bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB-264: Preclinical evaluation of DNA-PK as a therapeutic target in prostate cancer
Authors: Dylgjeri Emanuela , Goodwin Jonathan F. , McNair Christopher M. , Shafi Ayesha A. , Kothari Vishal , Feng Felix , Rathkop Dana , Knudsen Karen
Published: July 2017

Prostatic adenocarcinoma (PCa) is dependent on androgen receptor (AR) signaling at all stages of disease, as AR activation induces both cell proliferation and survival. Though organ–confined disease can be treated, the response is transient. Reactivation of AR leads to castration resistant prostate cancer (CRPC), which remains fatal. Previously published studies demonstrate that AR activation promotes tumor cell survival and proliferation through a feed-forward loop involving the DNA repair factor DNA-dependent protein kinase (DNA-PK). Recent data from our lab has highlighted the role of DNA-PK in DNA damage repair as well as transcriptional regulation of pro-metastatic signaling. Strikingly, DNA-PK is the most deregulated kinase in metastatic CRPC. DNAPK is highly elevated and hyperactivated, and is an independent predictor of metastasis and overall survival in patients with high-risk disease. Concordantly, DNAPK suppression attenuated DNA-PK functions in NHEJ and transcriptional regulation. DNA-PK inhibition is sufficient to prevent proliferation in vitro and ex vivo, as well as tumor metastasis in vivo. Combined these findings highlight importance of DNA-PK functions as a transcriptional regulator and a mediator of NHEJ DNA repair and nominate it as a therapeutic target in PCa.

Data presented here will interrogate the translational capacity of a specific DNA-PK inhibitor, a dual DNA-PK/TOR kinase inhibitor and a specific TOR kinase inhibitor in CRPC models. Currently, CC-115, a dual kinase inhibitor, is the only DNA-PK inhibitor in Phase1/2 trial in combination with Enzalutamide in PCa. Unbiased transcriptomic analyses were performed and will be used to identify mechanisms of action that lead to suppression of PCa growth in vitro and ex vivo. These findings will provide insight in the effectiveness of DNA-PK inhibitors as a single agent or combinatorial treatments and provide rational for its placement in the correct clinical space.

Citation Format: Emanuela Dylgjeri, Jonathan F. Goodwin, Christopher M. McNair, Ayesha A. Shafi, Vishal Kothari, Felix Feng, Dana Rathkop, Karen Knudsen. Preclinical evaluation of DNA-PK as a therapeutic target in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-264. doi:10.1158/1538-7445.AM2017-LB-264
Abstract LB-267: Metabolic alterations in tumors cause cachexia in pancreatic cancer
Authors: Dasgupta Aneesha , Shukla Surendra K. , Gunda Venugopal , Chaika Nina V. , Singh Pankaj K.
Published: July 2017

Cancer-associated cachexia is a complex metabolic syndrome which leads to excessive loss of skeletal muscle and adipose deposits. Up to 80% of pancreatic cancer patients suffer from cachexia and nearly one third die due to complexities related to the syndrome. Treatment of cachexia will not only improve the standard of living of pancreatic cancer patients but would also improve the patient survival. In the clinic, the majority of cancer patients are diagnosed at the refractory phase of cachexia, which cannot be reversed by dietary interventions. Till late, cachexia has mainly been attributed to systemic inflammation caused by cytokines released from the host and the tumor. But anti-inflammatory therapies have not shown promising results in clinical trials. Hence, there is an urgent need to identify new targets to combat cancer cachexia. It has been previously shown that there are constant metabolic interactions between the host body and the tumor. Increase in tumor burden and its demand for nutrition forces the host body to reprogram its metabolism leading to the breakdown of host body proteins into amino acids, which gets taken up and converted into carbohydrates by the tumor. To study the role of metabolic pathways in tumor cells on cachectic factor secretion, we pre-treated pancreatic cancer cells with metabolic inhibitors 3-Bromopyruvic acid and bis-2-(5-phenylacetomido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES). The conditioned media from control and treated cells were then evaluated for myotube degeneration potential in C2C12-dfferentitaed myotubes by measuring myotube thickness, protein content and expression of muscle specific ubiquitin ligases. We observed that that pre-treated conditioned-media had reduced myotubes degenerating potential as compared to controls. Furthermore, we inhibition of glycolytic flux in tumor cells by treatment with ketone bodies also diminished myotubes degenerating potential. Tumor-bearing mice had decreased tumor growth and cachexia when fed on a ketogenic diet. In conclusion, metabolic reprograming of tumor cells plays an important role in inducing pancreatic cancer-induced cachexia and delineating the metabolic pathways is crucial to elucidate important therapeutic targets for cancer cachexia.

Citation Format: Aneesha Dasgupta, Surendra K. Shukla, Venugopal Gunda, Nina V. Chaika, Pankaj K. Singh. Metabolic alterations in tumors cause cachexia in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-267. doi:10.1158/1538-7445.AM2017-LB-267
Abstract LB-270: Hexokinase II (HK2) regulates stemness of ovarian cancer cells
Authors: JIANG Yuxin , Siu Michelle KY , Wang Jingjing , Leung Thomas HY , Cheung Annie NY , Ngan Hextan YS , Chan Karen KL
Published: July 2017

Cancer stem cells (CSCs) constitute a small proportion of tumor cells and can drive tumor growth, metastasis and recurrence. Identification of CSCs in ovarian cancer has been reported. However, the mechanisms regulating ovarian cancer CSCs remain unknown. High lactate production and low glucose oxidation, despite oxygen availability, termed as the Warburg effect, are commonly found in cancers. Hexokinase 2 (HK2) converts glucose to glucose-6-phosphate, the first committed step in the Warburg effect. HK2 regulates tumorigenesis in different cancers. Yet, roles of HK2 and its underline mechanisms in ovarian cancer remain to be explored. In this study, we investigate the clinical significance, effects and mechanisms of HK2 on cell metastasis and CSCs regulation in ovarian cancer. HK2 was found to be up-regulated in ovarian cancer patients by immunohistochemistry when compared with benign ovarian cystadenomas. Significantly higher HK2 immunoreactivity was detected in metastatic foci than their corresponding primary tumors and associated with shorter disease-free survival. Decreased lactate production, impaired cell migration and invasion were detected in HK2 knockdown A2780CP cells using lactate assay, Transwell migration and invasion assays, respectively. Oppositely, ectopic expression of HK2 increased lactate production, cell migration and invasion in SKOV3 cells. We also found ectopic expression of HK2 in SKOV3 cells promoted anchorage-independent growth by soft agar assay. Then we further investigated the effect of HK2 on CSC load of ovarian cancer. Stable knockdown of HK2 in OVCAR3 cells led to impaired capacity to grow as multi-cellular spheroids in stem-condition culture system by sphere formation. Knockdown of HK2 in OVCAR3 cells down-regulated CD117 as measured by flow cytometry, which was accompanied by decreased mRNA/protein expression of Nanog, Bmi-1 and Klf-4, genes related to ovarian CSCs. Inversely, ectopic expression of HK2 in SKOV-3 cells promoted spheroids growth and increased CD117 proportion, which was accompanied by increased Nanog, Bmi-1 and Klf-4 mRNA/protein expression. Our data suggested that HK2 was associated with ovarian cancer progression, metastasis and stemness. HK2 could be a novel prognostic marker and potential therapeutic molecular target in ovarian cancer.

Citation Format: Yuxin JIANG, Michelle KY Siu, Jingjing Wang, Thomas HY Leung, Annie NY Cheung, Hextan YS Ngan, Karen KL Chan. Hexokinase II (HK2) regulates stemness of ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-270. doi:10.1158/1538-7445.AM2017-LB-270
Abstract LB-273: Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma
Authors: Mori Seiichi , Gotoh Osamu , Sugiyama Yuko , Kato Kazuyoshi , Noda Tetsuo
Published: July 2017

Carcinosarcoma (CS) of the uterus or the ovary, known as malignant mixed Muellerian tumor, is a biphasic neoplasm composed of malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements. CS is a rare disease (two per 100,000 women) and exhibits poor prognosis (5-year survival rates: uterus and ovary; 31 and 7.5 %, respectively). Treatment regimen for CS follows to that for endometrioid adenocarcinoma (EC) since CS has been considered as an aggressive form of high-grade EC. However, CS has a significantly worse prognosis than EC. Identification of a molecular target and/or a molecular mechanism in tumorigenesis from a large cohort study may improve unfavorable outcomes. Toward this aim, we perform targeted resequencing analysis with a panel of 596 genes, which were previously implicated as critical not only for uterine, ovarian or sarcomatus oncogenesis but also for molecular targets in therapeutics. Through analyses of 109 cases of uterine and ovarian CS, consensus clustering with deregulated pattern of CS genome identified four genomic subtypes that correlate with genetic or epigenetic alterations, histopathology and patient outcomes. Moreover, potentially actionable alterations were found in a substantial number of genes (including PIK3CA, MTOR, KRAS and CCNE1). This study would provide deep insights into the development of novel diagnostic and personalized treatment for CS patients.

Citation Format: Seiichi Mori, Osamu Gotoh, Yuko Sugiyama, Kazuyoshi Kato, Tetsuo Noda. Comprehensive sequencing analyses of uterine and ovarian carcinosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-273. doi:10.1158/1538-7445.AM2017-LB-273
Abstract LB-289: Computational detection of oncogene-centric pathway members
Authors: Broyde Joshua , Simpson David , Murray Diana , Lachmann Alexander , Giorgi Federico M. , Honig Barry , Sweet-Cordero Alejandro E. , Califano Andrea
Published: July 2017

Elucidation of the full complement of members of oncogenic signaling pathways is critical for understanding dysregulated function in cancers. Our knowledge of experimentally verified human gene-regulatory networks and protein-protein interactions remains incomplete, thus limiting their use for predicting novel members of these critical pathways. We present a method that uses a machine learning approach to predict novel members of these aberrantly activated or inactivated pathways. We integrate predictions of protein-protein interactions, gene regulatory networks, post-translational modifications and co-segregation of mutational status and protein activity. This approach produces novel predictions for these pathways. For the Kras and EGFR pathway, these predictions are highly enriched for genes known to by synthetic lethal for these two pathways. Knockdown of top candidates derived from this approach decreased growth in a Kras-activated context, indicating their importance in Kras regulated pathways.

Citation Format: Joshua Broyde, David Simpson, Diana Murray, Alexander Lachmann, Federico M. Giorgi, Barry Honig, Alejandro E. Sweet-Cordero, Andrea Califano. Computational detection of oncogene-centric pathway members [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-289. doi:10.1158/1538-7445.AM2017-LB-289
Abstract LB-291: Identification of CMTM6 and CMTM4 as PD-L1 protein regulators
Authors: Sun Chong , Mezzadra Riccardo , Jae Lucas T. , Gomez-Eerland Raquel , Vries Evert de , Wu Wei , Xiao Yanling , Heck Albert J. , Borst Jannie , Brummelkamp Thijn R. , Schumacher Ton N.
Published: July 2017

The clinical benefit in patients with diverse types of metastatic cancers that is observed upon blockade of the PD-1 - PD-L1 interaction has highlighted the importance of this inhibitory axis in the suppression of human tumor-specific T cell responses. In spite of the key role of PD-L1 expression by cells within the tumor microenvironment, our understanding of the regulation of the PD-L1 protein is limited. Using a haploid genetic screen, we here identify CMTM6, a poorly described type 3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all tumor cell types tested and also in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6 deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member CMTM4, but not by all other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 transcript levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with PD-L1 protein, and increases PD-L1 protein half-life. Consistent with this role, T cell inhibitory capacity of PD-L1 expressing tumor cells is enhanced by CMTM6. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.

[C.S., R.M., and L.T.J. contributed equally to this work. T.R.B. and T.N.M.S. are both corresponding authors.]

Citation Format: Chong Sun, Riccardo Mezzadra, Lucas T. Jae, Raquel Gomez-Eerland, Evert de Vries, Wei Wu, Yanling Xiao, Albert J. Heck, Jannie Borst, Thijn R. Brummelkamp, Ton N. Schumacher. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-291. doi:10.1158/1538-7445.AM2017-LB-291
Abstract LB-301: PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors
Authors: Higuchi Fumi , Cahill Daniel P. , Wakimoto Hiroaki
Published: July 2017

Background: Mismatch repair (MMR) deficiency through MSH6 alteration has been identified in approximately 30% of recurrent high grade gliomas, and represents a key molecular mechanism for the development of acquired resistance to the alkylating agent temozolomide (TMZ). Additionally, glioma progression post-TMZ treatment is frequently accompanied by distinct genomic alterations such as amplification of the MYC locus and resulting signaling activation. There is an urgent need to establish new treatment strategies that do not rely upon MMR to target MMR deficient, TMZ resistant glioma.

Methods: We first screened 14 compounds that modulate DNA damage response for their ability to suppress viability of an MSH6 knockdown, TMZ resistant glioma cell line. Efficacy of PLK1 inhibitors and combination with TMZ were assessed in glioblastoma cells lines and patient-derived glioblastoma neurosphere lines engineered with MSH6 silencing, MYC overexpression and controls. Impacts of PLK1 blockade on cell cycle distribution, apoptosis, and DNA damage effects were examined.

Results: The compound screening indentified PLK1 selective inhibitor, volasertib, as the most potent inhibitor of proliferation of both MMR intact and deficient glioblastoma cells. PLK1 inhibition induced G2/M cell cycle arrest, DNA damage and caspase-mediated apoptosis in glioblastoma cells, but no detectable toxicity in normal human astrocytes. Importantly, beneficial therapeutic effects of PLK1 inhibitors were not influenced by MMR deficiency due to MSH6 knockdown, whereas PLK1 inhibition had no additive or synergic effect when combined with TMZ. Furthermore, we found that MYC overexpression sensitized glioblastoma cells to PLK1 inhibitors.

Conclusions: Selective PLK1 inhibitors are potently cytotoxic to glioblastoma and their action is independent of MMR status of the cells. Cells with deregulated MYC are vulnerable to PLK1 inhibition suggesting genomic MYC alteration as a biomarker for PLK inhibitor sensitivity. Thus PLK inhibitor represents a novel therapeutic option for MMR deficient TMZ resistant recurrent gliomas, particularly those driven by MYC.

Citation Format: Fumi Higuchi, Daniel P. Cahill, Hiroaki Wakimoto. PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-301. doi:10.1158/1538-7445.AM2017-LB-301
Abstract LB-318: Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation
Authors: Torres-Guzmán Raquel , Baquero Carmen , Marugan Carlos , Mur Cecilia , Gharbi Severine I. , Gomez Sandra , Amat Joaquín , Boehnke Karsten , Iversen Philip W. , deDios Alfonso , Gong Xueqian , Buchanan Sean , Beckman Richard P. , Lallena Maria José J.
Published: July 2017

Lung cancer is the most common tumor cancer worldwide and approximately 15-25% of the patients with lung adenocarcinoma have KRAS driven tumors. These malignancies involve, in the majority of cases, a constitutive activation of KRAS signaling pathway (1,2) and are associated with poor prognosis in patients with advanced disease (metastatic setting).

Currently there is no specific therapy to target KRAS driven tumors approved by FDA (3), then finding alternative targeted therapies is a need to cover for this disease.

Pharmacological inhibition of CDK4 was been suggested as a beneficial therapy to treat NSCLC patients carrying K-RAS oncogenes; and researchers base the potential efficacy of this approach on a synthetic lethal interaction between K-ras and CDK4 in in this type of tumors (4). Hence, CDK4/6 inhibitors appear as promising therapy to treat this type of tumors.

Abemaciclib is a cell cycle inhibitor with selective activity against CDK4 and CDK6 and is being evaluated in advanced clinical trials for its potential to reduce NSCLC cancer growth. Here we describe studies towards the in-vitro mechanism of action of abemaciclib to reduce tumor cells growth in NSCLC cell lines harboring mutations in KRAS. Overall, abemaciclib reduces NSCLC cell growth as indicated by a reduction of cell number and proliferation biomarker Ki67 upon treatment. This tumor growth inhibition is mediated by arrest of cell cycle in G1 phase as a direct consequence of Rb phosphorylation blockade. In this study we are further reporting a phenotypic characterization of sensitive cell lines monitoring cell proliferation, senescence, and apoptosis markers using flow cytometry and high content imaging approaches as well as metabolic profiling.

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Ihle NT et al (2012) J Natl Cancer Inst. 104(3): 228-239.

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Roberts PJ et al (2010) J Clin Oncol. 28(31):4769-77

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Puyol M et al (2010) Cancer Cell 1(13): 63-73.

Citation Format: Raquel Torres-Guzmán, Carmen Baquero, Carlos Marugan, Cecilia Mur, Severine I. Gharbi, Sandra Gomez, Joaquín Amat, Karsten Boehnke, Philip W. Iversen, Alfonso deDios, Xueqian Gong, Sean Buchanan, Richard P. Beckman, Maria José J. Lallena. Characterization of the mechanism of action of abemaciclib in NSCLC cell lines harboring KRAS mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-318. doi:10.1158/1538-7445.AM2017-LB-318
Abstract LB-320: Reconstituting B55/protein phosphatase 2A activity in B55/PP2A-defective prostate cancer cells suppresses proliferation and tumorigenicity through pleiotropic mechanisms
Authors: Zhao Ziran , Kurimchak Alison , Makhov Petr , Johnson Katherine , Kolenko Vladimir , Duncan James , Graña Xavier
Published: July 2017

Prostate cancer accounts for close to 30,000 deaths annually in the United States. The most frequent alteration in the prostate oncogenome landscape is loss of chromosome 8p, which is also observed in other epithelial tumors. This region harbors NKX3.1, a prostate specific tumor suppressor, but 8p copy number loss does not correlate with its mRNA expression. The PPP2R2A gene, which encodes a regulatory subunit of protein phosphatase 2 (PP2A) designated B55, is located in 8p21.2 and is hemizygously lost in more that 50% of prostate adenocarcinomas. TCGA data analysis shows that hemizygous loss of PPP2R2A correlates with its reduced expression, poorer prognosis and that loss of PPP2R2A increases with metastasis to more than 80%. Of note, while homozygous loss is less common (4-10%), deletion of other subunits of the B55, but not other PP2A regulatory families, increases dramatically with metastasis despite their independent chromosomal locations. However, functional evidence that PPP2R2A acts as an haploinsufficient tumor suppressor and the potential mechanisms implicated are lacking. We have identified prostate cancer (PrCa) cell lines with reduced expression of B55 and shown that reconstitution of B55 expression reduces proliferation and induces senescence and loss of viability. B55 reconstitution in PC3 cells, an AR-negative model of human castration-resistant prostate cancer (CRPC), also blocks transformation in vitro and tumorigenicity in SCID mice. Reconstitution of B55 in PCa cells with reduced expression (PC3 and DU145 cells) induces cell cycle defects in G1, G2/M and mitosis diminishing and delaying phosphorylation of pRB pocket proteins and mitotic substrates and altering associated kinase networks. Mitogenic signaling is also attenuated. Importantly, the effects of B55 reconstitution are at least partially mimicked via treatment of these cells with PP2A activating drugs, which have anti-tumorigenic activity, indicating that development of specific B55/PP2A activating drugs targeting the unaltered B55 alleles remaining in PCa cells may have therapeutic potential for a high proportion of prostate tumors and perhaps other epithelial tumors such as luminal B breast and ovarian cancers which share this alteration.

Citation Format: Ziran Zhao, Alison Kurimchak, Petr Makhov, Katherine Johnson, Vladimir Kolenko, James Duncan, Xavier Graña. Reconstituting B55/protein phosphatase 2A activity in B55/PP2A-defective prostate cancer cells suppresses proliferation and tumorigenicity through pleiotropic mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-320. doi:10.1158/1538-7445.AM2017-LB-320
Abstract LB-323: Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2
Authors: Sakuragi Noriaki , Farah Mohamed Kamel , Mohamed Zeinab , Okasha Safwat , Watari Hidemichi , Mitamura Takashi , Khamisy sherif El , Ohba Yusuke
Published: July 2017

Ovarian cancer is the most aggressive female reproductive tract tumours. Taxane (TX) is widely used for ovarian cancer treatment. However, ovarian cancer often acquire chemoresistance. MicroRNAs (miR) have been reported to regulate many tumours’ chemoresistance. Here, we investigated the comparative microRNA expression profile between the ovarian cancer cells and their taxane-resistant counterpart, KF-TX to get novel markers for taxane resistance in ovarian cancer. The array data revealed that miR-486, miR143,miR145 and miR363 are the most upregulated miRNAs in association with TX resistance. However, miR-155, miR-100, miR-31 and miR-629 are the most significantly downregulated miRNAs after resistance development. We then focused on the role of miR-363 in chemoresistance of the ovarian cancer. qRT-PCR indicated that miR-363 was upregulated in KF-TX cells, confirming the array data, and introduction of miR-363 into sensitive ovarian cancer cells confers TX-resistance and significantly inhibited the expression of the Hippo member, LATS2, as indicated by viability, clonogenic assays and expression analysis. Furthermore, we validated the role of LATS2 in the TX-response by sh-based silencing, which also confers TX-resistance in the responsive ovarian cancer cells. On the other hand, specific inhibitor against miR-363 restored the response to TX. In addition, miR-363 was found to bind to the 3′-UTR of LATS2 mRNA, confirming that miR-363 directly targets LATS2 as indicated by dual luciferase assay. RT-PCR-based evaluation of miR-363 in a panel of human ovarian tumours revealed its upregulation in most of the tumour tissues identified as resistant while downregulation of the same gene in most of the tissues identified as sensitive ones. Moreover, higher levels of miR-363 in human ovarian cancer specimens were significantly correlated with TX chemoresistance and poor prognosis. Taken together, our study reveals the involvement of miR-363 in chemoresistance by targeting LATS2 in ovarian cancers, raising the possibility that combination therapy with a miR-363 inhibitor and TX may increase TX efficacy and reduce the chance of TX-resistance.

Note: This abstract was not presented at the meeting.

Citation Format: Noriaki Sakuragi, Mohamed Kamel Farah, Zeinab Mohamed, Safwat Okasha, Hidemichi Watari, Takashi Mitamura, sherif El Khamisy, Yusuke Ohba. Comparative miRNA microarray profiling indicates miR-363 promotes chemoresistance in ovarian cancer cells by targeting the Hippo member, LATS2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-323. doi:10.1158/1538-7445.AM2017-LB-323
Abstract LB-326: A novel oncomiR negatively regulates PTEN pathway in prostate cancer
Authors: Bhat Nadeem S. , Colden Melissa , Arora Prerna , Dar Altaf A. , Saini Sharanjot , Shahryari Varahram , Yamamura Soichiro , Tanaka Yuichiro , Katu Taku , Hashimoto Yutaka , Shiina Marisa , Kulkarni Priyanka , Dasgupta Pritha , Imai-sumida Mitsuho , Maekawa Shigekatsu , Deng Guoren , Dahiya Rajvir , Majid Shahana
Published: July 2017

Prostate carcinogenesis involves alterations in several signaling pathways, the most prominent being the PI3K/AKT pathway. This pathway is constitutively active and drives prostate cancer (PCa) progression to advanced metastatic disease. PTEN, a critical tumor and metastasis suppressor gene negatively regulates cell survival, proliferation, migration and angiogenesis via the PI3K/Akt pathway. PTEN is mutated, downregulated/dysfunctional in many cancers and its dysregulation correlates with poor prognosis in PCa. Here, we demonstrate that a novel microRNA, microRNA-4534 (miR-4534) is overexpressed in PCa and show that miR-4534 is hypermethylated in normal tissues and cell lines compared to PCa tissues/cells. miR-4534 exerts its oncogenic effects partly by downregulating the tumor suppressor PTEN gene. Knockdown of miR-4534 impaired cell proliferation, migration/invasion and induced G0/G1 cell cycle arrest and apoptosis in PCa. Suppression of miR-4534 and its effects on tumor growth was confirmed in a xenograft mouse model. We performed parallel experiments in non-cancer RWPE1 cells by overexpessing miR-4534 followed by functional assays. Overexpression of miR-4534 induced pro-cancerous characteristics in this non-cancer cell line. Kaplan-Meier and ROC analyses revealed that miR-4534 has potential to independently distinguish malignant from normal tissues and positively correlated with poor overall and PSA recurrence free survival. Taken together, our results show that depletion of miR-4534 in PCa induces a tumor suppressor phenotype partly through induction of PTEN. These results have important implications for identifying and defining the role of new PTEN regulators such as microRNAs in prostate tumorigenesis. Understanding aberrantly overexpressed miR-4534 and its downregulation of PTEN will provide mechanistic insight and therapeutic targets for PCa therapy.

Note: This abstract was not presented at the meeting.

Citation Format: Nadeem S. Bhat, Melissa Colden, Prerna Arora, Altaf A. Dar, Sharanjot Saini, Varahram Shahryari, Soichiro Yamamura, Yuichiro Tanaka, Taku Katu, Yutaka Hashimoto, Marisa Shiina, Priyanka Kulkarni, Pritha Dasgupta, Mitsuho Imai-sumida, Shigekatsu Maekawa, Guoren Deng, Rajvir Dahiya, Shahana Majid. A novel oncomiR negatively regulates PTEN pathway in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-326. doi:10.1158/1538-7445.AM2017-LB-326
Abstract LB-327: Restoration of MYC-repressed miR-29 in pancreatic cancer cells leads to increased reactive oxygen species and gemcitabine sensitization
Authors: Kwon Jason J. , Quirin Kayla , Aljoufi Arafat , Nafiseh Amira , Kota Janaiah
Published: July 2017

Pancreatic ductal adenocarcinoma (PDAC) still remains to be one of the most highly malignant human diseases and is resistant to the majority of current therapeutic modalities. Oncogene MYC has been known to be upregulated in PDAC and plays a key role in carcinogenesis and tumor progression. In our previous work, we found the downregulation of miR-29 is a common phenomenon of PDAC, and its restored expression reduced cancer cell migration/invasive potential, anchorage independent growth, and sensitized them to gemcitabine. Furthermore, we showed that miR-29 blocks autophagy in cancer cells by targeting key autophagy related proteins. However, the mechanism associated with the loss of miR-29 in PDAC has yet to be elucidated. Here we demonstrate that MYC inhibits miR-29 expression in PDAC. MYC nuclear localization negatively correlates with miR-29 expression in various pancreatic cancer cell lines, and knockdown of MYC led to an increased expression of both primary miR-29a/b1 transcript and mature miR-29a. Furthermore, miR-29 overexpression in combination with gemcitabine led to decreased cancer cell viability and increased intracellular reactive oxygen species (ROS) and cell death. Our findings show for the first time that MYC represses miR-29 in PDAC, and miR-29 sensitizes pancreatic cancer cells to gemcitabine through increased intracellular ROS. Taken together our results, indicating the potential use of miR-29a as a novel therapeutic agent for PDAC.

Citation Format: Jason J. Kwon, Kayla Quirin, Arafat Aljoufi, Amira Nafiseh, Janaiah Kota. Restoration of MYC-repressed miR-29 in pancreatic cancer cells leads to increased reactive oxygen species and gemcitabine sensitization [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-327. doi:10.1158/1538-7445.AM2017-LB-327
Abstract LB-328: Mir-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44
Authors: Cheng Ann-Joy , Lu Ya-Ching , Chang Joseph T.
Published: July 2017

Cancer stem cells preferentially acquire the specific characteristics of stress tolerance and high mobility, allowing them to progress to a therapy-refractive state. To identify a critical molecule to regulate cancer stemness is indispensable to erratically cure cancer. In this study, we identified miR-520b as a novel molecular target to suppress head-neck cancer (HNC) with stemness phenotype. MiR-520b inhibited cellular migration and invasion via the mechanism of epithelial-mesenchymal transition. It also sensitized cells to therapeutic drug and irradiation. Significantly, miR-520b suppressed spheroid cell formation, as well as reduced expressions of multiple stemness regulators (Nestin, Twist, Nanog, Oct4). The CD44 molecule was identified as a direct target of miR-520b, as shown by the reverse correlative expressions, the response to miR-520 modulation, the luciferase reporter assay, and the functional rescue analyses. These cellular results were confirmed by a tumor xenograft mice study. Administration of miR-520b dramatically restrained tumorigenesis and liver colonization. Conversely, miR-520b silencing led to an acceleration of tumor growth. Taken together, our study demonstrated that miR-520b inhibits the malignancy of HNC through regulation of cancer stemness conversion by targeting CD44. MiR-520b may serve as an emerging therapeutic target that may be further developed for the intervention of refractory HNC.

Note: This abstract was not presented at the meeting.

Citation Format: Ann-Joy Cheng, Ya-Ching Lu, Joseph T. Chang. Mir-520b as a novel molecular target for suppressing stemness phenotype of head-neck cancer by inhibiting CD44 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-328. doi:10.1158/1538-7445.AM2017-LB-328
Abstract SY19-01: Tumor-elicited inflammation in colorectal cancer
Authors: Karin Michael
Published: July 2017

The majority of sporadic human colorectal cancer is initiated by genetic loss or inactivation of tumor suppressor APC (Absent in Polyposis Coli). In addition to activation of beta-catenin signaling, we found that loss of APC results in upregulation of IL-6 signal transducer (IL6/gp130), thereby leading to activation of STAT3 and YAP, two transcription factors that make important contributions to colorectal tumorigenesis. In addition, APC loss results in deterioration of the intestinal epithelial barrier and immune homeostasis, barrier loss due to downregulation of genes encoding tight junction proteins, and suppression of mucin production. Together, such changes promote the invasion of inflammation-inducing colitogenic bacteria and their products. Loss of immune homeostasis is due to defective luminal transport of IgA dimers caused by loss of polyimmunoglobin receptor (PIgR) and CCL28, a chemokine responsible for recruitment of IgA-producing plasma cells. Defective luminal transport of IgA results in dysbiosis and over-representation of inflammation-causing bacteria that can accelerate colorectal tumor genesis through upregulation of IL-17 production.

Citation Format: Michael Karin. Tumor-elicited inflammation in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2017-SY19-01
Abstract SY22-03: Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal cancer
Authors: Soga Tomoyoshi
Published: July 2017

Metabolic reprogramming is a common hallmark of cancer. Most cancer cells produce ATP and the precursors of biomass (e.g., nucleotides, amino acids, and lipids) by shifting from oxidative phosphorylation to aerobic glycolysis, commonly known as the “Warburg effect.” Recently these cancer-specific metabolic pathways have been considered as attractive targets for cancer therapy. However, the mechanisms underlying the control of cancer cell metabolism are poorly understood. To address underlying mechanisms that induce metabolic reprogramming of cancer metabolism, we applied capillary electrophoresis mass spectrometry (CE-MS) metabolic profiling to paired normal tissues and tumor tissues obtained from 275 patients with colon cancer. Significant changes in the levels of many metabolites were observed between normal and tumor tissues. Unexpectedly, metabolite levels altered quite early and remained unchanged among cancer stages. S-Adenosylmethionine (SAM) was the most increased metabolite. Glucose was the second most decreased metabolite in tumor tissues, whereas lactate, the final product of glycolysis, was increased, which indicates activation of glycolysis (the Warburg effect). We then applied transcriptome analysis to paired normal-cancer colon tissues and revealed that alterations in mRNA levels also occurred at the adenoma stage. Regarding energy metabolism, mRNAs encoding glycolysis purine/pyrimidine synthesis, one-carbon metabolism, and fatty acid synthesis were highly expressed, whereas those in fatty acid oxidation were down-regulated in tumor tissue. Colon cancer is associated with mutations in oncogenes and tumor suppressor genes such as adenomatous polyposis coli (APC), Kirsten-ras (KRAS), and TP53. We applied next-generation sequencing technologies for the detection of somatic mutations to the tumor tissues and found mutation frequencies of 78% in APC, 68% in TP53, and 48% in KRAS. Similar to metabolome and transcriptome data, these mutations were umbiased among cancer stages. We investigated whether gene mutations including APC, KRAS, and TP53 mutations affected metabolism. Regardless of the presence or absence of the mutations, the levels of most metabolites were unaltered in tumor tissues. This raises the question of which molecules contribute to the regulation of metabolic reprogramming of colorectal cancer metabolism.

Citation Format: Tomoyoshi Soga. Multi-omics analysis of paired normal and tumor tissues reveals when and what causes altered metabolism in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY22-03. doi:10.1158/1538-7445.AM2017-SY22-03
Abstract SY23-02: Host immune responses to HPV and HPV vaccines
Authors: Pinto Ligia
Published: July 2017

Human papillomavirus (HPV) infection is the cause of multiple cancers in both women and men. There are three different licensed HPV prophylactic vaccines. Currently licensed L1 virus-like particles (VLP)–based HPV vaccines target two to nine different HPV types and have demonstrated excellent efficacy against the targeted HPV types and associated disease. Host immune responses to HPV vaccines and infection will be presented and discussed. Briefly, HPV vaccines induce nearly 100% seroconversion to all HPV types included in the vaccine. High titers of high-affinity anti-L1 IgG antibodies, to the HPV types included in the vaccine, are generated after vaccination, and these persist for several years after vaccination at levels considerably higher than those observed in natural infection. Although correlates of vaccine protection have not been identified, neutralizing antibodies are believed to be the main effectors of protection against HPV infection. Vaccine-induced antibodies are detectable not only in serum but also at mucosal sites of infection, such as the cervix and oral cavity. Local HPV-specific antibody levels, although lower, correlate well with circulating levels. Immunogenicity data have shown noninferiority of antibody responses after two doses of HPV vaccine, and the recommended number of vaccine doses was recently reduced from three to two. There is some evidence suggesting that even one dose of the bivalent HPV vaccine may provide similar protection to the recommended dose regimens. Antibody levels following one dose of the bivalent vaccine, although lower, have been shown to be stable over 4 years of follow-up and vaccine recipients remained HPV16/18 seropositive, suggesting that a single dose of the bivalent vaccine may provide durable protection against infection. The robust immunogenicity of the HPV vaccines contrasts with the immune responses observed after natural infection, in which seroconversion has been shown in only a percentage of individuals with incident HPV infection. Furthermore, levels of antibodies induced by vaccination are much higher than the levels observed after infection and appear to be preserved over time. A better understanding of long-term protection of the vaccine as well as a more comprehensive evaluation of correlates of immune protection against HPV infection are still needed.

Citation Format: Ligia Pinto. Host immune responses to HPV and HPV vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY23-02. doi:10.1158/1538-7445.AM2017-SY23-02
Abstract SY25-03: From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy
Authors: Sharma Padmanee
Published: July 2017

Immune checkpoint therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1, have led to significant clinical responses in cancer patients. To investigate immunologic changes and mechanistic pathways that are elicited by these therapies, we conducted presurgical and tissue-based clinical trials, which permit access to tumor tissues for laboratory studies. To compare and contrast data, we chose one tumor type that responds well to immune checkpoint therapy and one that does not. The first presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in a cohort of patients with localized bladder cancer. The second presurgical trial was conducted with anti-CTLA-4 (ipilimumab) in patients with localized prostate cancer. In addition, we evaluated data from patients with melanoma who received immune checkpoint therapy. These data enabled us to identify the ICOS/ICOSL pathway as relevant for antitumor immune responses in the setting of anti-CTLA-4 therapy. We also identified resistance mechanisms, including expression of other immune inhibitory pathways such as VISTA and loss of the IFNγ signaling pathway in tumor cells. These data will be discussed in greater detail.

Citation Format: Padmanee Sharma. From the clinic to the lab: Investigating response and resistance mechanisms to immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY25-03. doi:10.1158/1538-7445.AM2017-SY25-03
Abstract SY25-04: Tumor and host factors regulating immunotherapy responsiveness
Authors: Gajewski Thomas Frank
Published: July 2017

Checkpoint blockade immunotherapy is favored in patients having a T cell-inflamed tumor microenvironment at baseline. Therefore, absence of a T cell-inflamed phenotype represents a first approximation of immunotherapy resistance. Investigation of molecular features of tumor genomics, host genetics, and commensal microbiota that correlate with the degree of spontaneous T-cell infiltration has revealed multiple layers of pathways that impact on relative response versus resistance to immunotherapeutic interventions. The first tumor-intrinsic oncogene pathway demonstrated mechanistically to mediate T-cell exclusion from the tumor microenvironment and lack of checkpoint blockade efficacy is the Wnt/β-catenin pathway. Additional molecular aberrations correlated with deficient immune infiltration in various cancers include loss of function mutation or absence of PTEN, LKB1, or p53 and activation of FGFR3 or PPAR-γ. Mouse modeling has revealed that tumor cell-intrinsic β-catenin pathway activation also mediates downstream resistance to adoptive T-cell therapy, due to defective expression of key chemokines. In one patient case analyzed, transition from a β-catenin-negative to a β-catenin-positive phenotype has been associated with secondary resistance to immunotherapy. TCGA and other large genomic datasets have been an invaluable tool for identifying such molecular correlates, through availability of tumor RNAseq and exome sequencing data as well as germline SNP analysis. Host germline polymorphisms also have been identified that correlate with the degree of T-cell infiltration in the tumor, and mouse models are being utilized to investigate mechanisms. Specific commensal bacteria associated with the degree of T-cell infiltration also have been identified in animal models, and similar analyses are ongoing with human stool samples in patients undergoing checkpoint blockade therapy. A common feature of non-T cell-inflamed tumors is a relative lack of Batf3-dendritic cells and absence of a type I IFN gene signature. Thus, regulation at the level of innate immunity seems to be a key determining factor. Strategies aimed at boosting innate immune activation in the tumor microenvironment represent a major category of therapeutic intervention to convert non-T cell-inflamed tumors to T cell-inflamed, and STING agonists and probiotics are beginning to be investigated clinically.

Citation Format: Thomas Frank Gajewski. Tumor and host factors regulating immunotherapy responsiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY25-04. doi:10.1158/1538-7445.AM2017-SY25-04
Abstract SY28-01: Stromal contributions of adipocytes to cancer
Authors: Scherer Philipp E.
Published: July 2017

The past few years have provided substantial evidence for the vital role of the local tumor microenvironment in various aspects of tumorigenesis. With obesity and its pathophysiologic sequelae still on the rise, the adipocyte is increasingly moving to center stage in the context of tumor stroma-related studies. To date, we have limited insights into how systemic changes associated with obesity and altered adipokine secretion influence the incidence and progression of obesity-associated cancers. Adipocytes are the major constituents of adipose tissue and play a key role in whole body metabolism. They not only fulfill an important role as a buffer for excess triglycerides, but they also secrete many lipid and protein factors and are therefore considered major endocrine cells that influence metabolism of other tissues, including liver, muscle, brain, and pancreatic β-cells. With chronic excess of energy intake, adipocytes develop hypertrophy and face various physiologic insults, such as hypoxia, oxidative stress, and disruptions in the protein secretory pathway due to ER stress. As a result, adipocytes become dysfunctional and less efficient at fulfilling their primary function of storing and neutralizing potentially toxic free fatty acids. Adipocyte dysfunction has been widely appreciated as a major cause underlying obesity-related metabolic disorders, including insulin resistance, type 2 diabetes, cardiovascular disease, chronic inflammation, and cancers due to inappropriate release of mitogenic and inflammatory factors. As a result, these dysfunctional adipocytes also support the growth of infiltrating transformed ductal epithelial cells in the mammary gland, at the level of secretion of critical growth factors, proinflammatory cytokines, increased ECM production, and support of tumor lesion growth through release of critical metabolites. Therefore, the adipocyte with its paracrine influence on the microenvironment as well as its endocrine functions is an important area of research for both primary and metastatic tumor growth.

Citation Format: Philipp E. Scherer. Stromal contributions of adipocytes to cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY28-01. doi:10.1158/1538-7445.AM2017-SY28-01