bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1573: Detection of late-arising driver mutations using multi-sample tumor sequencing data
Authors: Gomez Karen , Miura Sayaka , Kumar Sudhir 
Published: July 2017

Abstract
Whole-genome sequencing of tumors has identified genetic mutations that drive the origination, growth, and spread of cancer. Most driver mutations detected from sequencing tumors have been categorized as early-occurring and are believed to play a role in initial tumor formation. However, single-region primary tumor samples represent just one snapshot of the continuously changing mutational landscape of a tumor. Drivers of initial tumor formation, occurring early on in tumor development, are present in more tumor cells and are more likely to be identified from a single tumor sample than drivers of later events like metastasis, which are likely to be found in only one or a few tumor samples. We analyzed 101 multi-region and/or multi-tumor sequencing data sets using driver mutation annotation and phylogenetic inference to determine whether driver mutations occur preferentially early on. We found driver mutations frequently arise late in the course of tumor evolution, even when statistically accounting for small amounts of total drivers and many early total mutations. In addition, the timing of driver mutation occurrence varies widely depending on cancer type as well as among different individuals with a single cancer subtype. Finally, we identify known cancer genes that are enriched in either early or late driver mutations, reflecting different selective pressures at various stages of cancer development. These results illustrate how drivers of primary tumorigenesis must be distinguished from drivers of treatment resistance, metastasis, or recurrence in order to better understand the genetic changes behind cancer progression.
Citation Format: Karen Gomez, Sayaka Miura, Sudhir Kumar. Detection of late-arising driver mutations using multi-sample tumor sequencing data [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 1573. doi:10.1158/1538-7445.AM2017-1573
Abstract 1577: GRK3 is a direct target of ADT-induced CREB1 activation and it promotes neuroendocrine differentiation of prostate cancer cells
Authors: Zheng Dayong , Hulsurkar Mohit , Sang Meixiang , Zhang Songlin , Xu Jianming , Gleave Martin , Ittmann Michael , Li Wenliang 
Published: July 2017

Abstract
Treatment-related neuroendocrine prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer that is believed to arise through neuroendocrine differentiation (NED) from prostate adenocarcinoma (PAC) upon castration resistance to androgen deprivation treatment (ADT). t-NEPC is highly metastatic with poor prognosis. With the recent introduction of potent ADT drugs in clinic, the incidence of t-NEPC is expected to increase dramatically. No effective therapeutic is available for t-NEPC and its molecular mechanisms remain poorly understood. We reported that GRK3 (G protein-coupled receptor kinase 3) promotes prostate cancer progression. We further demonstrated that the ADT activates CREB1 (cAMP response element binding protein 1), which directly targets and induces GRK3. GRK3 expression is higher in t-NEPC than in PAC cells and mouse models, and it positively correlates with the expression and activity of CREB1 in human prostate cancers. Notably, overexpression of GRK3 in PAC cells increased the expression of NE markers. Conversely, silencing GRK3 blocked CREB1-induced NED in PAC cells, reversed NE phenotypes and inhibited proliferation of t-NEPC cells in culture and in xenograft. Currently, we are investigating the mechanisms underlying NEPC progression promoted by the CREB1/GRK3 axis. Taken together, these results indicate that GRK3 is a new critical activator of NE phenotypes and mediator of CREB1 activation in promoting NED of prostate cancer cells.
Citation Format: Dayong Zheng, Mohit Hulsurkar, Meixiang Sang, Songlin Zhang, Jianming Xu, Martin Gleave, Michael Ittmann, Wenliang Li. GRK3 is a direct target of ADT-induced CREB1 activation and it promotes neuroendocrine differentiation of prostate 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 1577. doi:10.1158/1538-7445.AM2017-1577
Abstract 1579: Bicalutamide-induced expression of T-type Ca2+ channels in prostate cancer cells undergoing neuroendocrine differentiation in vitro
Authors: Martin-Caraballo Miguel , Hall Megan , Todd Bryan , Kwon Yoon Jung , Nguyen Vu , Hearne Jennifer L. 
Published: July 2017

Abstract
The growth of prostate cancer cells depends on the activation of androgen receptors. Anti-androgen therapies that inhibit androgen synthesis or receptor activation are effective in limiting tumor growth. However, prolonged treatment with anti-androgen therapies result in the transition of prostate cancers into an androgen refractory state. Neuroendocrine differentiation (NED) has been associated with the progression of prostate cancers to an androgen resistant phenotype. In this work we investigated the effect of the androgen receptor blocker bicalutamide in promoting NED of LNCaP cells and whether it is accompanied by increased T-type Ca2+ channel expression. The ability of bicalutamide to evoke morphological and biochemical changes associated with NED was assessed by PCR, western blot and immuno-histochemical analysis. Changes in the Cav3.2 T-type Ca2+ channel subunit expression was studied using PCR analysis, western blot and whole cell recordings. The role of T-type Ca2+ channels in promoting the differentiation of LNCaP cells was assessed by a cell viability assay and changes in cell morphology, specifically the development of neurite-like processes. PCR analysis of bicalutamide-stimulated cells indicates no significant changes in Cav3.2 mRNA, yet results in Cav3.2 protein expression and functional channels. Western blot and immuno-histochemical analysis of LNCaP cells simulated with bicalutamide for 4-10 day reveals biochemical changes consistent with NED including the expression of tubulin IIIbeta and neuron-specific enolase. Pharmacological inhibition of T-type Ca2+ channel function with nickel ions and NNC 33-0936 disrupts the morphological differentiation and cell viability of LNCaP cells treated with bicalutamide. These results suggest that bicalutamide treatment of LNCaP cells evokes significant morphological and biochemical changes associated with NED and results in increased expression of T-type Ca2+ channels, which can significantly alter Ca2+ homeostasis.
Citation Format: Miguel Martin-Caraballo, Megan Hall, Bryan Todd, Yoon Jung Kwon, Vu Nguyen, Jennifer L. Hearne. Bicalutamide-induced expression of T-type Ca2+ channels in prostate cancer cells undergoing neuroendocrine differentiation in vitro [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 1579. doi:10.1158/1538-7445.AM2017-1579
Abstract 1585: Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress
Authors: Lee Joo Hyoung , Kang Minsung , Naik Gurudatta , Mobley James A. , Sonpavde Guru , Garvey W. Timothy , Darley-Usmar Victor M. , Ponnazhagan Selvarangan 
Published: July 2017

Abstract
Androgen-deprivation therapy has been identified to induce oxidative stress in prostate cancer (PCa), leading to re-activation of androgen receptor (AR) signaling in a hormone-refractory manner. Thus, antioxidant therapies have gained attention as adjuvants for castration-resistant PCa (CRPC). Here, we report for the first time that human endostatin (ES) prevents androgen-independent growth phenotype in PCa cells through its molecular targeting of AR and glucocorticoid receptor (GR), and downstream pro-oxidant signaling. This reversal following ES treatment significantly decreased PCa cell proliferation through downregulation of GR, and upregulation of manganese superoxide dismutase and reduced glutathione levels. Proteome and biochemical analyses of ES-treated PCa cells further indicated a significant upregulation of enzymes in major ROS scavenging machinery, including catalase, glutathione synthetase, glutathione reductase, NADPH-cytochrome P450 reductase, biliverdin reductase and thioredoxin reductase, resulting in a concomitant reduction of intracellular ROS. ES further augmented antioxidant system through upregulation of glucose influx, pentose phosphate pathway (PPP) and NAD salvaging pathway. This shift in cancer cell redox homeostasis by ES significantly decreased the effect of protumorigenic oxidative machinery on androgen-independent PCa growth, suggesting that ES can suppress GR-induced CRPC phenotype upon AR antagonism, and dual targeting action of ES on AR and GR can be further translated to PCa therapy.
Citation Format: Joo Hyoung Lee, Minsung Kang, Gurudatta Naik, James A. Mobley, Guru Sonpavde, W. Timothy Garvey, Victor M. Darley-Usmar, Selvarangan Ponnazhagan. Endostatin inhibits androgen-independent prostate cancer growth by suppressing nuclear receptor-mediated oxidative stress [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 1585. doi:10.1158/1538-7445.AM2017-1585
Abstract 16: Evaluation of the efficacy of clotrimazole treatment in human melanoma cell lines that overexpress the multidrug resistance-associated protein (MRP) and the lung resistance-related protein (LRP)
Authors: Blake Steven D. , McKamey Shelby G. , Tweed Christopher M. , Koh David W. 
Published: July 2017

Abstract
Drug resistance to chemotherapy, mediated in part by overexpression of P-glycoprotein (MDR-1), multidrug resistance-associated protein (MRP), or lung resistance-realted protein (LRP), continues to be a major problem in the treatment of melanoma. Because we previously demonstrated the ability of clotrimazole to enhance cytotoxicity in human metastatic melanoma cells, here we evaluated the ability of clotrimazole to treat drug-resistant human melanoma cells that overexpress MRP and/or LRP. We utilized human melanoma cell lines that overexpress either MDR or LRP, and human melanoma cell lines that overexpress both. Cell growth and cell death were analyzed by flow cytometry, proliferation assays, and immunoblotting after drug treatments and RNA interference. Clotrimazole caused significant decreases in proliferation and increases in cell death in both drug-sensitive melanoma lines and those overexpressing MRP and LRP. No extensive cell death was induced by clotrimazole treatment in noncancerous human skin cell lines. These results indicate that clotrimazole selectively induces cytotoxicity in both drug-sensitive and drug-resistant melanoma lines. As clotrimazole is known to inhibit various transient receptor potential (TRP) ion channels, we pretreated these melanoma lines with TRP inhibitors or RNAi. Inhibitors of the TRP melastatin-8 channel (TRPM8) or TRP vanilloid-1 (TRPV1) failed to produce comparable levels of cell death caused by clotrimazole. However, RNAi silencing of the TRPM2 cation channel caused significant levels of cell death in both drug-sensitive and drug-resistant melanoma lines. These results indicated that inhibition of TRPM2 channels may have a primary role in the ability of clotrimazole to treat drug-sensitive and drug-resistant melanoma lines.
In conclusion, this study demonstrated that clotrimazole selectively increases cell death in drug-resistant melanoma lines, with minimal deleterious effects in normal skin cells. Taken together, we conclude that clotrimazole has in vitro efficacy toward the treatment of drug-resistant human melanoma cells. Thus, these preliminary studies indicate that clotrimazole has the potential to successfully treat drug resistant melanoma in the future.
Citation Format: Steven D. Blake, Shelby G. McKamey, Christopher M. Tweed, David W. Koh. Evaluation of the efficacy of clotrimazole treatment in human melanoma cell lines that overexpress the multidrug resistance-associated protein (MRP) and the lung resistance-related protein (LRP) [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 16. doi:10.1158/1538-7445.AM2017-16
Abstract 1602: Generation of anti-IL-17B antibodies neutralizing IL-17B-mediated alterations of the immune microenvironment, promotion of tumor cell initiating capacity and chemoresistance
Authors: Laprevotte Emilie , Docquier Aurélie , Bastid Jeremy , Déjou Cécile , Lapierre Marion , Alberici Gilles , Bensussan Armand , Eliaou Jean-François , Bonnefoy Nathalie 
Published: July 2017

Abstract
Interleukin 17B (IL-17B) is a pro-inflammatory cytokine that belongs to a family encompassing 6 interleukins (IL-17A to F) and binds to the IL-17 receptor B (IL-17RB). Recently, amplified IL-17B/IL-17RB signaling was found critical for breast and pancreatic tumorigenesis and elevated expression of IL-17RB has been associated with the shortest survival rates in patients with breast or pancreatic cancer. Using IL-17B knock-out (IL-17B KO) mice we demonstrate here that melanoma, fibrosarcoma and breast cancer cell tumorigenicity is strongly impaired in immunocompetent IL-17B KO mice compared to WT littermates, including a large number of tumor free mice. Reduced tumor incidence in IL-17B KO mice is associated with alterations of the immune tumor microenvironment especially within innate lymphocyte and myeloid sub-populations. We further demonstrate that IL-17B is a key cytokine shaping the tumor initiating cancer cell niche. Indeed, MDA-MB-468 human breast cancer cells overexpressing IL-17B exhibit 10 times higher frequency of tumor initiating cells when xenografted at a serial limiting dilution in nude mice. Tumor progression is, again, associated with alterations of NK cells within the tumor microenvironment and with increased percentages of CD44hi/CD24lo tumor cells, a phenotype associated with breast cancer stem cells (CSC). This is associated with resistance to conventional chemotherapeutic agents such as taxol, an effect that is totally abrogated by disrupting IL-17B-IL-17RB signaling with a neutralizing antibody. Altogether our results point out the key role of IL-17B in regulating the immune microenvironment as well as cardinal features of CSC, one of the alleged causes of resistance to therapy and tumor relapse. Thereby, IL-17B and its receptor appear as potential therapeutic targets for cancer immunotherapy. Collectively, these data support the ongoing development of IL-17B neutralizing antibodies.
Citation Format: Emilie Laprevotte, Aurélie Docquier, Jeremy Bastid, Cécile Déjou, Marion Lapierre, Gilles Alberici, Armand Bensussan, Jean-François Eliaou, Nathalie Bonnefoy. Generation of anti-IL-17B antibodies neutralizing IL-17B-mediated alterations of the immune microenvironment, promotion of tumor cell initiating capacity and chemoresistance [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 1602. doi:10.1158/1538-7445.AM2017-1602
Abstract 1614: Intratumoral delivery of a P2A-linked bicistronic IL-12 construct leads to high intratumoral expression and systemic anti-tumor response
Authors: Canton David A. , Burkart Christoph , Shirley Shawna A. , Mukhopadhyay Anandaroop , Connolly Richard J. , Bahrami Arya , Campbell Jean S. , Pierce Robert H. 
Published: July 2017

Abstract
The use of immunomodulatory cytokines has been shown effective in regressing a wide range of tumors. However, systemic delivery of recombinant cytokines can result in serious adverse effects, often life-threatening. DNA transfer via electroporation (EP) is a safe and effective method of delivering cytokines to target tissues.
Intratumoral (IT) electroporation of Interleukin 12 (IL-12), a potent immunomodulatory cytokine, is well tolerated with an acceptable safety profile and objective response rates of 34-40% and 33% in Phase II clinical trials in advanced melanoma and Merkel cell carcinoma, respectively. We sought to improve the systemic anti-tumor response of IT pIL-12-EP by improving IL-12p70 expression and electroporation conditions, which were evaluated in vitro and in vivo with a two-tumor syngeneic mouse model of melanoma. As functional IL-12 p70 is a heterodimer, we compared different expression constructs to achieve high levels of IL-12 protein expression. IL-12p70 protein expression from a plasmid that incorporated a picornavirus-derived co-translational cleavage site (P2A) was higher than constructs with an internal ribosomal entry sequence (IRES) or a fusion of the p35 and p40 subunits. In functional in vitro assays, pIL-12(P2A) was superior to pIL-12(IRES) and the fusion protein. Using the murine B16.F10 tumor model, we show that IT EP of pIL-12 (P2A) plasmid regresses the treated lesions in a dose-dependent manner compared to control treatments. Systemic effects of IT-expressed IL-12 was assessed by monitoring generation of an antigen-specific CD8 T cell response and regression of B16.F10 contralateral (untreated) tumors following primary tumor electroporation. IT-pIL12-EP treatment with the P2A-linked construct resulted in a significant increase in antigen-specific CD8 T cells, as well as enhanced contralateral tumor growth inhibition suggesting the induction of strong systemic anti-tumor immune response.
* Contributed equally to this work
Citation Format: David A. Canton, Christoph Burkart, Shawna A. Shirley, Anandaroop Mukhopadhyay, Richard J. Connolly, Arya Bahrami, Jean S. Campbell, Robert H. Pierce. Intratumoral delivery of a P2A-linked bicistronic IL-12 construct leads to high intratumoral expression and systemic anti-tumor 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 1614. doi:10.1158/1538-7445.AM2017-1614
Abstract 1615: C-Reactive protein and radiotherapy-induced skin toxicity in breast cancer
Authors: Hu Jennifer J. , Case Doug , Lively Mark O. , Lee Eunkyung , Takita Cristiane , Urbanic James J. , Lesser Glenn J. , Shaw Edward G. 
Published: July 2017

Abstract
Background: Post-surgery adjuvant radiotherapy (RT) for breast cancer significantly reduced the local recurrence rate. However, many patients develop early adverse skin reactions (EASRs) that impact quality of life.
Methods: In a large prospective study of 1,000 breast cancer patients undergoing RT, we evaluated an inflammatory biomarker, C-reactive protein (CRP) in predicting RT-induced EASRs. In each patient, we measured pre- and post-RT plasma CRP levels using a highly-sensitive ELISA CRP assay. RT-induced EASRs were assessed using the Oncology Nursing Society Skin Toxicity Criteria. Association between EASRs and CRP were assessed using logistic regression models after adjusting for potential confounders.
Results: The study population includes 405 non-Hispanic White, 280 African Americans, 218 Hispanic Whites, 52 Asians, and 45 others. RT-induced grade 3+ and 4+ skin toxicity at the end of RT were observed in 42% and 15% patients, respectively. CRP levels differ significantly by race/ethnicity at baseline and at the end of RT. RT-induced grade 4+ skin toxicity was significantly associated with: obesity and pre-RT CRP &gt; 2mg/L (OR=3.27; 95%CI=1.88, 5.68), obesity and post-RT CRP &gt; 2mg/L (OR=4.42; 95%CI=2.38, 8.23), or obesity and change of CRP &gt; 1mg/L (OR=3.58; 95%CI=2.00, 6.39).
Conclusion: The current data validate our previous findings that the inflammatory biomarker CRP is associated with RT-induced EASRs, particularly combined with obesity.
Impact: Our current findings support the discovery and development of anti-inflammatory agents to protect normal tissue from RT-induced EASRs and improve quality of life in breast cancer patients undergoing RT.
Citation Format: Jennifer J. Hu, Doug Case, Mark O. Lively, Eunkyung Lee, Cristiane Takita, James J. Urbanic, Glenn J. Lesser, Edward G. Shaw. C-Reactive protein and radiotherapy-induced skin toxicity in 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 1615. doi:10.1158/1538-7445.AM2017-1615
Abstract 1622: The role of the CCL-2 on lymphopenia-induced myeloid derived suppressor cells
Authors: Innamarato Pasquale P. , Weber Amy , Pilon-Thomas Shari 
Published: July 2017

Abstract
The induction of lymphopenia prompts the expansion of CD11b+Ly6ChiLy6G- monocytic MDSCs (M-MDSCs) and CD11b+Ly6C+Ly6G+ polymorphonuclear MDSCs (PMN-MDSCs). Patients receiving adoptive cell therapy (ACT) require nonmyeloablative chemotherapy to induce lymphopenia and support anti-tumor immunity. However, the role of MDSCs in the setting of ACT is not fully understood. As high levels of CCL-2 can be measured in lymphopenic mice, in this study we investigate the role of CCL-2 in the expansion and function of lymphopenia-induced MDSCs using CCR2KO mouse models. Lymphopenia was induced in melanoma-bearing C57BL/6 (WT) and CCR2KO mice by 600rad of total body irradiation or combination therapy with cyclophosphamide and fludarabine. We first evaluated the percentages of splenic MDSCs in WT and CCR2KO mice after the induction of lymphopenia. At day 14, the expansion of total MDSCs were similar in WT (279% of normal) and CCR2KO (241% of normal). However, the mean percentages of M-MDSCs (3.5%) and PMN-MDSCs (30.3%) in CCR2KO mice were altered compared to M-MDSCs (22.2%) and PMN-MDSCs (21.7%) in WT mice. In addition, M-MDSCs in B16 tumors grown in CCR2KO mice were decreased compared to intratumoral M-MDSCs in WT mice (p&lt;0.001). In contrast, the percentages of M-MDSCs and PMN-MDSCs were unchanged in the bone marrow (BM). To investigate the suppressive capacity of lymphopenia-induced MDSCs, OVA antigen-specific CD8+ T cells were co-cultured with OVA peptide in the presence of MDSCs purified from the spleens of CCR2KO and WT mice. Both CCR2KO and WT MDSCs potently suppressed T cell proliferation as measured by 3H thymidine incorporation. CCR2KO and WT MDSCs had significant arginase activity and production of nitrites. To investigate the efficacy of ACT, B16 tumor-bearing CCR2KO and WT mice were lymphodepleted and gp100 antigen-specific Thy1.2+CD8+ T cells were adoptively transferred followed by 3 days of IL-2 treatment. We found that donor T cell tumor infiltration was similar and no difference in tumor growth was observed between CCR2KO and WT mice. Collectively, these results suggest that the role of CCL-2 is important for the egress of lymphopenia-induced M-MDSCs from the BM, but has no effect on the expansion or function of PMN-MDSCs in the setting of lymphopenia. These data suggest that factors besides CCL-2 play an important role in the expansion and function of MDSCs after the induction of lymphopenia.
Citation Format: Pasquale P. Innamarato, Amy Weber, Shari Pilon-Thomas. The role of the CCL-2 on lymphopenia-induced myeloid derived suppressor 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 1622. doi:10.1158/1538-7445.AM2017-1622