bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 416: Identification of therapeutic combinations in glioblastoma using personalized gene expression networks
Authors: Stathias Vasileios , Forlin Michele , Allen Bryce , Schürer Stephan , Ayad Nagi G.
Published: July 2017

The goal of our study was to identify patient-specific gene expression networks from Glioblastoma Patient-Derived Xenografts (PDXs) and determine novel therapeutic compound combinations using those networks.

Glioblastoma is the most common malignant primary adult brain tumor with a standard of care consisting of maximal surgical resection followed by radiotherapy and adjuvant temozolomide (TMZ) chemotherapy. However, despite medical advances in the field, recurrence is almost universal, suggesting the need for more personalized and targeted therapeutic approaches.

For this, we obtained, transcriptional data from Glioblastoma PDXs and used them to identify their respective differentially expressed genes. Patient-specific gene expression networks were then created and their biological relevance was supplemented by integrating them with TCGA Glioblastoma transcriptional data. In order to identify compound combinations specific for those networks, we used the extensive chemical perturbation signatures from the Library of Network-based Cellular Signatures (LINCS). From the large number of L1000 transcriptional data we extracted gene expression signatures that were indicative of specific LINCS compounds. We then compared those signatures to the patient-specific networks in order to prioritize compound combinations that were inducing discordant transcriptional changes in distinct sub-networks of the PDXs transcriptome. The most orthogonal compound combinations were then chosen and used in in-vitro cell viability assays of Glioblastoma PDXs in order to evaluate their effectiveness. The above process can be used to prioritize compound combinations with potential therapeutic effect in a patient-specific manner.

Citation Format: Vasileios Stathias, Michele Forlin, Bryce Allen, Stephan Schürer, Nagi G. Ayad. Identification of therapeutic combinations in glioblastoma using personalized gene expression networks [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 416. doi:10.1158/1538-7445.AM2017-416
Abstract 4166: Role of CD44 as a regulator of adaptive plasticity in pancreatic cancer cells
Authors: Chen Chen , Zhao Shujie , Zhao Xiangru , Freeman James W.
Published: July 2017

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) may show an initial objective response to chemotherapy that is usually of short duration. Our research goal is to understand the molecular mechanisms for this short duration response and to more fully define differences between chemosensitive and chemoresistant cells. Cancer cells that undergo an EMT and metastatic tumors show an increase in CD44s expression. In this study, we use CD44 Low and CD44 High isogenic cell models to identifying key molecular networks and potential targets that could benefit therapy.

Experiments design: CFPAC1-CD44 Hi and Low cells were sorted by flowcytometry and single clone selection. Isogenic model systems were generated by overexpression CD44s in CF-Low cells. Western blot, MTT, migration and invasion assays had been used to characterize cell growth, invasiveness and gemcitabine sensitivity. Receptor Tyrosine Kinase arrays were used to identify the CD44 regulated molecular networks in these isogenic cell models treated with/without CD44 ligand hyaluronan acid (HA).

Summary: CD44s high cells show an EMT phenotype (increase of vimentin and loss of E-cadherin) and increase invasion. Expression of CD44s in CD44 low cells was sufficient to drive EMT partially and drive invasion. By in vitro testing over expressing CD44s is not sufficient to decrease sensitivity to gemcitabine. By Receptor Tyrosine Kinase arrays, CD44 Hi clone cells show increase in IGF-1R phosphorylation. Preliminary data had shown that HA may stimulate ROR2, VEGFR1, and EphB2 phosphorylation in CD44 Hi clone cells.

Conclusion: Our previous study suggested that CD44 could be a therapeutic target in Gemcitabine resistant PDAC cells. The current study will further identify the molecular targets that regulated by CD44 pathways. These newly identified targets could be hopefully used for the optimized multimodality therapy to sensitize the PDAC cells to therapy and to benefit the pancreatic cancer patients.

Citation Format: Chen Chen, Shujie Zhao, Xiangru Zhao, James W. Freeman. Role of CD44 as a regulator of adaptive plasticity in pancreatic 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 4166. doi:10.1158/1538-7445.AM2017-4166
Abstract 4168: Altering cisplatin sensitivity by manipulating the cellular metallome
Authors: Amable Lauren , Shide Eric
Published: July 2017

The cellular metallome serves as an important reservoir to meet the biological needs of the cell, serving as enzyme co-factors and ensuring proper protein folding. Recent studies have suggested that cancer cells adapt their metallome in order to accommodate rapid cellular growth and metabolism pathways. Thus, altering the cancer metallome may yield new avenues to target cancer and change the responsiveness to chemotherapy. Here, we aim to characterize and understand how changes in the ovarian cancer metallome affect sensitivity to the chemotherapy drug cisplatin. Five ovarian cancer cell lines were used in experiments: A2780, A2780/CP70, SKOV3, OVCAR3, and CAOV3. The metallome was manipulated by treating cells with either zinc, copper, magnesium, calcium, iron, manganese, or the metal chelator tetrathiomolybdate. Cisplatin sensitivity after metal treatment was measured by WST-1 cell proliferation assays. Metallomes were quantitated by Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) by measuring the following metals: zinc, copper, magnesium, calcium, molybdenum, manganese, iron, phosphorous, and sulfur. Cellular metal concentrations were normalized to sulfur levels. Changes in cisplatin sensitivity were evaluated by measuring cellular cisplatin uptake by ICP-MS. Treatment of ovarian cancer cells with various metals resulted in differences in cellular proliferation and metallome composition. The changes in the metallome were not singular in nature because altering one metal resulted in changes in multiple metals. Cisplatin sensitivity was additionally affected under different metal treatments. Preliminary data suggest that cisplatin uptake was altered as a mechanism to mediate the cellular response to cisplatin, however other mechanisms such as DNA repair might also play a role. In conclusion, we demonstrate that perturbations of the cancer metallome result in changes of various metals, cellular proliferation, and sensitivity to the chemotherapy drug cisplatin. The data lend further insight into how an individual’s metallomic status, a combination of nutritional and harmful metal exposure, might result in the development and progression of cancer and affect the response to chemotherapy.

Citation Format: Lauren Amable, Eric Shide. Altering cisplatin sensitivity by manipulating the cellular metallome [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 4168. doi:10.1158/1538-7445.AM2017-4168
Abstract 4173: Drug target mutations as a mechanism of acquired resistance to small molecules activators of protein phosphatase 2a
Authors: Tohme Rita , Sangodkar Jaya , Kiselar Janna , Leonard Daniel , O'Connor Caitlin , Gandhe Sai , Xu Wenqing , Brautigan David , Chance Mark , Ohlmeyer Michael , Narla Goutham
Published: July 2017

The sustainable activation of the RAS/MAPK and PI3K/AKT signaling pathways in cancer is promoted by a reduction in the activity of the tumor suppressor protein phosphatase 2A (PP2A). Therefore, a novel therapeutic strategy consists of directly activating PP2A, leading to the simultaneous inhibition of these oncogenic pathways. PP2A is a heterotrimeric complex, consisting of a scaffolding A subunit, catalytic C subunit, and one of many regulatory B subunits responsible for substrate specificity. Our lab has successfully developed first-in-class Small Molecule Activators of PP2A (SMAPs), which induce tumor growth inhibition in both transgenic and patient derived xenograft mice models. However, alterations to the drug binding site is one of the most common mechanisms of acquired resistance, and we hypothesized that point mutations of the drug binding amino acid residues of PP2A would lead to decreased sensitivity to SMAP treatment. Determining potential mechanisms responsible for the development of resistance to SMAPs would guide the development of novel therapeutic strategies to improve patients’ prognosis. In silico docking calculations, photo affinity labeling, and hydroxyl radical footprinting studies were used to identify K194, E197, and L198 as the putative residues of PP2A-Aα that were interacting with SMAPs. K194R, E197K, and L198V mutations were generated by site-directed mutagenesis. H358, a KRAS-driven lung adenocarcinoma cell line, was used to create isogenic cell lines stably overexpressing mutated and wild type PP2A-Aα. These mutations did not affect the phosphatase activity or its ability to form holoenzymes in a cell-free system.  SMAP response was investigated in vivo using a xenograft model of H358 isogenic cell lines and it was determined that tumors harboring mutant K194R and L198V PP2A-Aα were resistant to SMAPs treatment. Together, our results suggest that residues K194 and L198 are required for drug binding and subsequent target engagement. These findings shed light on possible mechanisms of acquired resistance to SMAPs in patients and have potential to guide the design of second-generation drugs.

Citation Format: Rita Tohme, Jaya Sangodkar, Janna Kiselar, Daniel Leonard, Caitlin O'Connor, Sai Gandhe, Wenqing Xu, David Brautigan, Mark Chance, Michael Ohlmeyer, Goutham Narla. Drug target mutations as a mechanism of acquired resistance to small molecules activators of protein phosphatase 2a [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 4173. doi:10.1158/1538-7445.AM2017-4173
Abstract 4179: Potent and selective TRK inhibitor CH7057288
Authors: Tanaka Hiroshi , Sase Hitoshi , Tsukaguchi Toshiyuki , Tanimura Hiromi , Hasegawa Masami , Hasegawa Kiyoshi , Ono Yoshiyuki , Oikawa Nobuhiro , Sakamoto Hiroshi , Mio Toshiyuki
Published: July 2017

TRK receptor tyrosine kinases are expressed as fusion proteins encoded by various fusion genes across a wide variety of cancer types, including lung and colorectal cancer. These fusion proteins have potent oncogenic activity and are thought to be an attractive therapeutic target. In a kinase inhibitor screening we identified CH7057288, a potent and selective TRK inhibitor belonging to a novel chemical class. Our inhibitor showed selective inhibitory activity against TRKA, TRKB, and TRKC in cell-free kinase assays and suppressed proliferation of TRK fusion-positive cell lines, but not that of TRK-negative cell lines. In subcutaneously implanted xenograft models of TRK fusion-positive cells, strong tumor growth inhibition was observed. Furthermore, CH7057288 induced regression of intracranial tumors and greatly improved event-free survival in an intracranial implantation model mimicking brain metastasis. Recently, resistant mutations in TRK have been reported in patients showing disease progression after treatment with a TRK inhibitor under clinical development. Our compound maintained similar levels of in vitro and in vivo activity against some of the resistant mutants as it did to wild-type TRK. In summary, CH7057288 could be a promising therapeutic agent for TRK fusion-positive cancer.

Citation Format: Hiroshi Tanaka, Hitoshi Sase, Toshiyuki Tsukaguchi, Hiromi Tanimura, Masami Hasegawa, Kiyoshi Hasegawa, Yoshiyuki Ono, Nobuhiro Oikawa, Hiroshi Sakamoto, Toshiyuki Mio. Potent and selective TRK inhibitor CH7057288 [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 4179. doi:10.1158/1538-7445.AM2017-4179
Abstract 4193: A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor scaffold
Authors: Shi Yihui , Park Jaehyeon , Lagisetti Chandraiah , Zhou Wei , Sambucetti Lidia C. , Webb Thomas R.
Published: July 2017

The splicing of pre-mRNA is a critical process in normal cells and is deregulated in cancer. Compounds that modulate this process have recently been shown to target a specific vulnerability in tumors. We have developed a novel cell-based assay that specifically activates luciferase in cells exposed to SF3B1 targeted compounds, such as sudemycin D6. This assay was used to screen a combined collection of approved drugs and bioactive compounds. This screening approach identified several active hits, the most potent of which were CGP-74514A and aminopurvalanol A, both have been reported to be cyclin-dependent kinases (CDKs) inhibitors. We found that these compounds, and their analogs, show significant cdc2-like kinase (CLK) inhibition and clear structure-activity relationships (SAR) at CLKs. We prepared a set of analogs and were able to ‘dial out’ the CDK activity and simultaneously developed CLK inhibitors with low nanomolar activity. Thus, we have demonstrated the utility of our exon-skipping assay and identified new molecules that exhibit potency and selectivity for CLK, as well as some structurally related dual CLK/CDK inhibitors.

Citation Format: Yihui Shi, Jaehyeon Park, Chandraiah Lagisetti, Wei Zhou, Lidia C. Sambucetti, Thomas R. Webb. A triple exon-skipping luciferase reporter assay identifies a new CLK inhibitor scaffold [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 4193. doi:10.1158/1538-7445.AM2017-4193
Abstract 4203: Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion
Authors: Thatte Jayant , Talaoc Elvira C. , Scott Colleen , Ren Ken , Broudy Thomas
Published: July 2017

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct primary hepatic malignancy that has conventionally been considered to be a histologic variant of hepatocellular carcinoma. However, it has more recently been recognized as a distinct clinical entity with respect to its epidemiology and prognosis. The etiology of FL-HCC is unclear and there is no clinical or histological evidence for association with chronic liver disease. Recent genetic studies have identified the fusion gene DNAJB1-PRKACA as a recurrent genetic lesion in the disease. Molecular pathogenesis of FL-HCC; however, is not well understood and has been reported to occur in association with focal nodular hyperplasia. Overexpression of genes in PIK3, MAPK and RAS pathways is observed in FL-HCC and in contrast to viral-associated HCC, epigenetic instability is rare in FL-HCC.

Here we describe development of a novel FL-HCC Patient Derived Xenograft (PDX) model LI5132. RNASeq analysis revealed presence of DNAJB1-PRKACA gene fusion on chromosome 19, a molecular signature of FL-HCC. Clinical diagnosis as HCC of fibrolamellar type was confirmed by H&E staining in the PDX tumor. The PDX tumor had a distinctive intratumoral fibrosis with a lamellar pattern. PDX model was established by inoculating patient tumor cells subcutaneously in NOD-SCID mice. Robust tumor growth was observed with a 100% take rate in NOD-SCID mice.

To evaluate the translational relevance of this model toward therapeutic development, the efficacy of a novel multi-target Aurora kinase A and angiokinase inhibitor, ENMD-2076, was evaluated in a therapeutic mode in this model. ENMD-2076 showed significant efficacy in suppressing tumor growth in NOD-SCID mice, at the 200 mg/kg dose evaluated in this study. Weight loss observed during the treatment period could not be attributed to ENMD-2076 as it was similar to weight loss observed with vehicle treatment. ENMD-2076 has now progressed in to phase II trials in the clinic for treatment of FL-HCC. This demonstrates the translational utility of this FL-HCC model in development of anti-cancer therapeutic agents.

Citation Format: Jayant Thatte, Elvira C. Talaoc, Colleen Scott, Ken Ren, Thomas Broudy. Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion [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 4203. doi:10.1158/1538-7445.AM2017-4203
Abstract 4204: ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models
Authors: Reddy Sanjeeva P. , Rao Niranjan , Zammit David , Thompson Scott K. , Smith Roger A. , Denis Louis
Published: July 2017

Spleen tyrosine kinase (SYK) and Janus kinase (JAK) play important roles in the pathogenesis of various types of lymphomas, solid tumors, and myeloproliferative and inflammation disorders. Inhibition of both SYK and JAK kinases has been shown to suppress tumor growth in various preclinical and/or clinical studies. ASN002 is a novel and potent dual inhibitor of SYK and JAK kinases with IC50 values of 4-46 nM in biochemical assays. In mechanistic cell-based studies, ASN002 strongly suppressed the SYK and JAK family kinase signaling pathways as measured in pLAT and pSTAT assays, respectively. When profiled in a panel of 178 cell lines, the compound showed strong anti-proliferative activity in many lymphoid/leukemia cell lines, including SU-DHL-6, SU-DHL-4, OCI-LY10, H929 and Pfeiffer. The proliferation of many solid tumor cell lines representing bladder, lung and colorectal cancer tumor types was also potently inhibited. Importantly, it also strongly inhibited the growth of ibrutinib and idelalisib resistant cell lines. ASN002 was highly efficacious in inhibiting the tumor growth in several tumor xenograft models which include Pfeiffer (diffuse large B-cell lymphoma, DLBCL), SU-DHL-6 (DLBCL), H929 (myeloma), HEL (erythroleukemia), and RT112 (bladder). ASN002 shows little to no inhibition of CYP450 isozymes suggesting low potential for drug-drug interactions. ASN002 is currently being evaluated in a Phase I/II clinical study in patients with lymphomas (DLBCL, mantle cell lymphoma and follicular lymphoma) and solid tumors.

Citation Format: Sanjeeva P. Reddy, Niranjan Rao, David Zammit, Scott K. Thompson, Roger A. Smith, Louis Denis. ASN002: A novel dual SYK/JAK inhibitor with strong antitumor activity in both hematological and solid tumor xenograft models [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 4204. doi:10.1158/1538-7445.AM2017-4204
Abstract 4209: Inhibitory activity of lichen secondary metabolite, physciosporin, against lung cancer cell motility
Authors: Yang Yi , Yu Young Hyun , Ha Hyung-Ho , Lee Kyung-Hwa , Moon Kyung-Sub , Kim Kyung Keun , Kim Hangun
Published: July 2017

Lichens produce various unique chemicals that can be used for pharmaceutical purposes. To screen for novel lichen secondary metabolites showing inhibitory activity against lung cancer cell motility, we tested acetone extracts of 13 lichen samples collected in Chile. Physciosporin, isolated from Pseudocyphellaria coriacea (Hook f. & Taylor) D.J. Galloway & P. James, was identified as an effective compound and showed significant inhibitory activity in migration and invasion assays against human lung cancer cells. Physciosporin treatment reduced both protein and mRNA levels of N-cadherin with concomitant decreases in the levels of epithelial-mesenchymal transition markers such as snail and twist. Physciosporin also suppressed KITENIN (KAI1 C-terminal interacting tetraspanin)-mediated AP-1 activity in both the absence and presence of epidermal growth factor stimulation. Quantitative real-time PCR analysis showed that the expression of the metastasis suppressor gene, KAI1, was increased while that of the metastasis enhancer gene, KITENIN, was dramatically decreased by physciosporin. Particularly, the activity of 3'-untranslated region of KITENIN was decreased by physciosporin. Moreover, Cdc42 and Rac1 activities were decreased by physciosporin. These results demonstrated that the lichen secondary metabolite, physciosporin, inhibits lung cancer cell motility through novel mechanisms of action.

Citation Format: Yi Yang, Young Hyun Yu, Hyung-Ho Ha, Kyung-Hwa Lee, Kyung-Sub Moon, Kyung Keun Kim, Hangun Kim. Inhibitory activity of lichen secondary metabolite, physciosporin, against lung cancer cell motility [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 4209. doi:10.1158/1538-7445.AM2017-4209
Abstract 4218: Racial similarities in the effects of depression on hospital cost of breast cancer
Authors: Husaini Baqar A. , Miller Oscar , Novotny Meggan , Levine Robert
Published: July 2017

Objective: Breast cancer (BC) incidence is reported to have declined in the nation. However, the role of depression on hospital costs for BC by race remains unknown. In this presentation, we examine two issues: (i) prevalence of BC with comorbid depression among discharged hospital patients; (ii) racial variation in the effect of co-morbid depression on hospital costs of BC patients.

Methods: We extracted data on depression and breast cancer from the 2008 Tennessee Hospital Discharge Data System (HDDS). The BC sample (n=2,523) patients were mostly white (86%) with an average age of 63 years. We computed age-adjusted BC prevalence rates per CDC methodology, and compared the hospital costs for BC patients with vs. without depression.

Results: Age adjusted BC rates (per 100,000) were higher among white than black patients (92.2 vs. 43.3, p<.000). Nearly one-fourth (23%) of BC patients had depression (no racial differences: (25% white vs. 24% black BC patients). Hospital costs for BC patients were 17% higher compared to non-BC patients, and cost was 55% higher among BC patients with co-morbid depression compared to non-depressed BC patients ($64,439 vs. $41,344). The higher cost for depressed BC patients was similar across both white and black BC females.

Conclusion: BC is higher among white females compared to black females. BC patients cost with depression tended to be significantly higher compared to non-depressed patients regardless of race. Since nearly one-fourth of BC patients were depressed with higher hospital cost, these results point to possible significant costs savings by treating depression before the need for hospitalization among BC patients.

Citation Format: Baqar A. Husaini, Oscar Miller, Meggan Novotny, Robert Levine. Racial similarities in the effects of depression on hospital cost of 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 4218. doi:10.1158/1538-7445.AM2017-4218
Abstract 4225: Disparities in cervical cancer screening participation: a comparison of Russian, Somali and Kurdish immigrants with the Finnish general population
Authors: Idehen Esther E. , Koponen Päivikki , Harkanen Tommi , Korhonen Tellervo
Published: July 2017

Background: Cervical cancer screening through Pap test has been shown as an effective preventive measure for early detection of precancerous in the cervix. Finland offers mass Pap test screening to all eligible women. Knowledge about disparities in the screening participation among immigrants compared with the Finnish general population is limited.

Objectives: (1) To compare Pap test screening participation in the past five years among Russian, Somali and Kurdish immigrants living in Finland with the Finnish general female population; (2) to examine if the observed disparities remain similar when adjusted for socio- demographic and health-related confounding factors.

Methods: Data from the Finnish Migrant Health and Well-being Study and Finnish Health 2011 Survey were used. Random samples of persons living in six cities in Finland were drawn from the national population registry. Data of self-reported cervical screening participation (Pap test) among women aged 29-60 were available from the women of Russian (n=257), Somali (n=113), Kurdish (n=167) origin and the general population (n= 436). Logistic regression was used for statistical analysis.

Results: The age-adjusted Pap test participation rates were 79% among the Russian, 41% among the Kurdish, and 64% among the Somali, compared to 94% among the Finnish general population. After adjusting for age, socio - demographic, and health-related confounders, the immigrants had significantly lower likelihood for screening compared with the Finnish reference group (Russian Odds Ratio[OR] 0.33, 95% confidence interval [CI] 0.19-0.58; Somali [OR]0.08, [CI] 0.03-0.19; Kurdish [OR] 0.17 [CI]0.08-0.34).

Conclusions: Initial results demonstrate significantly lower likelihood for Pap test screening among the immigrant groups compared with the Finnish general population.

Note: This abstract was not presented at the meeting.

Citation Format: Esther E. Idehen, Päivikki Koponen, Tommi Harkanen, Tellervo Korhonen. Disparities in cervical cancer screening participation: a comparison of Russian, Somali and Kurdish immigrants with the Finnish general population [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 4225. doi:10.1158/1538-7445.AM2017-4225
Abstract 4229: Metabolically active macrophages: A novel link between obesity and TNBC
Authors: Tiwari Payal , Schoenfelt Kelly , Blank Ariane , Cui Chang , Rosner Marsha Rich , Becker Lev
Published: July 2017

Triple negative breast cancer (TNBC) patients have an extremely poor prognosis due to their high metastatic potential and lack of targeted drug therapies. Emerging epidemiological data suggest that obesity is strongly linked to the incidence and severity of TNBC. However, mechanisms by which obesity potentiates TNBC progression are unclear. Adipose tissue macrophages (ATMs) are an attractive mechanistic link between obesity and TNBC because they are the predominant type of macrophage in the breast during early tumorigenesis and obesity causes accumulation of ATMs. However, during obesity, the macrophage phenotype was reported to switch from an apparent pro-tumorigenic M2-like phenotype to an apparent anti-tumorigenic M1-like phenotype. This result raises a paradox: how does obesity promote tumor progression if it activates an anti-tumorigenic macrophage phenotype? Here we show that metabolic dysfunction promotes a mechanistically distinct pro-inflammatory phenotype (metabolic activation; MMe) in breast adipose tissue macrophages isolated from obese women. These ATMs express cell surface markers of MMe (CD36, ABCA1) but not M1 (CD38, CD319, CD274) macrophages. We further demonstrate that pretreating TNBC cells with conditioned media derived from MMe but not M1 macrophages promotes mammosphere formation as well as invasion in vitro, and intravasation of cancer cells into the blood in vivo. Moreover, pre-treated cancer cells showed a two-fold increase in the expression of stem-like cell markers (OCT4, SOX2 and NANOG). Remarkably, we saw the same effect on ‘stemness’ of tumor cells in a spontaneous TNBC mouse model when fed a 60% high fat diet and a significant increase in tumor incidence in obese mice compared to lean mice in a syngeneic mouse model. We further show that blocking inflammatory cytokines expression in MMe(s) using genetic knockouts inhibits the ability of MMe(s) to promote both mammosphere formation and invasion. These findings suggest that obesity-induced changes to mammary adipose tissue reprogram macrophages to an MMe phenotype that potentiates TNBC initiation and metastasis via inflammatory cytokines. A comprehensive understanding of the signaling mechanism(s) involved in metabolic activation of mammary ATMs would enable development of directed therapies towards this specific pro-tumorigenic macrophage phenotype, thereby leaving the immune system of cancer patients intact.  

Citation Format: Payal Tiwari, Kelly Schoenfelt, Ariane Blank, Chang Cui, Marsha Rich Rosner, Lev Becker. Metabolically active macrophages: A novel link between obesity and TNBC [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 4229. doi:10.1158/1538-7445.AM2017-4229
Abstract 424: Landscape of somatic mutations in drug-resistant acute myeloid leukemia
Authors: Eldfors Samuli , Kontro Mika , Akimov Yevhen , Kallioniemi Olli , Porkka Kimmo , Heckman Caroline
Published: July 2017

Introduction: Most patients with acute myeloid leukemia (AML) initially respond to cytarabine-anthracycline induction chemotherapy. However, in many patients, the disease recurs in a lethal drug-resistant form. Somatic mutations underlying the pathogenesis of AML have been extensively characterized by sequencing of newly diagnosed AMLs. However, the mutations driving therapy resistance and disease progression at relapse have not been well characterized. In this study, we have exome sequenced a cohort of relapsed and refractory AMLs and compared the landscape of somatic mutations at relapse to diagnosis phase AMLs to identify mutations that contribute to therapy resistance and disease progression.

Materials and Methods: We performed exome sequencing of diagnosis phase AMLs (n=70) and relapsed or primary refractory AMLs (n=54). Patients with AML M3 subtype were excluded from the study. Paired diagnosis and relapse samples were available from 27 patients. A skin biopsy was used as the germline control. Nine patients had received an allogeneic hematopoietic stem cell transplant before relapse. Somatic mutations were called using varscan2 and copy number aberrations using copyCat. Since the identification of large insertions from next-generation sequencing data remains challenging using existing algorithms, FLT3 internal tandem duplications (FLT3-ITDs) were identified using a novel custom algorithm optimized for FLT3-ITD detection. Population variants were filtered out to remove donor-derived germline variants in chimeric post-transplant relapse samples.

Results: Comparison of somatic mutation frequencies in diagnosis and relapse and refractory samples showed that on average relapsed tumors have a higher number of driver mutations than tumors at diagnosis. WT1, TP53, CBL, IDH1 and PTPN11 were mutated at a higher frequency in relapsed samples than at diagnosis, with 13 %, 11 %, 11 %, 9 % and 9 % of relapsed or refractory samples and 4 %, 6 %, 3 %, 4 % and 7 % of diagnosis mutated respectively. Analysis of paired diagnosis-relapse samples showed that in patients with WT1, CBL or PTPN11 mutation at diagnosis the second allele is frequently mutated or lost due to uniparental disomy occurring at relapse.

Conclusions: On average relapsed AMLs have a higher number of driver mutations than diagnosis phase AMLs indicating that acquisition of additional driver mutations contributes to relapse. AMLs frequently acquire additional mutations in the same genes and pathways that already harbored mutations at diagnosis.

Citation Format: Samuli Eldfors, Mika Kontro, Yevhen Akimov, Olli Kallioniemi, Kimmo Porkka, Caroline Heckman. Landscape of somatic mutations in drug-resistant acute myeloid leukemia [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 424. doi:10.1158/1538-7445.AM2017-424
Abstract 4253: Expression profiling of paired benign and breast cancer lesions in African American women
Authors: Holowatyj Andreana Natalie , Ruterbusch Julie J. , Ali-Fehmi Rouba , Bandyopadhyay Sudeshna , Mehner Christine , Mann Melody Stallings , Dyson Gregory , Radisky Derek , Cote Michele L.
Published: July 2017

Benign breast disease, a known risk factor for subsequent breast cancer, includes a histological spectrum of lesions that can be subdivided based on the overall impression into non-proliferative lesions, proliferative lesions without atypia, and atypical hyperplasia. Yet little is known about the molecular characteristics of benign breast tissue from African American women, who suffer from disproportionately high breast cancer mortality rates. 72 breast samples from African American women were obtained. RNA was extracted from archival formalin-fixed, paraffin-embedded (FFPE) blocks. Gene expression profiling was performed on these samples using the Affymetrix HTA2.0 exon array chip. A fit linear model using generalized least squares identified probe sets with differential expression in benign-in situ and benign-invasive breast cancer paired lesions. 36 benign and 36 breast cancer paired lesions were included in the study. In the benign-in situ set (n=20), 978 probe sets were differentially expressed (threshold: fold-change, 1.50; p < 0.05). Probe sets mapped to 125 annotated genes, of which 69 (55.2%) were involved in cancer. The benign-invasive set (n=52) identified 351 differentially expressed probe sets that mapped to 84 annotated genes, of which 61 (72.6%) had known cancer significance. Genes involved in cellular growth and proliferation were significantly over-expressed in both benign-in situ and benign-invasive lesions (p-values < 0.0104). In the population of 36 paired samples, differentially expressed genes were found to regulate the estrogen receptor (ESR1) through distinct network associations. Many genes are differentially expressed by benign and breast cancer lesions, and in situ/invasive histology contribute to the distinct molecular characteristics and pathways of breast malignancy. Our findings highlight the first study to assess expression profiling of paired benign and breast cancer lesions among African American women.

Citation Format: Andreana Natalie Holowatyj, Julie J. Ruterbusch, Rouba Ali-Fehmi, Sudeshna Bandyopadhyay, Christine Mehner, Melody Stallings Mann, Gregory Dyson, Derek Radisky, Michele L. Cote. Expression profiling of paired benign and breast cancer lesions in African American women [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 4253. doi:10.1158/1538-7445.AM2017-4253
Abstract 4256: Impact of diesel engine exhaust exposure on the airway transcriptome
Authors: Drizik Eduard I. , Corbett Sean , Vermeulen Roel , Dai Yufei , Hu Wei , Lenburg Marc , Ren Dianzhi , Duan Huawei , Niu Yong , Xu Jun , Fu Wei , Meliefste Kees , Zhou Baosen , Yang JuFang , Ye Meng , Jia Xiaowei , Meng Tao , Bin Ping , Zheng Yuxin , Silverman Debra , Rothman Nathaniel , Spira Avrum , Lan Qing
Published: July 2017

Rationale: Recent epidemiological studies show that Diesel Engine Exhaust (DEE) exposure is associated with lung cancer, however the mechanism by which this occurs is not well understood. The goal of this study was to assess the transcriptomic alterations in the nasal epithelium of DEE exposed workers from factories where diesel engines are utilized.

Methods: Nasal epithelium brushings were obtained from 41 subjects who work in a factory with DEE exposure, and 38 comparable control subjects who work in factories without any DEE exposure. The median Elemental Carbon (EC) levels of exposed individuals was 60.7μg/m3, with a range of 17.2-105.4 μg/m3, respectively. RNA was isolated from nasal epithelial cells, and profiled for gene expression using Affymetrix microarrays. Linear modeling was used to detect differential expression between DEE exposure and controls. Pathway enrichment in differentially expressed genes was assessed using GO Biological Process and KEGG terms via EnrichR.

Results: We found 234 genes that were differentially expressed between samples derived from DEE exposed participants versus controls at FDR q < 0.25. Within this set of genes, we observed a higher expression of genes involved in oxidative stress response, as well as cell proliferation, cellular transcription, and regulation of apoptosis. In addition, we found that genes involved in ion transport, such as CFTR, were expressed at lower levels in DEE exposed samples.

Conclusions: Chronic DEE exposure associates with changes in the airway transcriptome, with increased stress response as a major effect of DEE exposure. The transcriptomic alterations we identified may help provide insight into the underlying mechanisms of DEE carcinogenicity.

Citation Format: Eduard I. Drizik, Sean Corbett, Roel Vermeulen, Yufei Dai, Wei Hu, Marc Lenburg, Dianzhi Ren, Huawei Duan, Yong Niu, Jun Xu, Wei Fu, Kees Meliefste, Baosen Zhou, JuFang Yang, Meng Ye, Xiaowei Jia, Tao Meng, Ping Bin, Yuxin Zheng, Debra Silverman, Nathaniel Rothman, Avrum Spira, Qing Lan. Impact of diesel engine exhaust exposure on the airway transcriptome [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 4256. doi:10.1158/1538-7445.AM2017-4256
Abstract 4260: Increased mutation burden in normal-appearing lung tissues with high cancer risk
Authors: Kubo Emi , Takeshima Hideyuki , Motoi Noriko , Ushijima Toshikazu
Published: July 2017

Background:

Genetic alterations are considered to be accumulated in normal tissues at extremely low levels by exposure to various carcinogenic factors, and the degree of accumulated alterations, namely mutation burden, is likely to be associated with cancer risk. In lung tissues, smoking is a well-known carcinogenic factor, and is considered to be involved in accumulation of mutation burden. However, due to the limitation of detection methods of such extremely low frequency mutations, the presence of mutation burden in normal human lung tissues has been unclear. To overcome this limitation, we recently developed a new method to detect mutations with extremely low frequency by sequencing 100 DNA molecules using a next generation sequencer[Yamashita, submitted].

Aim:

We aimed to reveal 1) the presence of mutation burden in normal lung tissues, and 2) its association with cancer risk.

Methods and results:

The presence of somatic mutations was analyzed in 55 cancer-related genes (totally 15,724 bp) in normal lung tissues (n = 11) obtained from background tissues of lung metastasis of cancer patients, without smoking history, other than those with lung cancers (''entirely normal lung tissues'') and non-cancerous lung tissues (n = 11) of lung cancer patients with smoking history (''smoking-exposed normal tissues'').

The mutation frequency in smoking-exposed normal tissues (2.7 ± 0.8×10-5/bases) was significantly higher than that in entirely normal tissues (1.8 ± 0.5×10-5/bases) (p= 0.0189). C to T transition was most frequent in both smoking-exposed normal tissues (60% of detected base substitutions) and entirely normal tissues (61%), but the fractions were not different between the two groups. In contrast, C to A transversion, the signature mutation of smoking, was more frequent in smoking-exposed normal tissues (4%) than in entirely normal tissues (2%). Accumulation of somatic mutations tended to be associated with cancer risk [OR = 3.75 (95% CI = 0.54-26.046)].

Conclusion:

It was shown, for the first time, that somatic mutations were accumulated in normal lung tissues with high cancer risk, possibly by exposure to tobacco smoking.

Citation Format: Emi Kubo, Hideyuki Takeshima, Noriko Motoi, Toshikazu Ushijima. Increased mutation burden in normal-appearing lung tissues with high cancer risk [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 4260. doi:10.1158/1538-7445.AM2017-4260
Abstract 429: Integrated genomic DNA and RNA profiling to predict cancer immunotherapy response
Authors: Du Pan , Wang Xiaohong , Zhao Zhixin , Wang Huiquang , Jia Shidong
Published: July 2017

Immunotherapy response varies widely, making it difficult for physicians to know whether immunotherapy will be effective for a given patient. Recent studies have reported that patients with high PD-L1 gene expression are likely to respond to checkpoint blocking drugs, but there are still many patients whose tumor test for the PD-L1 protein are negative and can respond to the drugs. In addition to the potential link between mismatch repair (MMR) gene mutations and clinical response to anti-PD1 immunotherapy drug, recent findings show that tumor mutation burden and microsatellite instable (MSI) are good indicators of the cancer immunotherapy responses. Using Predicine’s proprietary Gene RADAR (RNA and DNA single molecular digital Readings) technology, here we report the development of PrediSeq-CI (Cancer Immunotherapy) panel for comprehensive genomic profiling of DNA and RNA that are associated with cancer immunotherapy response. The panel has been tested using both tissue biopsy and plasma samples. The development of PrediSeq-CI test has potential to enable precision medicine in cancer immunotherapy. Finally, we also developed a liquid biopsy droplet digital PCR test to measure PD-L1 expression in blood.

Citation Format: Pan Du, Xiaohong Wang, Zhixin Zhao, Huiquang Wang, Shidong Jia. Integrated genomic DNA and RNA profiling to predict cancer immunotherapy response [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 429. doi:10.1158/1538-7445.AM2017-429
Abstract 4293: Siramesine and lapatinib induce ferroptosis in glioblastoma and lung adenocarcinoma cells
Authors: Blankstein Anna R. , Ma Shumei , Gibson Spencer B.
Published: July 2017

Ferroptosis, a morphologically and biochemically distinct cell death pathway, is characterized by iron-dependent accumulation of reactive oxygen species (ROS) within the cell. The combination of siramesine, a lysosome disruptor, and lapatinib, a dual tyrosine kinase inhibitor, has been shown to synergistically induce cell death in breast cancer cells. This cell death was blocked by the ferroptosis inhibitor ferrostatin-1 (Fer-1) and the iron chelator deferoxamine (DFO). The objective of the present study was to determine whether lysosome disruptors and tyrosine kinase inhibitors, in combination, induced synergic cell death via the ferroptotic pathway in additional types of cancer. U87 (glioblastoma) and A549 (lung adenocarcinoma) cells were treated with various lysosome disruptors (siramesine or desipramine) in combination with tyrosine kinase inhibitors (lapatinib or sorafenib), and the amount of cell death was measured by trypan blue exclusion. We found that these combinations synergistically induced cell death in U87 and A549 cells. To determine whether ferroptosis was the mechanism of cell death, cells were pretreated with either Fer-1 or DFO (inhibitors of ferroptosis), or with exogenous iron chloride (an inducer of ferroptosis) before treatment with the combination of siramesine and lapatinib. Pretreatment with Fer-1 or DFO decreased cell death by approximately 35%. Pretreatment with iron chloride increased the effect of the drug combination by approximately 45%. Prussian Blue staining demonstrated that there was an increase in intracellular iron accumulation following treatment with the combination of siramesine and lapatinib. Collectively, these data show that in U87 and A549 cells, the combination of lysosome disruptors and tyrosine kinase inhibitors, specifically siramesine and lapatinib, induces ferroptotic cell death. Therefore, inducing ferroptosis in tumor cells is a potential strategy for therapy in these cancers with limited treatment options.

Citation Format: Anna R. Blankstein, Shumei Ma, Spencer B. Gibson. Siramesine and lapatinib induce ferroptosis in glioblastoma and lung adenocarcinoma 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 4293. doi:10.1158/1538-7445.AM2017-4293
Abstract 430: Combination of CB-839 and everolimus is effective in inhibiting growth of endocrine resistant breast cancer in vivo
Authors: Fallah Yassi , Demas Diane M. , Demo Susan , Shajahan-Haq Ayesha N.
Published: July 2017

About 70% of all breast cancers are estrogen receptor alpha positive (ER+). Anti-hormone therapy such as antiestrogens are often used to treat ER+ breast cancer but breast cancer cells can develop resistance to these drugs (endocrine resistance). Unfortunately, ~50% percent of all antiestrogen treated tumors eventually develop endocrine resistance, and therefore, there is an urgent need to find ways to treat this incurable disease. We have shown that endocrine resistant breast cancer cells show an increased dependence on the amino acid glutamine and this process is regulated by MYC activation via the unfolded protein response (UPR). Metabolites of glutamine such as glutamate and proline are significantly elevated in endocrine resistant cells. Cellular changes in glutamine are sensed by the mammalian target of rapamycin (mTOR) complex, mTORC1, which is known to be deregulated in endocrine resistant breast cancer. In this study, we used human antiestrogen (Fulvestrant/Faslodex or Tamoxifen) sensitive and resistant ER+ breast cancer cells and xenografts to test the efficacy of CB-839, an anti-glutaminase, and everolimus (Afinitor), a mTORC1 inhibitor. Combination of CB-839 and everolimus, but not each drug alone, inhibited growth of antiestrogen resistant tumors compared to vehicle alone at 4 weeks post-treatment. The combination treatment did not significantly inhibit growth of antiestrogen sensitive tumors compared with its respective vehicle alone treatment. Thus, a combination strategy that targets glutamine dependence and increased mTOR activation may be a novel strategy in treating endocrine resistant breast cancer.

Citation Format: Yassi Fallah, Diane M. Demas, Susan Demo, Ayesha N. Shajahan-Haq. Combination of CB-839 and everolimus is effective in inhibiting growth of endocrine resistant breast cancer in vivo [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 430. doi:10.1158/1538-7445.AM2017-430