bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1119: Targeting tankyrases as a therapeutic strategy for triple-negative breast cancer
Authors: Mathew Maya , Campo Loredana , Kim Jung-Lye , Ha Geun-Hyoung , Breuer Eun-Kyoung 
Published: July 2017

Abstract
Tankyrases (TNKS1 and TNKS2) are members of the human poly(ADP-ribose) polymerase (PARP) family and catalyze PARsylation by using NAD+ as a substrate to modify various proteins in order to regulate various cellular processes including Wnt/β-catenin signaling. TNKS1 has been shown to be overexpressed and to be correlated with highly aggressive disease and prognosis in various types of human cancers. A small molecule inhibitor of TNKS1, XAV-939 has been proven to be a potent inhibitor of Wnt/β-catenin signaling by stabilizing Axin. However, the effect of tankyrase inhibitors as potential breast cancer therapy is still under investigation. In this study, we found that TNKS1 is highly expressed in breast cancer cell lines, particularly in triple-negative breast cancer (TNBC) cells and that the expression of TNKS1 correlates with anti-proliferative efficacy of tankyrase inhibitors, XAV-939 and JW55. Also, XAV-939 treatment suppressed cell migration and invasion capabilities and epithelial-mesenchymal transition (EMT) signaling in triple-negative breast cancer cell lines. Moreover, XAV-939 reduced expression of stemness markers. It was shown that polo-like kinase 1 (PLK1) functions as a positive regulator of TNKS1 protein stability. Interestingly, we found that combination treatment of XAV-939 with PLK inhibitor GW843682X significantly suppressed cell growth, clonogenic potential, migratory and invasive capabilities of breast cancer cells. The combination of XAV-939 with ionizing radiation (IR) also showed an additional therapeutic effect. Therefore, our findings highlight the important value of TNKS1 as a therapeutic target and suggest the potential for improving the clinical efficacies of tankyrase inhibitors in combination with either PLK inhibitors or radiotherapy for patients with triple-negative breast cancer.
Citation Format: Maya Mathew, Loredana Campo, Jung-Lye Kim, Geun-Hyoung Ha, Eun-Kyoung Breuer. Targeting tankyrases as a therapeutic strategy for triple-negative breast 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 1119. doi:10.1158/1538-7445.AM2017-1119
Abstract 112: Identifying drugs that target ovarian cancer tumor initiating cells
Authors: Ozaki Michelle K. , House Carrie D. , Annunziata Christina M. 
Published: July 2017

Abstract
Ovarian cancer is the most lethal gynecological cancer, with overall five-year survival for women with advanced disease being at only 25%. The current standard of care is treatment with a platinum-based chemotherapy drug. Unfortunately, a subpopulation of tumor cells often persists, contributing to platinum-based chemotherapy resistance and disease recurrence. In this study we investigated drugs to target these putative tumor-initiating cells (TICs), and explored the pathways of these drugs in both adherent proliferative cell culture conditions and non-adherent TIC-enriched cultures. We conducted a drug screen under both growth conditions, in order to identify compounds that are able to inhibit growth of TICs. Of the drugs identified, we focused further efforts on those involved with inhibiting the NF-kappaB pathway because prior studies have linked NF-kappaB activity with drug resistance and poor survival. Cell viability assays done with the four drugs, bardoxolone methyl, salinomycin, disulfiram, and elesclomol, show these drugs inhibit the growth of ovarian cancer cell lines both as TICs and in corresponding adherent cultures. Disulfiram showed preferential killing of TICs in some of the cell lines tested. All drugs showed some evidence for inhibiting NF-kappaB on Western blot, and ability to decrease CD133/ALDH double-positive TICs on flow cytometry. Carboplatin is known to kill proliferative ovarian cancer cells, and increase the relative percentage of CD133/ALDH positive TICs. Our ongoing studies will address combination of each drug with carboplatin, with the hypothesis that these drugs will increase in vivo efficacy by suppressing TICs, and thereby decrease recurrence of platinum-resistant ovarian cancer.
Citation Format: Michelle K. Ozaki, Carrie D. House, Christina M. Annunziata. Identifying drugs that target ovarian cancer tumor initiating 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 112. doi:10.1158/1538-7445.AM2017-112
Abstract 1120: Chronopharmacology of cisplatin: role of the circadian rhythm in modulating cisplatin-induced toxicity in melanoma mouse model
Authors: Dakup Panshak , Porter Kenneth , Gajula Rajendra , Gaddameedhi Shobhan 
Published: July 2017

Abstract
Purpose: The goal of this research is to highlight novel and divergent molecular mechanisms of the circadian system in modulating the response of cisplatin therapy against melanoma tumors. Cisplatin is one of the most commonly used chemotherapeutic drugs in treating a variety of tumors including cancers of ovaries, testis, lungs, blood and solid tumors of the head and neck, and is more recently under clinical trials for potential application in melanoma tumors. However, the major limitation of cisplatin as a chemotherapeutic drug is its tumor resistance and nephrotoxicity. Hence, improving the effectiveness and reducing the toxicities associated with cisplatin therapy are desirable outcomes. Studies on human models have shown decreased renal and blood toxicity by time-of-the-day. Consequently, our project seeks to study the chronopharmacological effects and understand the mechanisms that have been successfully demonstrated in human models. We hypothesize a mechanistic, circadian rhythm-based cause for these outcomes.
Experimental Design: Studies were done on B16F10 melanoma mouse models of wild-type and circadian disrupted Per1/2 -/- animals treated with 3 doses of 5 mg/kg cisplatin in the morning (7 AM) and evening (5 PM). Animal weights and tumor sizes were measured regularly post-treatment. Upon sacrifice, tissues (skin, kidney, and tumor) were harvested and analyzed for cisplatin-induced toxicities and DNA damage responses using H & E staining, western blot, and KIM-1 and immuno-slot blot assays.
Results: Weight measurements show a clock-regulated response to cisplatin toxicity. AM-treated wild-type animals showed significant weight loss compared to PM-treated wild-type animals. This treatment time differential is lost in the Per1/2 -/-. On a molecular level, kidney tissue DNA samples showed clock-controlled cisplatin-DNA repair activity in wild-type animals compared to Per1/2 -/-. These initial findings strongly suggest that nephrotoxicity and DNA damage response function might be regulated by the circadian rhythm.
Conclusions: These findings indicate a possible mechanism for the chronopharmacology of cisplatin in minimizing the toxicity associated with it and reveal a target for future study of additional mechanistic causes of circadian dosing changes in cisplatin and other genotoxic stress-mediated anti-cancer agents.
Citation Format: Panshak Dakup, Kenneth Porter, Rajendra Gajula, Shobhan Gaddameedhi. Chronopharmacology of cisplatin: role of the circadian rhythm in modulating cisplatin-induced toxicity in melanoma mouse model [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 1120. doi:10.1158/1538-7445.AM2017-1120
Abstract 1123: Sphingolipids transfer proteins (GLTP and CPTP) regulate the neoplastic progression of colon and breast cancer cells
Authors: Mishra Shrawan K. , Brown Rhoderick E. 
Published: July 2017

Abstract
Sphingolipids have previously been shown to affect cancer progression by regulating cell death (apoptosis) and survival (autophagy). While apoptosis is promoted by elevations in sphingosine and ceramide, increases in sphingosine-1-phosphate and ceramide-1-phosphate can tip the balance toward survival. Changes in the expression of sphingolipid transfer proteins such as GLTP (glycolipid transfer protein) and CPTP (ceramide-1-phosphate transfer protein) have been shown to modulate cell shape change and regulate pro-inflammatory cytokine release, respectively, in human cancer epithelial cell lines. To gain a better understanding of the situation, we investigated further. We discovered that GLTP overexpression inhibits the growth of human colon carcinoma cell lines (HT-29; HCT-116), but spares normal colonic epithelial cells (HCEC) largely due to growth arrest at the G0/G1 cell cycle checkpoint. Mechanistically, we found that GLTP overexpression modulated cell cycle progression by upregulating Kip1/p27 and Cip1/p21 protein and mRNA levels, while decreasing CDK2, CDK4, cyclin E and cyclin D1 protein levels. The cell cycle arrest and growth inhibition induced by GLTP overexpression led to apoptotic cell death of HT-29 cells. Neither GLTP nor CPTP overexpression induced apoptosis in breast cancer cell lines (T47D and HTB-126). However, depletion of CPTP, but not GLTP, induced autophagy as indicated by increased LC3 transcript and autophagosome levels (GFP-LC3-II puncta). In the breast cancer cell lines, increased transcript levels of cPLA2 and CERK were detected consistent with the earlier pro-inflammatory effect reported for CPTP depletion in A549 lung epithelial carcinoma cells. Our findings shed light on the mechanistic ways by which GLTP and CPTP affect apoptosis and autophagy to impact cancer progression. Future in vivo studies are planned to ascertain the role(s) of these new players in cancer development and therapy.
[Support: NIH GM45928, HL-125353, Paint-the-Town-Pink (PTTP) Cancer Funds, Hormel Fdn]
Citation Format: Shrawan K. Mishra, Rhoderick E. Brown. Sphingolipids transfer proteins (GLTP and CPTP) regulate the neoplastic progression of colon and breast 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 1123. doi:10.1158/1538-7445.AM2017-1123
Abstract 1124: Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy
Authors: Khazak Vladimir , Skobeleva Natalia , Vetkina Anastasiia , Serebriiskii Ilya , Timms Kirsten M. , Davies Angela , Astsaturov Igor 
Published: July 2017

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals annually in the US, with almost 90% lethality even when diagnosed prior to metastasis. There is an urgent unmet medical need both for new therapies as well as better matching of existing therapies to patients. To address this emergency, we are assessing the feasibility of implementing a strategy of using HRD (Homologous Recombination Deficiency) scores for better therapy matching in PDAC patients. Using a panel of 77 patient-derived xenograft (PDX) models that were developed from fresh surgical PDAC tumor samples, HRD scores were generated based on analysis of three biomarkers (LOH, TAI and LST) and mutational data for 45 genes. All 77 samples met inclusion criteria, 75 FFPE specimens generated mutation data. HRD analysis was successful for 71 specimens (range= 1 - 63 (median=22)), with the primary cause of failure identified as high non-tumor content. 53 PDX models had mutations in KRAS gene and 45 in TP53. We have also identified 4 PDX models with mutations in BRCA2, 3 models with mutations in ATM, 4 models with mutations in RAD51. We have also found frequent mutations in several other DNA repair genes (ATR, PALB2, MLH1, MSH2, MSH3, MSH6, FANCM), but most of these models retained one functional allele and were not associated with a high HRD score. Using this genomic analysis, all 71 PDX models were stratified into three clusters with high, medium and low HRD scores. Three PDX models with the highest and lowest HRD scores each were selected for an in vivo study with DNA-damaging platinum-based chemotherapeutic agents Cisplatin and Carboplatin, as well as with a clinically relevant PARP inhibitor Niraparib. The results of the PDX study will be reported and compared with responses to chemotherapy using RECIST V1.1 in patients.
Note: This abstract was not presented at the meeting.
Citation Format: Vladimir Khazak, Natalia Skobeleva, Anastasiia Vetkina, Ilya Serebriiskii, Kirsten M. Timms, Angela Davies, Igor Astsaturov. Assessment of HRD score as predictor of chemosensitivity of PDAC PDX xenograft models to DNA-damaging chemotherapy [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 1124. doi:10.1158/1538-7445.AM2017-1124
Abstract 1127: Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma
Authors: Matsangou Maria , Ugolkov Andrey , Taxter Timothy J. , Samant Sandeep , Mazar Andrew P. , Giles Francis J. 
Published: July 2017

Abstract
Background: Recurrent/metastatic head and neck squamous cell carcinoma (SCCHN) and salivary gland malignancies are difficult to treat with limited standard of care options at the present time. Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been implicated as a potential therapeutic target in human cancer. Our in vivo studies demonstrated that our novel GSK-3 inhibitors significantly potentiated the effects of conventional chemotherapy in patient-derived xenograft models of glioblastoma and breast cancer leading to regression of tumors. In order to develop a rationale to test our novel GSK-3 inhibitors in head and neck (H&N) malignancies, we evaluated the expression pattern of GSK-3beta in human H&N benign tissue and malignant tumors.
Methods: We used immunohistochemical staining of H&N tumor tissue Microarray (TMA), 48 total cases (20 benign tissues, 28 malignant), to study the expression pattern of GSK-3beta. GSK-3beta nuclear accumulation was defined as positive staining of more than 50% of cancer cell nuclei throughout the tumor regardless of cytoplasmic staining.
Results: Of the 20 malignant H&N samples (15 SCCHN, 1 nasopharyngeal and 5 other histology), 13 (65%) were found to have aberrant nuclear accumulation of GSK-3beta. Amongst SCCHN, 73% (11 of 15 samples) had aberrant nuclear accumulation of GSK-3beta. In contrast, none (0%) of the 11 benign non-salivary H&N tissue showed detectable expression of GSK-3beta. Of interest, 60% of salivary adenoid cystic carcinoma specimens and 44% of benign salivary gland tissue showed GSK-3beta expression.
Conclusions: Our results demonstrate for the first time, that there is aberrant nuclear expression of GSK-3beta in SCCHN. This finding supports further exploring of our novel GSK-3beta inhibitor as a potential therapeutic target for recurrent/metastatic SCCHN and also, as a potential prognostic and predictive biomarker for risk of recurrent disease and chemo- or radio-resistance. Its role in salivary gland malignancies requires further studying.
Citation Format: Maria Matsangou, Andrey Ugolkov, Timothy J. Taxter, Sandeep Samant, Andrew P. Mazar, Francis J. Giles. Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma [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 1127. doi:10.1158/1538-7445.AM2017-1127
Abstract 113: Evaluating the anticancer activity of two flexible heteroarotinoid analogs on breast cancer
Authors: Ginn Emily , Zou Hongye , Fallatah Maryam M. , Liu Shengquan , Louie Maggie C. 
Published: July 2017

Abstract
Flexible heteroarotiniods (flex-hets) are compounds derived from retinoic acid and recent studies have indicated that these compounds exhibit anti-cancer activity. Amongst the flexible heteroarotinoids, SHetA2 has been to shown block the growth of cervical, head and neck, kidney, lung, and ovarian cancers, and most recently, prostate and breast cancers. However, due to SHetA2’s limitations— a high degree of hydrophobicity, non-selectivity, and potential liver toxicity— a second generation of analogs was developed. Results from our recent study suggest that one of the second-generation analogs, 1-(1-(naphthalen-1-yl)ethyl)-3-(4-nitrophenyl)thiourea (SL-1-09) exhibits anti-cancer activities against both ERα+ and ER- breast cancer cells at micromolar concentrations. Since SL-1-09 is a racemic mixture, the R (SL-1-29) and S (SL-1-30) enantiomers were purified and investigated for their anti-cancer properties. Our results suggest that SL-1-30 has greater growth inhibitory effects on T47D, MCF7, MDA-MB-453, MDA-MB-468 cells in comparison to SL1-29, suggesting that the activity observed in SL-1-09 is likely associated with the S enantiomer. Consistent with this data, breast cancer cells treated with SL-1-09 and SL-1-30 express lower levels of proteins that regulate the cell cycle (i.e, cyclin A, cyclin B, cyclin D1, cyclin E and cdk2). These results demonstrate that SL-1-30 and SL-1-09 inhibit breast cancer cell growth, potentially by blocking cell cycle progression, however further studies are necessary for determining the mechanisms of action.
Citation Format: Emily Ginn, Hongye Zou, Maryam M. Fallatah, Shengquan Liu, Maggie C. Louie. Evaluating the anticancer activity of two flexible heteroarotinoid analogs on breast 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 113. doi:10.1158/1538-7445.AM2017-113
Abstract 1133: Discovery of novel small molecule inhibitors of RNA-binding protein Musashi-1
Authors: Lan Lan , Smith Amber , Wu Xiaoqing , Roy Anuradha , Gowthaman Ragul , Karanicolas John , Somoza Amber D. , Wang Clay C.C. , Oakley Berl , Guzman Roberto De , Neufeld Kristi , Xu Liang 
Published: July 2017

Abstract
1) Background and Objective: Musashi-1(Msi1) is an RNA-binding protein that negatively regulates translation by binding to the 3′-UTRs of target mRNAs including Numb, APC and p21WAF-1, key regulators of Notch, Wnt signaling and cell cycle progression, respectively. We aim to identify small molecule inhibitors of Msi1’s mRNA-binding activity thus blocking the growth of a broad range of cancer cells.
2) Methods: Fluorescence polarization assay was used to screen for small molecules that disrupt the binding of Msi1 to its consensus RNA binding site. Hits were validated by surface plasmon resonance, amplified luminescent proximity homogeneous assay and nuclear magnetic resonance.
3) Results: Among ~2,000 small molecules we screened, we found several clusters of compounds that disrupt the Msi1-numb RNA binding potently, including natural products, herbal extracts and fungal metabolites. One of the clusters is the derivatives of the secondary metabolites from Aspergillus nidulans. The top hit, Aza-9, from this cluster was validated by amplified luminescent proximity homogeneous assay. Further validation by surface plasmon resonance and nuclear magnetic resonance indicate that Aza-9 binds to Msi1 directly, in the RNA binding pocket.
4) Discussion and Conclusions: Our study supports the hypothesis that Msi1 inhibition is a viable and effective anti-cancer strategy. More target validation assays will be carried out for the compounds from other clusters.
Citation Format: Lan Lan, Amber Smith, Xiaoqing Wu, Anuradha Roy, Ragul Gowthaman, John Karanicolas, Amber D. Somoza, Clay C.C. Wang, Berl Oakley, Roberto De Guzman, Kristi Neufeld, Liang Xu. Discovery of novel small molecule inhibitors of RNA-binding protein Musashi-1 [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 1133. doi:10.1158/1538-7445.AM2017-1133
Abstract 1141: Evaluation of GABRP as a novel therapeutic target in triple negative breast cancer
Authors: Wali Vikram B. , Patwardhan Gauri A. , Hatzis Christos , Pusztai Lajos 
Published: July 2017

Abstract
Triple Negative breast cancers (TNBC) represent nearly 20% of all breast cancers but do not have any targeted therapies available due to lack of amplification of HER2 and expression of estrogen and progesterone receptors. To identify potentially druggable targets for TNBC, we compared TNBC to non-TNBC tumors in large independent gene expression clinical datasets to identify highly expressed genes in TNBC that encode for proteins expressed on the cell surface. We found gamma-aminobutyric acid type A receptor pi (GABRP) to be the most overexpressed receptor protein gene in TNBC, while its expression in normal tissues was low and comparable to that of proteins targeted by drugs or therapeutic antibodies already in clinical testing. We compared GABRP mRNA and protein expression across panel of breast cancer cell lines and found it to be particularly elevated in HCC1143 and MDA-MB-468 TNBC cells. Knockdown of GABRP using siRNA suppressed TNBC cell growth and stable GABRP knock-down by shRNA suppressed growth of MDA-MB-468 xenografts in nude mice. Sub-cellular fractionation of TNBC cells and subsequent Western blot analysis confirmed that GABRP is located predominantly in the cell membrane. GABRP protein expression on cell surface was also detected by flowcytometry. Interestingly, treatment with 5-100μg/ml of anti-GABRP antibody that binds to the extracellular domain (ECD) itself inhibited growth of TNBC cell lines expressing higher GABRP, while the same doses of a control antibody had no effect in these cells in culture. Our goal is to generate an antibody drug conjugate (ADC) for TNBC by conjugating anti-GABRP antibody with a maytansinoid such as DM1, which has proven cytotoxicity in breast cancer cells. Together, our results suggest that GABRP is a potential therapeutic target for triple-negative breast cancers.
Citation Format: Vikram B. Wali, Gauri A. Patwardhan, Christos Hatzis, Lajos Pusztai. Evaluation of GABRP as a novel therapeutic target in triple negative breast 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 1141. doi:10.1158/1538-7445.AM2017-1141