bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2129: Breast tumor microenvironment & metastasis is controlled by activity of a2 isoform of V-ATPase in mammary epithelium
Authors: Katara Gajendra K. , Kulshrestha Arpita , Sahoo Manoranjan , Beaman Kenneth 
Published: August 2018

Abstract
Extracellular matrix (ECM) critically impacts tumor progression and is influenced by both cancer and host tissue cells. While our understanding of cancer cell ECM remodeling is widespread, the importance of host tissue ECM, which provides an initial congenial environment for primary tumor formation, is only partly understood. Previously, we have shown that epithelial cell associated vacuolar (V)-ATPase ‘a2' isoform (a2V) regulates stiffness of mammary gland ECM. Here, we investigated how a2V mediated alterations in ECM of breast tissues affects the tumor microenvironment and metastasis of breast cancer. We also established the correlation of a2V expression in the normal breast tissue with metastatic occurrence in cancer patients. In this study, using the MMTV-Cre-Lox system, we deleted the a2V gene in epithelial cells of mouse mammary glands. Tumors were transplanted in mammary fat pads of a2V conditional knockout mice (a2VcKO) using E0771/Py230 mouse mammary cancer cells. These tumors were evaluated for the histopathology, ECM stiffness, immune cell populations, cytokines, angiogenic factors and metastasis. We show that in a2VcKO, breast tumors exhibit less tumor rigidity, increased inflammation and a more necrotic tumor microenvironment. These mice showed an increased metastasis of tumors compared to control evident by cytokeratin (Ck)14 staining of cancer cells in lung tissues (3.3 fold increase, P=0.004). Immuno-phenotyping of breast tumor microenvironment revealed increased infiltration of CD45 cells with higher number of anti-tumor M1 macrophages (2.1 fold increase, P=0.007) and elevated expression of inflammatory cytokines TNF-α and iNOS in a2VcKO mice compared to control (P=0.01). The tumors in a2VcKO mice were much more highly vascularized and angiogenic compared to control (P=0.01) evident by increased number of Meca32+SMA+ cells. Clinically, in cancer patients, low a2V expression levels in normal breast tissue correlated directly with lymph-node metastasis. Thus, this study has identified a2V expression in epithelial cells as a key modulator of tumor microenvironment and its expression levels can significantly modulate breast tumor dissemination.
Citation Format: Gajendra K. Katara, Arpita Kulshrestha, Manoranjan Sahoo, Kenneth Beaman. Breast tumor microenvironment & metastasis is controlled by activity of a2 isoform of V-ATPase in mammary epithelium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2129.
Abstract 2154: A potent and orally available tubulin inhibitor ABI-231 suppresses triple negative breast cancer tumor growth and metastasis
Authors: Deng Shanshan , Krutilina Raya , Wang Qinghui , Seagroves Tiffany N. , Miller Duane D. , Li Wei 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is the most aggressive type and accounts for at least 15% of all types of breast cancer in the USA. TNBC is defined as tumors that lack the expression of estrogen receptor, progesterone receptor and human epithermal growth factor 2, and it is always characterized by poor prognosis due to the lack of molecular targets and the rapid development of resistance to many chemotherapeutic drugs. Interfering with microtubule dynamics is a validated drug target. Currently, one of the standard cares for TNBC treatment is using taxanes based chemotherapy, such as paclitaxel, which targets microtubules. However, drug resistance and neurotoxicities often limit their clinical efficacy, thus there are continuous needs to develop more effective therapies that could overcome these clinical limitations. In this study, we evaluated the preclinical efficacy of our potent tubulin inhibitor, ABI-231, in treating TNBC in mouse xenograft models. ABI-231 inhibited tubulin polymerization and effectively overcame P-gp mediated multidrug resistance, and it is orally available. ABI-231 showed remarkable anticancer activities against two TNBC cell lines at low nanomolar concentrations, and it could inhibit the cancer cell colony formation. Treatment with ABI-231 suppressed invasion and migration of TNBC cells, and significantly induced apoptosis of TNBC cells in vitro. ABI-231 inhibited TNBC tumor growth in a dose-dependent manner without acute toxicity in an orthotopic TNBC xenograft model. ABI-231 had similar efficacy to that of paclitaxel as tested in this mouse model. In addition, ABI-231 significantly reduced metastasis of TNBC in a tail vein mouse model. Collectively, these preliminary studies strongly suggest that ABI-231 is potent to inhibit the growth and metastasis of TNBC both in vitro and in vivo, and this potent tubulin inhibitor is a promising drug candidate for the more effective treatment of TNBC. Supported by NIH grant R01CA148706.
Citation Format: Shanshan Deng, Raya Krutilina, Qinghui Wang, Tiffany N. Seagroves, Duane D. Miller, Wei Li. A potent and orally available tubulin inhibitor ABI-231 suppresses triple negative breast cancer tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2154.
Abstract 2156: Lung niche factors for progenitor cell self-renewal sustain lung cancer stem cells and contribute to drug resistance to kinase inhibitors in non-small cell lung cancer
Authors: Mitsui Akinori , Yokokawa Sachiko , Nagano Osamu , Saya Hideyuki 
Published: August 2018

Abstract
A mechanism underlying anti-cancer drug resistance relies on the existence of cancer stem cells (CSCs). However, CSCs are either absent or are few in number in xenograft tumors and syngeneic mouse models. We developed new lung cancer mouse models with CSCs to elucidate the role of CSCs in resistance to targeted therapeutics in non-small cell lung cancer (NSCLC). Mouse lung organoids containing progenitor cells were cultured in complete medium containing lung niche factors, FGF-10 and HGF, and were infected with a retrovirus encoding a Kras mutation (G12D), an Egfr deletion, and the EML4-ALK fusion protein. These induced CSCs were transplanted into mice, and the established tumors were cultured in vitro to test for drug sensitivity to trametinib, erlotinib, and crizotinib in the presence or absence of niche factors. The tumors that were poorly differentiated contained EpCAM-, Cd49f-, and Sca-1-positive CSCs. These mouse models allowed the prediction of clinical responses to targeted therapeutics, i.e., the tumor cells with the Egfr deletion and those with EML4-ALK fusion proteins showed strong responses to erlotinib and crizotinib, respectively. In addition, we found that Kras mutant cancer cells were resistant to trametinib due to activation of the HGF/Met pathway since HGF is an essential niche factor for lung progenitor cell proliferation. Combination treatment with trametinib and a Met inhibitor showed a synergistic effect in Kras mutant tumors. Based on these results, we propose a treatment approach that focuses on the use of niche factors for lung progenitor cells in NSCLC.
Citation Format: Akinori Mitsui, Sachiko Yokokawa, Osamu Nagano, Hideyuki Saya. Lung niche factors for progenitor cell self-renewal sustain lung cancer stem cells and contribute to drug resistance to kinase inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2156.
Abstract 2157: Chemotherapeutic tolerability and estrogen dose response in the B6;129-Rag2
tm1Fwa
IL2rg
tm1Rsky/DwlHsd (R2G2) mouse model
Authors: Naden Jamie L. , Melton Michele , Bast Athena , Gardner Jermaine 
Published: August 2018

Abstract
The B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) knockout mouse was developed by backcrossing an IL2rg (common gamma) knockout model to a RAG2 (recombinase activating gene) knockout model. The resulting mouse lacks various cytokines including IL-2, IL-4, IL-7, IL-9 and IL-15. In addition, this model lacks B cells, T cells, NK cells and has a deficit in lymphocyte development. This model was developed to provide another immunodeficient option for the oncology and immunology fields. The literature supports better tolerability of DNA-damaging oncology treatments for models that do not carry the SCID mutation. We have already reported in a white paper that the R2G2 mouse model is more tolerant of whole-body radiation than a model with the SCID mutation. Herein we describe a study examining chemotherapeutic tolerability of common DNA-damaging oncology drugs including 5-fluorouracil (5-FU), doxorubicin (Doxo), and cyclophosphamide (CTX) (n = 10 per group). 5-FU was given at 30, 60 or 100 mg/kg, intraperitoneally, twice weekly for five weeks. Doxo was given at 2 or 5 mg/kg, intraperitoneally, once weekly for three weeks. CTX was given at 100 or 140 mg/kg intraperitoneally, once weekly for three weeks. The low dose was chosen based on the average dose used in immunodeficient mouse models and the high dose was chosen based on the average dose used in immunocompetent mouse models. This was done to determine if the R2G2 mouse model can tolerate higher doses of these chemotherapeutic agents compared to other immunodeficient mouse models. Results show that the R2G2 mouse model tolerates higher doses of these chemotherapeutic drugs than doses found in the literature for SCID models. Exogenous estrogen tolerance is another common concern in oncology research as some immunodeficient mouse models cannot tolerate the subcutaneous estrogen pellets, developing negative secondary effects resulting in removal from study. We performed an estrogen pellet dose-response study using four doses of 60-day release 17-β estradiol pellets at 0.18, 0.36, 0.72, and 1.7 mg/pellet (n = 10 per group). R2G2 mice show dose-dependent effects of estrogen on morbidity. These data will allow researchers to determine the optimal dose for use in the R2G2 model. In conclusion, these data support that the R2G2 mouse model may be a good alternative to SCID models when administering DNA-damaging chemotherapies or when estrogen supplementation is required for xenograft growth.
Citation Format: Jamie L. Naden, Michele Melton, Athena Bast, Jermaine Gardner. Chemotherapeutic tolerability and estrogen dose response in the B6;129-Rag2tm1FwaIL2rgtm1Rsky/DwlHsd (R2G2) mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2157.
Abstract 2160: MEN1611, a novel α-selective PI3K inhibitor in solid tumors
Authors: Merlino Giuseppe , Fiascarelli Alessio , Bigioni Mario , Bressan Alessandro , Irrissuto Clelia , Pellacani Andrea , Scaltriti Maurizio , Binaschi Monica 
Published: August 2018

Abstract
The PI3K pathway regulates various cellular processes such as proliferation, growth, apoptosis and cytoskeletal rearrangement. This pathway is frequently de-regulated and considered an oncogenic driver in human cancer. In most solid tumors, the activation of the PI3K pathway is induced by mutations of the catalytic subunit PI3Kα, present in approximately 20% to 50% of breast cancer, 14% of colorectal cancer and in 5-10% of NSCLC. Besides being an actionable target, the PI3K pathway is implicated in de novo and acquired treatment resistant in various tumor types treated with targeted therapy. As a matter of fact, the most interesting antitumor activity with PI3K inhibitors has been observed in combination. Here, we present MEN1611 (previously PA799), a PI3-kinase inhibitor with a peculiar biochemical profile targeting with high inhibition potency the mutated forms of PI3Kα and PI3Kγ. In the current study we demonstrate the anticancer activity and the pharmacodynamic effects of MEN1611 as monotherapy or in combination with targeted therapies in both xenograft and PDX models of breast cancer and in colorectal cancer and in NSCLC models, all with defined genetic profiles. MEN1611, at a clinically relevant dose, showed good antitumor activity in combination with targeted therapy agents against breast cancer, colorectal cancer and NSCLC models bearing PI3Kα mutations. A reduced activity was instead observed when the tumor models were wild type for PI3Kα or had low levels of PTEN. The antitumor activity of MEN611 was supported by its pharmacodynamic activity. In all the models, both AKT and S6 phosphorylation, markers of PI3K inhibition, were significantly inhibited upon treatment. In agreement with the biochemical profile of the drug, in PTEN null xenograft models where the tumor driver is the PI3K β-isoform, we observed lower effects in term of antitumor activity and of molecular inhibition of the pathway. Last, MEN1611 induction of hyperglycemia and insulin release was studied in the tumor models at clinical relevant dose as a marker of class-effect toxicity. MEN1611 showed significant antitumor activity in combination with other targeted therapies in breast, colon and NSCL cancer PI3Kα mutant models. Our results support the evidence that MEN611 is a PI3Kα specific inhibitor and provided the basis for the planned phase IB/II.
Citation Format: Giuseppe Merlino, Alessio Fiascarelli, Mario Bigioni, Alessandro Bressan, Clelia Irrissuto, Andrea Pellacani, Maurizio Scaltriti, Monica Binaschi. MEN1611, a novel α-selective PI3K inhibitor in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2160.
Abstract 2185: Multiple region whole-genome sequencing reveals intratumor heterogeneity and branching clonal architecture of non-clear-cell renal cell carcinoma
Authors: Zhu* Bin , Poeta* Luana , Costantini* Manuela , Zhang* Tongwu , Sentinelli Steno , Shi Jianxin , Brown Kevin , Hua Xing , Yeager Meredith , Wang Mingyi , Hicks Belynda , Chanock* Stephen , Gallucci* Michele , Fazio* Vito , Landi* Maria Teresa 
Published: August 2018

Abstract
Limited knowledge about the intratumor heterogeneity (ITH) of non-clear-cell renal cell carcinoma (nccRCC) hinders therapeutic efficacy. We performed multi-region whole-genome sequencing, genome-wide methylation profiling and deep targeted sequencing of both primary and paired metastatic tumors in 124 samples from 29 subjects with papillary renal cell carcinoma type 1, papillary renal cell carcinoma type 2 and collecting duct kidney tumors. Samples were taken from the tumors' center to the periphery at ~1.5cm from each other. We conducted integrative ITH analysis of single nucleotide variants, somatic copy number alterations, structural variants, transposon element insertions, telomere length and DNA methylation, and inferred their respective evolutionary history. We also analyzed the concordance between physical and lineage phylogenetic evolution, and inferred the regions from which the metastases likely originated.
ITH varied significantly across tumors and histological subtypes. For example, the average number of structural variants per tumor was 1.2 in papillary RCC type 1 vs. 23.6 in papillary RCC type 2. In papillary tumors, ITH was lowest for copy number alterations (~5% subclonal changes across all tumor types), intermediate for single nucleotide variants (~32%), and highest for structural variants (~60%), suggesting a tumor molecular evolution along these steps. Lineage trees commonly showed branching evolutions with a dominant subclone. Focal deletion of the CDKN2A gene characterized the collecting duct tumors. Methylation ITH was highest in the enhancer regions. Metastatic and primary tumors shared similar mutation signatures. Telomere length was generally longer in normal vs. tumor samples and was similar in physically adjacent samples.
In summary, our study characterized ITH of nccRCC with unprecedented details for multiple types of somatic alterations, and delineated the branching architecture of clonal evolution, including the metastatic phase.
Citation Format: Bin Zhu*, Luana Poeta*, Manuela Costantini*, Tongwu Zhang*, Steno Sentinelli, Jianxin Shi, Kevin Brown, Xing Hua, Meredith Yeager, Mingyi Wang, Belynda Hicks, Stephen Chanock*, Michele Gallucci*, Vito Fazio*, Maria Teresa Landi*. Multiple region whole-genome sequencing reveals intratumor heterogeneity and branching clonal architecture of non-clear-cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2185.
Abstract 2186: Drug treatment induces phenotypic switch and stemness during acquisition of drug resistance
Authors: Ranganathan Santhalakshmi , Rangarajan Annapoorni 
Published: August 2018

Abstract
The breast tumor heterogeneity and development of drug resistance has become a challenge for anti-cancer therapy. Tumor cells acquire resistance due to intra-tumor heterogeneity imposed by epithelial to mesenchymal transition. The drugs which target epithelial cells may fail to target mesenchymal and the intermediate phenotypes due to which the cancer cells acquire drug resistance. This concept provoked us to understand the phenotypic diversity among the tumor heterogeneity which might lead to drug resistance. Hence the aim of our study is to identify the mechanisms of anti-cancer drug resistance which would ultimately help in identification of new clinical targets.
Treatment of breast cancer cell lines MCF7 and MDA MB 231 with Doxorubicin showed a loss of epithelial markers and gain of mesenchymal markers in MCF7 cells, and vice versa in MDA MB 231 cells, thereby shifting them into an intermediate phenotype. Moreover, Doxorubicin treatment of MDA MB 231-Nanog stable cells led to an increase in Nanog positive cells confirming that the treatment-induced increase in stemness property of cancer cells. We predict that phosphoproteomic dataset of the anti-cancer drug-resistant cells let us analyze the possible molecular players involved in the phenotypic switch and hence drug resistance (work in progress). Thus, our current data suggest that
the anti-cancer therapy induces cancer cells to undergo a phenotypic switch and increases the stemness property which might be responsible to gain resistance. Identification of the critical regulators of the phenotypic switch by phosphoproteomics analysis is likely to help us investigate the possible mechanisms underlying anti-cancer drug resistance. Previous reports also suggest that conventional therapies fail to eliminate cancer stem cells thereby allowing tumor relapse.
These results suggest that understanding the protein abundance and phosphorylation state of key signaling molecules would elucidate specific signaling interactions or/and pathways differentially active in drug-resistant tumors would help us predict novel kinases, and hence identify drug targets.
Citation Format: Santhalakshmi Ranganathan, Annapoorni Rangarajan. Drug treatment induces phenotypic switch and stemness during acquisition of drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2186.
Abstract 2212: Risk prediction for Barrett's esophagus and esophageal adenocarcinoma: Incorporation of epidemiologic risk factors and 23 confirmed genetic loci
Authors: Dong Jing , Thrift Aaron 
Published: August 2018

Abstract
Background & Aims: We developed comprehensive risk prediction models for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) that incorporate a polygenic risk score (PRS) and non-genetic factors.
Methods: We used pooled data from 3,288 BE, 2,511 EAC, and 2,177 controls from BEACON, the United Kingdom Barrett's Esophagus Gene Study, and United Kingdom Stomach and Oesophageal Cancer Study. A PRS was created from 23 BE/EAC risk loci. We developed and compared risk models with various combinations of non-genetics factors and the PRS. We assessed their predictive accuracy using the area under the receiver operating characteristic curve (AUC).
Results: Individuals in the highest quartile of the PRS had 2-fold higher risks of BE (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.89-2.60) and EAC (OR, 2.46; 95% CI, 2.07-2.92) compared to those in the lowest quartile of the PRS. Risk models including only demographic/lifestyle factors (age, sex, smoking, body mass index, and nonsteroidal anti-inflammatory drugs) or only gastroesophageal reflux disease (GERD) symptoms had AUCs ranging from 0.637 to 0.667. The AUCs for models adding demographic/lifestyle factors to GERD symptoms were 0.793 and 0.745 for BE and EAC, respectively. Small absolute improvement in AUCs for each model was observed when including the PRS in the model (AUCs range, 0.656-0.799). Including the PRS in the model of non-genetic factors provided 3.0% and 5.6% improvement in the net reclassification index for BE and EAC, respectively.
Conclusions: Although adding the PRS improved discrimination and net reclassification, the absolute magnitude of improvement is not sufficient to justify its clinical use.
Citation Format: Jing Dong, Aaron Thrift. Risk prediction for Barrett's esophagus and esophageal adenocarcinoma: Incorporation of epidemiologic risk factors and 23 confirmed genetic loci [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2212.