bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B192: The EPR effect of CDP-tubulysin in the recurrence of lung and pancreatic cancers
Authors: Tsai Pei-Yi , Jheng Huei-Lin , Hsieh Yen-Ju , Tsai Yung-Jen , Ahrweiler Michael , Richter Wolfgang , Abbas Muhammad , Pasut Gianfranco , Chang Jia-Ming 
Published: August 2018

Abstract
Tubulysins, a tubulin-targeted class of natural compounds, are highly active in multidrug-resistant cells and potential agents to overcome clinical drug resistance in recurrent tumors. Unfortunately, the extraordinary activity of the potent tubulysins poses considerable complications for chemotherapeutic applications due to toxicity against normal cells and tissues. Nanoparticle drug delivery systems provide the potential to increase the intracellular concentration of drugs in cancer cells while avoiding toxicity in normal cells through the enhanced permeability and retention (EPR) effect. In this study, the efficacy of β-cyclodextrin-based polymeric tubulysin (CDP-tubulysin) administered by intravenous injection was tested on subcutaneous lung and pancreatic xenograft models. The single-dose pharmacokinetic study and tumor distribution of CDP-tubulysin and tubulysin alone were also determined in tumor-bearing mice. Our data demonstrated that CDP-tubulysin showed potent efficacy in treating lung and pancreatic cancers. The recurrent lung and pancreatic tumors were also regressed by treating with CDP-tubulysin but not gemcitabine. Moreover, the conjugation of CDP to tubulysin showed control-release behavior in the blood resulting in increased distribution of tubulysin in tumors. In conclusion, CDP conjugation was an effective delivery of tubulysins to avoid toxicity and provide potency in recurrent tumors through the EPR effect.
Citation Format: Pei-Yi Tsai, Huei-Lin Jheng, Yen-Ju Hsieh, Yung-Jen Tsai, Michael Ahrweiler, Wolfgang Richter, Muhammad Abbas, Gianfranco Pasut, Jia-Ming Chang. The EPR effect of CDP-tubulysin in the recurrence of lung and pancreatic cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B192.
Abstract B202: Covalent irreversible usp7 inhibitors for cancer immunotherapy
Authors: Kumar Suresh , Wu Jian , Wang Feng , Wang Liqing , Chen Lee , Sokirniy Ivan , Wang Hui , Sterner David , Grove Charles , Cunnion Brigid , Weinstock Joseph , Mattern Michael , Hancock Wayne 
Published: August 2018

Abstract
Tumors employ diverse strategies to suppress and evade the immune system’s ability to recognize and destroy tumor cells. Immune-suppressive Foxp3+ regulatory T cells (Tregs) in the tumor microenvironment correlate with poor prognosis in solid tumors. Therefore, selective depletion of tumor-associated Tregs or impairment of Treg function is considered an attractive cancer immunotherapy approach. The pro-tumorigenic deubiquitylase (DUB) USP7 is also essential for Treg functions. USP7 controls Treg function largely by regulating post-translational modification of Foxp3 and TIP60. Deletion of USP7 in Tregs results in impairment of Treg functions and autoimmunity in mice. Progenra has developed potent, selective covalent irreversible USP7 inhibitors that impair Treg functions ex vivo and in vivo. Most importantly, USP7 inhibitors exhibit robust antitumor activity against several syngeneic solid tumor models in immunocompetent mice. In addition, Progenra’s USP7 inhibitors enhance the efficacy of anti-PD1 antibody, anti-CTLA4 antibody, and cancer vaccines. These studies strongly suggest that USP7 inhibitors alone or in combination regimens can improve the efficacy and expand the scope of cancer immunotherapy.
Citation Format: Suresh Kumar, Jian Wu, Feng Wang, Liqing Wang, Lee Chen, Ivan Sokirniy, Hui Wang, David Sterner, Charles Grove, Brigid Cunnion, Joseph Weinstock, Michael Mattern, Wayne Hancock. Covalent irreversible usp7 inhibitors for cancer immunotherapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B202.
Abstract B203: Heterogeneity in androgen receptor and IL-1beta expression by prostate cancer cells in skeletal metastases
Authors: Worrede-Mahdi Asurayya A. , Fatatis Alessandro 
Published: August 2018

Abstract
Bone metastases are a prevalent complication of advanced prostate cancer (PCa). The current standard of care for advanced PCa patients is androgen deprivation therapy (ADT), which fails within approximately two years and patients progress to castration-resistant prostate cancer (CRPC). CRPC presents with additional metastasis in soft tissues and is incurable. We have found that in PCa patients, bone metastases have heterogeneous androgen receptor (AR) expression, and that cells lacking AR are the only cell type that secretes the cytokine Interleukin-1 beta (IL-1β). Furthermore, preclinical work in our lab has revealed the role for IL-1β in promoting bone colonization by AR+ PCa cells and generation of heterogeneous skeletal metastases. A significant barrier to studying tumor heterogeneity in PCa metastasis has been the lack of an animal model to study the interaction between multiple PCa phenotypes in the bone microenvironment. By engrafting a suspension containing both AR− and AR+ cells directly into the left cardiac ventricle of mice, our lab has developed an in vivo model that allows us to study the progression of both AR− and AR+ cells in skeletal and soft tissue metastases. AR− and AR+ cells were genetically engineered to express two different Luciferase constructs (630 nm Red-shifted Luc and 540 nm Luc2, respectively) thereby allowing the progression of AR− and AR+ cells to be independently tracked and quantified. We used this model in combination with histologic and radiographic analyses to assimilate the pathologic features of our in vivo mixed AR+/AR− metastases to the human clinical scenario. Finally, we used castrated mice to determine whether IL-1β secreting PCa cells could support the growth and survival of IL-1β-/AR+ cells in androgen-deprived conditions. Coinjection of AR− (PC3-ML) and AR+ cells (LNCaP, VCaP, and 22Rv1) leads to increased establishment of soft tissue metastases as compared to injecting AR− cells alone. Unlike the metastases generated by PC3-ML cells alone, which show exclusively osteolytic activity, AR−/AR+ mixed metastases are both osteosclerotic and osteolytic, thereby recapitulating clinical pathology. Finally, preliminary results suggest that coinjection with IL-1β-secreting AR− cells enables the growth of androgen-dependent AR+ cells in castrated mice. This animal model of metastasis heterogeneity recapitulates human pathology and enables further interrogation of the mechanism by which IL-1β supports survival of AR+ cells and the potential role for AR− in evading AR-targeted therapy during CRPC.
Citation Format: Asurayya A. Worrede-Mahdi, Alessandro Fatatis. Heterogeneity in androgen receptor and IL-1beta expression by prostate cancer cells in skeletal metastases [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B203.
Abstract B205: Intervenolin suppresses gastric cancer cell growth via stromal secreted factors
Authors: Yoshida Junjiro , Abe Hikaru , Watanabe Takumi , Kawada Manabu 
Published: August 2018

Abstract
Background: Tumor-stromal cell interactions are attractive targets for cancer chemotherapy because fibroblast-like stromal cells modulate cancer cells both positively and negatively through secreted factors as well as proteins of the extracellular matrix. We have focused on the negative regulation of cancer cells by secreted factors of stromal cells as it offers a novel strategy for discovering new cancer therapeutics. We used a coculture system to screen small molecules from natural sources such as microbial culture media, seeking molecules that modulated tumor-stromal cell interactions. In a recent study, we found a novel compound, intervenolin (ITV), from the culture medium of Nocardia sp. ML96-86F2. ITV inhibited the in vitro growth of human gastric cancer cells. Importantly, inhibition was greater when the cancer cells were cocultured with stromal cells. Here we report the mechanism of ITV action. Materials and Method: Human gastric cancer MKN-7 and MKN-74 cells were cultured with human gastric stromal Hs738 cells in the presence of ITV. The growth of MKN-7 and MKN-74 cells cultured in only CM taken from Hs738 cells treated with ITV (ITV CM) was also inhibited more strongly than it was cultured alone. We prepared serum-free CM from Hs738 cells to determine the anticancer factors secreted by ITV-treated HS738 cells using LC-MS/MS analysis. Results: Conditioned medium (CM) of ITV-treated Hs738 cells inhibited the growth of MKN-7 or MKN-74 cells and suppressed c-MYC protein level in MKN-74 cells. This result suggested that ITV induced the negative modulation of cancer cells through secreted factors from stromal cells. Proteome analysis of ITV-treated Hs738 CM revealed that one of the candidates could be thrombospondin-1 (TSP-1). As a result, recombinant TSP-1 inhibited the growth of gastric cancer cells and downregulated c-MYC. Conclusions: ITV inhibits gastric cancer cell growth through inducing TSP-1 secretion from Hs738 cells in coculture system in vitro. No conflict of interest.
Citation Format: Junjiro Yoshida, Hikaru Abe, Takumi Watanabe, Manabu Kawada. Intervenolin suppresses gastric cancer cell growth via stromal secreted factors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B205.
Abstract B212: N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion
Authors: Paluncic Jasmina , Lane Darius J. R. , Saletta Federica , Rahmanto Yohan S. , Kovacevic Zaklina , Richardson Des R. 
Published: August 2018

Abstract
Iron is critical for cellular proliferation and its depletion leads to a suppression of both DNA synthesis and global translation. These observations suggest that iron depletion may trigger a cellular “stress response.” A canonical response of cells to stress is the formation of stress granules, which are dynamic cytoplasmic aggregates containing stalled preinitiation complexes that function as mRNA triage centers. By differentially prioritizing mRNA translation, stress granules allow for the continued and selective translation of stress response proteins. Although the multi-subunit eukaryotic initiation factor 3 (eIF3) is required for translation initiation, its largest subunit, eIF3a, may not be essential for this activity. Instead, eIF3a is a vital constituent of stress granules and appears to act, in part, by differentially regulating specific mRNAs during iron depletion. Considering this, we investigated eIF3a’s role in modulating iron-regulated genes/proteins that are critically involved in proliferation and metastasis. In this study, eIF3a was downregulated and recruited into stress granules by iron depletion as well as by the classical stress inducers, hypoxia and tunicamycin. Iron depletion also increased expression of the metastasis suppressor, N-myc downstream regulated gene-1 (NDRG1), and a known downstream repressed target of eIF3a, namely the cyclin-dependent kinase inhibitor, p27kip1. To determine if eIF3a regulates NDRG1 expression, eIF3a was inducibly overexpressed or ablated. Importantly, eIF3a positively regulated NDRG1 expression and negatively regulated p27kip1 expression during iron depletion. This activity of eIF3a could be due to its recruitment to stress granules and/or its ability to differentially regulate mRNA translation during cellular stress. Additionally, eIF3a positively regulated proliferation, but negatively regulated cell motility and invasion, which may be due to the eIF3a-dependent changes in expression of NDRG1 and p27kip1 observed under these conditions.
Citation Format: Jasmina Paluncic, Darius J. R. Lane, Federica Saletta, Yohan S. Rahmanto, Zaklina Kovacevic, Des R. Richardson. N-myc downstream regulated 1 (NDRG1) is regulated by eukaryotic initiation factor 3a (eIF3a) during cellular stress caused by iron depletion [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B212.
Abstract LB-A02: Oncoyeasti: a web-based application to translate data obtained from yeast high-throughput drug screens into cancer therapeutics
Authors: Gupta Ruby , Anand Nikhilesh , Cayenne Samir , Otohinoyi David , Talukdar Debjyoti , Patil Ashish 
Published: August 2018

Abstract
The budding yeast (Saccharomyces Cerevisiae) and Fission yeast (Saccharomyces Pombe) gene deletion libraries are a useful tool for high throughput screening of anti-cancer drugs. But using the data derived by high-throughput screening of yeast library to identify corresponding human homologs and their status in various human cancers is a cumbersome process. We have developed a web based application called Oncoyeasti, that enables the researcher to automatically identify the corresponding human homologs of S Cerevisiae and S Pombe genes and the status of these homolog genes in more than 45000 tumor sample datasets of The Cancer Genome Atlas (TCGA) Database and the cancer cell lines datasets present in Cancer Cell Line Encyclopedia. We used server side scripting language PHP for web development platform along with MYSQL interface for matching the input S. Cerevisiae or S. Pombe genes with the corresponding Human Homologs and generate an URL link for the cBio Cancer Genomics Portal, used to navigate TCGA Database and CCLE databases. Our web based application has the capability to analyze up to 100 S. Cerevisiae or S. Pombe genes at once. This would enable the scientists to translate their research from yeast to humans by identifying the human cancers and cancer cell lines in which the human homologs of the corresponding yeast genes are perturbed.
Citation Format: Ruby Gupta, Nikhilesh Anand, Samir Cayenne, David Otohinoyi, Debjyoti Talukdar, Ashish Patil. Oncoyeasti: a web-based application to translate data obtained from yeast high-throughput drug screens into cancer therapeutics [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A02.
Abstract LB-A04: Transcriptional regulatory programs in gynecological cancers
Authors: Osmanbeyoglu Hatice U. , Jelinic Petar , Levine Douglas , Leslie Christina S. 
Published: August 2018

Abstract
Cancer cells acquire genetic and epigenetic alterations that often lead to dysregulation of oncogenic signal transduction pathways, which in turn alter downstream transcriptional programs. The Cancer Genome Atlas (TCGA) has studied several of the most common and aggressive gynecologic tumors including high-grade serous ovarian carcinomas (HGSOC), uterine carcinosarcoma (UCS), and the serous-like subset of endometrial cancer (UCEC), together with basal breast cancer, which shares many genomic features with serous ovarian tumors. These tumors all lack accurate predictors of response and resistance and share an unmet need for adequate treatment of recurrent disease. We developed a multitask learning framework for integrating regulatory sequence from ATAC-mapped promoters and enhancers with RNA-seq data from patient tumors in order to infer transcription factor (TF) regulatory activities and explore similarities and differences between endometrial, ovarian, and basal breast tumors. We showed that our multitask learning framework enables us to selectively share the information across tumors and strongly improves the accuracy of gene expression prediction models for gynecological and basal breast tumors. Our analysis identified histologic type specific and common TF regulators of gene expression as well as predicted distinct dysregulated transcriptional regulators downstream of somatic alterations in these different cancers. Moreover, many of the identified TF regulators were significantly associated with survival outcome within the histological subtype. Computationally dissecting the role of TFs in these cancers may ultimately lead to new therapeutics tailored to subtype or individual.
Citation Format: Hatice U. Osmanbeyoglu, Petar Jelinic, Douglas Levine, Christina S. Leslie. Transcriptional regulatory programs in gynecological cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A04.
Abstract LB-A07: Clinical utility of genomic assessment of blood-derived circulating tumor (ctDNA) in patients with colorectal cancers
Authors: Schwaederle Maria C. , Kato Shumei , Choi In Sil , Fanta Paul T. , Leichman Lawrence , Lippman Scott , Kurzrock Razelle 
Published: August 2018

Abstract
Background: Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with colorectal cancers (CRC) were correlated with clinical characteristics and therapeutic outcomes.
Methods: Plasma ctDNA testing (54-73 genes; all non-synonymous alterations are analyzed herein) was performed in 94 patients with CRC (PREDICT-UCSD; NCT02478931).
Results: Ninety-six percent of patients had metastatic or recurrent disease at the time of blood draw. The median number of alterations/patient was 3 (range, 0-30). The most frequent alterations involved TP53 (52.1%), KRAS (34%), and APC (28.7%) genes; no two patients had identical molecular portfolios. Altogether, 74 patients (79%) had ≥ 1 alteration; 69 patients (93% of patients with ≥ 1 detectable ctDNA alteration) had ≥ 1 actionable alteration; 61 patients had an alteration actionable by an FDA-approved drug (on or off-label). Concordance between ctDNA and tissue genomics for the most frequent genes altered in ctDNA ranged from 63% to 86%, depending on the gene (median ~6 months between samples). Improved survival (multivariate) correlated with lung metastasis and with all ctDNA alteration fractions &lt; 5%. To date, 35 patients (median of one prior therapy in the metastatic setting) were treated with matched (N = 18) or unmatched (N = 17) therapy after ctDNA testing. Overall, 67% versus 27% of patients (matched vs unmatched) achieved SD ≥ 6 months/PR/CR (P=0.02); PFS of 6.1 vs 2.3 months (P = 0.08); OS (13.2 vs 5.1 months; not significant) (all multivariable). In serial samples from patients on anti-EGFR therapy, multiple emerging alterations in genes known to be involved in therapeutic resistance, including KRAS, NRAS, BRAF, EGFR, ERBB2, and MET were detected.
Conclusion: Most patients demonstrated potentially actionable ctDNA alterations. Improved outcomes were associated with lung metastases and low ctDNA percentage. Treatment with matched therapy correlated with significantly higher rates of SD ≥ 6 months/PR/CR (67% vs 27%). Dynamic changes in ctDNA were evident after anti-EGFR treatment, with emergence of resistance mutations, some of which may be druggable. Larger studies in CRC and other malignancies are ongoing.
Citation Format: Maria C. Schwaederle, Shumei Kato, In Sil Choi, Paul T. Fanta, Lawrence Leichman, Scott Lippman, Razelle Kurzrock. Clinical utility of genomic assessment of blood-derived circulating tumor (ctDNA) in patients with colorectal cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A07.
Abstract LB-A21: PRAS40 (AKT1S1) ablation modulates breast cancer by increasing tumor-free survival in HER-2/neu overexpressing mice
Authors: Malla Ritu , Faridi Jesika S. 
Published: August 2018

Abstract
HER-2 is over-expressed in around 20% of breast cancer patients and is correlated with a shorter relapse time and poor prognosis. This makes it crucial to identify novel downstream molecular targets in spite of a number of clinically approved drugs that target HER-2. In this study, we determined if loss of proline-rich Akt substrate of 40 kDa (PRAS40) gene increases tumor-free survival in HER-2/neu over-expressing double transgenic mice. Tumor kinetics was determined in HER-2 overexpressing PRAS40+/+ (wild-type) versus PRAS40-/- (knock-out) mice. Mammary intraepithelial neoplasias (MINs or precancerous lesions) in mammary tissues were analyzed using whole mount analysis. We observed significant increase of tumor-free survival in HER-2 overexpressing PRAS40-/- versus PRAS40+/+ parous female mice, however this effect was not significant in virgin mice. In virgin mice, we observed post-menopausal switch of tumor-free survival. The pre-menopausal protection from mammary tumors could be due to presence of Estrogen (ER). Irrespective of parity, we observed significant reduction of mammary intraepithelial neoplasias (MINs or precancerous lesions) in PRAS40-/- versus PRAS40+/+ mice. To investigate the mechanism of action of ER in HER-2 over-expressing mice we treated ER positive cells with Doxorubicin, ER or the combination in vitro. Modulation of cell proliferation and apoptosis was determined by PRAS40 transient knockdown (siPRAS40) versus non-targeting (NT) following treatment in ER positive ZR-751 cells. To interrogate the effect of Doxorubicin, ER, in vitro, cell lines were treated with 6-24 hr Doxorubicin, ER or both. Doxorubicin, ER or combination treatment led to significant reduction in proliferation and increased apoptosis in siPRAS40 versus non-targeting (NT) ZR-751 cells. Together, our data suggests that ER may have an effect upon PRAS40 knockdown in vitro and in vivo. Our results show that PRAS40 could be a novel ‘druggable’ target for treating aggressive HER-2 positive breast cancers.
Citation Format: Ritu Malla, Jesika S. Faridi. PRAS40 (AKT1S1) ablation modulates breast cancer by increasing tumor-free survival in HER-2/neu overexpressing mice [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A21.