vitro synergistic effect between onvansertib and paclitaxel, this combination was tested in vivo in nude mice transplanted with MCAS cells. Onvansertib as single agent was inactive, while paclitaxel at the dose used was active. Interestingly enough, the combination of the two drugs was well tolerated and was much more active than paclitaxel single agent, with both a stronger tumor regression and more sustained tumor growth inhibition that translated in a longer survival time. These data suggest that onvansertib and paclitaxel could represent a new active therapeutic option in mEOC.
Citation Format: Roberta Affatato, Rosaria Chilà, Monica Lupi, Valentina Restelli, Mark Erlander, Laura Carrassa, Giovanna Damia. PLK1: a new therapeutic target in mucinous ovarian carcinoma [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 3062.
Abstract 3063: Over expression of protein kinase Nek1 and its modulation by Thioridazine in prostate cancer
Authors: Singh Vibha , Jaiswal Praveen K. , Koul Hari K. , Yu Xiuping , Benedetti Arrigo 
Published: August 2019

Abstract
Introduction: Prostate Cancer (PCa) is one of the most common urological malignancies in men in the United States. We have identified NIMA kinase NEK1 through a proteomic approach, that interacts and co-localizes with Tousled Like kinases (TLKs) and has a role in the DDR, upstream of ATR and Chk1. In the present study we have checked the NEK1 activity in PCa patient samples and tested Thioridazine (THD), an anti-psychotic drug and inhibitor of TLKs in inhibiting the activity of NEK1 in human and mice derived prostate cancer cell lines and xenografts derived from LNCaP cells.
Material & Methods: We have used tissue microarray (TMA) derived from patient samples and respective benign control. We have used a human prostate cancer cell lines: LNCaP, C4-2, C4-2b, 22Rv1, DU145 and PC3 and normal prostate cell line RWPE-1 as well as TRAMP-C2 cell lines derived from TRAMP mice. Clonogenic activity was measured by colony formation assay. Immunoblotting and immunohistochemistry was done for TLKs, NEK1, p-ATR, p-Chk1, cell cycle and apoptosis related protein in PCa cell lines and tumor tissues from xenografts. Xenografts derived from LNCaP and LNCaP-NEK1 mutant were used in present study. We have used THD (alone) or in combination with the anti-androgen drug bicalutamide in PCa cell lines as well as in xenografts mice model.
Results: We found a significant over expression of NEK1 activity as measured by p-NEK1 with PCa samples as compare to benign control (p&lt;0.001) and also correlated with high Gleason score patients. Treatment with THD significantly impaired the colony formation efficiency in human PCa cells in vitro (even of androgen independent lines) as well in TRAMP-C2 cells. THD treatment halts the PCa cells in subG0 phase and affects the cyclin D1, p27, p21 levels and leads to apoptosis with induction of cleaved PARP and Caspase-3 activity. Further p-ATR and p-Chk1 axis was inhibited by treatment with THD and in combination with bicalutamide. Combination therapy of THD and Bicalutamide remarkably inhibited the tumor growth in LNCaP xenografts model while tumor growth in LNCaP xenografts with NEK1 mutant were inhibited by Bicalutamide treatment alone. Following DNA damage, addition of the THD impaired ATR and Chk1 activation, that leads to TLK1&gt;NEK1&gt;ATR&gt;Chk1 pathway activation in PCa.
Conclusions: Our data indicated that NEK1 is over-expressed in PCa patients and its activity can be suppressed by treatment with THD (that inhibits its activating kinase, TLK1) in vitro and in vivo.
Citation Format: Vibha Singh, Praveen K. Jaiswal, Hari K. Koul, Xiuping Yu, Arrigo Benedetti. Over expression of protein kinase Nek1 and its modulation by Thioridazine in prostate 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 3063.