bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5908: Cancer-associated fibroblast driven drug resistance in colorectal cancer
Authors: Garvey Colleen M. , Chen Oscar , Mumenthaler Shannon M. 
Published: July 2017

Abstract
Drug resistance remains a major problem in the treatment of most cancers. For example, KRAS wild-type colorectal cancers (CRCs) are typically treated with the anti-epidermal growth factor receptor (EGFR) therapy cetuximab in combination with standard chemotherapy; however, of the 40% of patients that do respond, virtually all relapse within 3-12 months. Additionally, around 25% of nonresponders have no identifiable resistance mechanisms. This suggests that it is not just cell-intrinsic mechanisms that result in resistance, but that extrinsic factors play a role. The purpose of this study was to investigate how the dynamics of the tumor microenvironment, specifically cancer-associated fibroblasts (CAFs) and hypoxia, modify the response of CRC cells to cetuximab. We used a novel high-content imaging platform to generate quantitative phenotypic data (i.e. morphology, birth/death rates) of cellular co-cultures perturbed by multiple, co-occurring microenvironmental conditions. Preliminary data demonstrated reduced sensitivity of tumor cells to cetuximab in the presence of CAFs, which was dependent on patient specifics and time scale of co-culture. Additionally, we found that low oxygen conditions altered the effect of CAFs on tumor cell phenotypes, which highlights the importance of studying co-occurring microenvironmental factors. This work underlies the importance of considering not just the genetic makeup of patient tumors, but also the heterogeneity of the surrounding microenvironment when designing personalized treatment strategies.
Citation Format: Colleen M. Garvey, Oscar Chen, Shannon M. Mumenthaler. Cancer-associated fibroblast driven drug resistance in colorectal 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 5908. doi:10.1158/1538-7445.AM2017-5908
Abstract 591: Efficacy of ALKS 4230, a novel immunotherapeutic agent, in murine syngeneic tumor models alone and in combination with immune checkpoint inhibitors
Authors: Losey Heather C. , Lopes Jared E. , Dean Reginald L. , Huff Michael R. , Moroso Rosemarie A. , Alvarez Juan C. 
Published: July 2017

Abstract
ALKS 4230 is a novel immunotherapeutic agent being tested in an ongoing phase 1 study to evaluate safety and tolerability in the treatment of patients with refractory solid tumors. ALKS 4230 is a selective agonist of the intermediate-affinity interleukin 2 (IL-2) receptor that when administered to mice results in a significant increase in numbers of memory CD8+ T cells and NK cells with no expansion of CD4+ regulatory T cells (Tregs). The selectivity achieved by ALKS 4230 is due to the fact that the molecule is a fusion of circularly permuted IL-2 to the extracellular portion of the IL-2 receptor α, and the resulting fusion protein is sterically prevented from binding to the high-affinity IL-2 receptor expressed on Tregs. The efficacy of ALKS 4230 was compared to recombinant human IL-2 in a B16F10 lung tumor metastasis model. ALKS 4230 treatment resulted in dose-dependent reduction of lung tumor colonization, with 100% inhibition at the highest dose tested. In contrast, while IL-2 was able to reduce lung tumor colonization, the maximal level of inhibition achieved was 60-70% at multiple dose levels such that increasing doses did not result in greater inhibition. Thus, the activation and expansion of effector cells without expansion of Tregs in response to ALKS 4230 treatment correlates with its improved efficacy over IL-2, which non-selectively expands both effector cells and Tregs. The antitumor efficacy mediated by ALKS 4230 was further evaluated in several murine subcutaneous syngeneic tumor models, including B16F10, MC38 and EMT6. Treatment with ALKS 4230 or its murine ortholog resulted in inhibition of tumor growth and improved survival in multiple models. When dosed in combination with anti-CTLA-4 or anti-PD-1 antibodies, ALKS 4230 resulted in further improvement of tumor growth inhibition and survival. These results demonstrate the murine antitumor efficacy of ALKS 4230 alone and in combination with immune checkpoint inhibitors and support the ongoing clinical evaluation of ALKS 4230 as an immunotherapy for cancer.
Citation Format: Heather C. Losey, Jared E. Lopes, Reginald L. Dean, Michael R. Huff, Rosemarie A. Moroso, Juan C. Alvarez. Efficacy of ALKS 4230, a novel immunotherapeutic agent, in murine syngeneic tumor models alone and in combination with immune checkpoint inhibitors [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 591. doi:10.1158/1538-7445.AM2017-591
Abstract 5912: Tumor micoenvironment modulates RTK signaling
Authors: Thakar Dhruv , Low-Nam Shalini T. , Groves Jay T. , Weaver Valerie M. 
Published: July 2017

Abstract
Receptor tyrosine kinases (RTKs) and their associated signaling molecules are mutated or dysregulated in many aggressive cancers such as non-small cell lung carcinoma (NSCLC), breast cancer, and colorectal cancer. Despite therapeutic interventions such as tyrosine kinase inhibitors (TKI) that target RTKs, majority of patients develop resistance even after initial tumor regression. Although clinical studies suggest sequential treatments with TKI, chemotherapy, and radiation can eliminate most cancer cells, resistance inevitably emerges (Sequist, et al., Sci Trans Med, 2011). We demonstrated that alterations in the extracellular matrix (ECM) correlate with cancer progression and that RTK signaling is subject to spatiotemporal regulation (Paszek, et al., Cancer Cell, 2005.; Salaita, et al., Science, 2010). Thus, geometric and mechanical properties of the ECM may directly modulate RTK signaling. Here, we use silicone gel substrates that exhibit tunable stiffness in the physiological range (100s Pa - 100s kPa) to measure RTK-adaptor protein interactions in mammary epithelial cells (MECs; MCF10A) (Ou, et al. Integ. Biol., 2016). These gels are compatible with total internal reflection fluorescence (TIRF) imaging and enable single molecule detection of activated RTK phosphotyrosine residues via recruitment of Grb2 tagged with the fluorescent protein mEos3.2. We demonstrate a spectrum of Grb2 behaviors that are determined by the stiffness of the substrate. This indicates that the same receptor is capable of different signaling activities that are dictated by material properties. These new insights create opportunities to target the tumor microenvironment to address RTK inhibitor resistance and metastasis in cancer patients and to develop effective therapeutic strategies for better prognosis and prolonged patient survival.
Citation Format: Dhruv Thakar, Shalini T. Low-Nam, Jay T. Groves, Valerie M. Weaver. Tumor micoenvironment modulates RTK signaling [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 5912. doi:10.1158/1538-7445.AM2017-5912
Abstract 5913: The impact of daily exercise on tumor perfusion
Authors: Wiggins Jennifer M. , Lepler Sharon , Pampo Christine , Rice Lori , Lee Jennifer A. , Siemann Dietmar 
Published: July 2017

Abstract
Aberrant blood vessel networks in solid tumors lead to impaired tissue perfusion and areas of hypoxia (pO2 &lt; 10 mmHg). Tumor hypoxia is associated with aggressive progression, dissemination, and therapeutic resistance. It is found in 40% of breast cancers, and can constitute a major obstacle to anticancer therapy. Exercise is associated with improvements in cardiovascular and respiratory function, aerobic capacity and overall health. In cancer patients undergoing therapy, exercise has been shown to decrease treatment related side effects and general fatigue. The goal of the present investigation was to determine whether aerobic exercise could be applied to improve tumor perfusion and oxygenation in a breast cancer model. Such modulation of the tumor physiology and host environment would be expected to lead to enhanced antitumor efficacy when combined with radiotherapy or chemotherapy. The effects of a single and daily bouts of moderate intensity treadmill running were studied in mice bearing the syngeneic murine mammary carcinoma 4T1. The exercise intensity was determined by measuring the anaerobic threshold, which was assessed by measuring the steady rise in blood lactate during exercise. Initial studies examined the effect of a single moderate bout of exercise (18 m/min) in mice bearing ~500 mm3 orthotopic tumors. In subsequent experiments mice were exercised at 18 m/min, 5 days a week, for 8 weeks prior to orthotopic injection of tumor cells and continued exercise (5 days a week) for 2 weeks during tumor growth. Controls for each treatment consisted of sedentary mice exposed to a stationary treadmill for the equivalent amount of time. At the end of each of the exercise regimen, tumors were harvested, sectioned, stained, and tile mapped to assess physiological changes by immunofluorescence. The detection of open blood vessels (Hoechst-33342) was used as an indirect indicator of perfusion. Tumor hypoxia was determined using the 2-nitroimidazole (EF5). Blood vessels were stained using the endothelial cell marker CD-31. All markers were quantified using Photoshop and ImageJ NIH software. Our results indicate that in the 4T1 breast cancer model moderate intensity exercise did not significantly alter tumor growth, oxygenation or blood vessel number. However, daily bouts of exercise did significantly increase the number of open tumor vessels indicating improved tumor perfusion. These results suggest that a daily exercise regimen may have the potential to improve drug delivery to mammary tumors
Citation Format: Jennifer M. Wiggins, Sharon Lepler, Christine Pampo, Lori Rice, Jennifer A. Lee, Dietmar Siemann. The impact of daily exercise on tumor perfusion [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 5913. doi:10.1158/1538-7445.AM2017-5913
Abstract 592: Distinct cellular mechanisms mediate anti-CTLA-4 and anti-PD-1 checkpoint blockade
Authors: Wei Spencer C. , Levine Jacob H. , Pe'er Dana , Allison James P. 
Published: July 2017

Abstract
Checkpoint blockade is able to achieve durable responses in a subset of patients, however the biological variables that distinguish responders from non-responders are not well understood. Furthermore, we lack a satisfying comprehension of the underlying mechanisms of anti-CTLA-4 and anti-PD-1 induced tumor rejection. Given that PD-1 and CTLA-4 attenuate T cell activity through distinct mechanisms that are separated spatially and temporally, we hypothesized that responses to anti-CTLA-4 and anti-PD-1 are driven by distinct mechanisms. To address this hypothesis we utilized mass cytometry to comprehensively profile the effect of checkpoint blockade on tumor immune infiltrates in murine tumor models. This approach allows for the interrogation of greater than 40 analytes at single cell resolution. We demonstrate that high dimensional mass cytometry analysis enables unsupervised identification of biologically relevant tumor infiltrating immune populations with high sensitivity and specificity.
Using this approach we analyzed immune infiltrates of MC38 and B16BL6 murine tumors in mice treated with anti-CTLA-4, anti-PD-1, or control antibodies. In both tumor models we identify 15 distinct T cell populations with 0.5% or greater frequency. The T cell populations identified in MC38 and B16BL6 tumors were highly congruent. Notably, some but not all of these T cell populations were responsive to checkpoint blockade. A subset of tumor infiltrating CD8 T cell populations expanded following both anti-CTLA-4 and anti-PD-1. Conversely, a subset of regulatory T cell populations contracted following both anti-CTLA-4 and anti-PD-1. Interestingly, we observed expansion of a Th1-like CD4 effector T cell population only in response to anti-CTLA-4 treatment. Thus, we find that anti-PD-1 predominantly engages subsets of tumor infiltrating CD8 T cells whereas anti-CTLA-4 engages both the CD4 and CD8 effector compartments.
Our findings indicate that anti-CTLA-4 and anti-PD-1 utilize distinct cellular mechanisms to induce tumor rejection. These findings highlight the importance of expanding our mechanistic understanding of immunotherapeutic approaches for the rational design of combinatorial therapeutic approaches. Furthermore, these results demonstrate that mass cytometry analysis can be utilized to identify biologically relevant tumor infiltrating T cell populations.
We acknowledge the MDACC core facility NCI Support Grant P30CA16672.
Citation Format: Spencer C. Wei, Jacob H. Levine, Dana Pe'er, James P. Allison. Distinct cellular mechanisms mediate anti-CTLA-4 and anti-PD-1 checkpoint blockade [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 592. doi:10.1158/1538-7445.AM2017-592
Abstract 5925: Mapping the molecular communication within the tumor microenvironment of pancreatic cancer as well as between tumor and peritumoral tissue
Authors: Alhamdani Mohamed S. , Bauer Andrea S. , Hoheisel Jörg D. 
Published: July 2017

Abstract
We are analyzing in detail the molecular communication between the different cell types in the microenvironment of pancreatic ductal adenocarcinomas (PDAC). Also, its regulation is being investigated, looking at aspects such as the kind and mixture of molecules needed for triggering a particular regulative function, and unraveling the inter- and intracellular processes utilized to transmit a molecular message.
Although a rare tumor entity, adding up to only about 3% of all cancer cases in the Western world, PDAC is the fourth most frequent cause of cancer-related death; mortality is nearly identical to incidence. There is no real remedy apart from surgery, which can be applied to only 10 to 20% of patients. Even then, basically all patients will experience tumor recurrence.
Our study is based on a large basic set of data at the levels of DNA, RNA and protein that was generated from some 1000 pancreatic tumor samples [1], supplemented with information from studies that aim at an elucidation of functional molecules and comparative analyses in other tumors. This has already led to the creation of basic functional knowledge about metastasis [e.g., 2], the establishment of means for diagnosis [3, 4], an accurate disease prognosis [1], the characterization of communication processes [5] and the identification of new therapeutic avenues [6].
At the conference, we will report about the status of mapping particularly the protein-mediated communication between the different cell types in the tumor microenvironment. Also, we will show results about the effect that PDAC tissue has on the wider peritumoral environment and vice versa. The peritumoral tissue is exhibiting a field defect that does not seem to be dependent on DNA-methylation. A comparison of PDAC and cystic pancreatic tumors revealed that differences in communicating with the peritumoral tissue could actually be more important to the known pathological difference between the two cancer entities than the molecular variations in the tumor cells.
1. Bauer et al. (2017), work submitted for publication
2. Botla et al. (2016) Cancer Res. 76, 4149-4159
3. Keller et al. (2014) BMC Med. 12, 224
4. Moskalev et al. (2015) Oncotarget 6, 4418-4427
5. Dror et al. (2016) Nature Cell Biol. 18, 1006-1017
6. Jandaghi et al. (2016) Gastroenterology, in press (doi: 10.1053/j.gastro.2016.08.040)
www.dkfz.de/funct_genome/
Note: This abstract was not presented at the meeting.
Citation Format: Mohamed S. Alhamdani, Andrea S. Bauer, Jörg D. Hoheisel. Mapping the molecular communication within the tumor microenvironment of pancreatic cancer as well as between tumor and peritumoral tissue [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 5925. doi:10.1158/1538-7445.AM2017-5925
Abstract 5927: Eribulin modulates tumor microenvironment through vascular remodeling for antitumor effect in multiple mouse xenograft models
Authors: Ito Ken , Hamamichi Shusei , Abe Takanori , Akagi Tsuyoshi , Shirota Hiroshi , Kawano Satoshi , Asano Makoto , Asano Osamu , Yokoi Akira , Matsui Junji , Umeda Izumi O. , Fujii Hirofumi 
Published: July 2017

Abstract
Eribulin mesilate (Eribulin), a first-in-class halichondrin B-based microtubule dynamics inhibitor, has been reported to remodel tumor vasculature (i.e., improvement of tumor vessels and perfusion) in human breast cancer xenograft models; however, the role of this vascular remodeling in anti-tumor effects is not fully understood. Here, we investigated the effects of eribulin-induced vascular remodeling on anti-tumor activities in multiple human cancer xenograft models. Microvessel densities (MVDs) were evaluated by immunohistochemistry (CD31 staining), and anti-tumor effects were examined in 10 human cancer xenograft models treated with eribulin. Eribulin treatment significantly increased MVDs compared to the corresponding control groups in 7 out of 10 models with a correlation between enhanced MVD levels and anti-tumor effects (R2=0.55). Because of observed increases in MVDs, we next utilized 111In-labeled PEGylated liposomes to examine if eribulin treatment would result in increased tumoral accumulation levels of such liposomes, and indeed, we found that eribulin, unlike vinorelbine another tubulin inhibitor, enhanced them. Since eribulin treatment increased accumulation of 111In-labeled PEGylated liposomes, we postulated that this treatment might enhance anti-tumor effect of Doxil (a liposomal anti-cancer agent). As expected, eribulin enhanced anti-tumor activity of Doxil in the PE-H1650 xenograft model. Then, we evaluated whether eribulin facilitated the recruitment of immune cells into the tumor. Infiltrating CD11b-positive immune cells were significantly increased in the multiple eribulin-treated xenografted tumors, and natural killer (NK) cell depletion reduced anti-tumor effects of eribulin. Collectively, these findings suggested a contribution of the immune cells for anti-tumor activities of eribulin. Taken together, our results obtained from multiple human cancer xenograft models suggested that vascular remodeling induced by eribulin therapy would act as a microenvironment modulator, and contributed to show anti-tumor effects of eribulin.
Citation Format: Ken Ito, Shusei Hamamichi, Takanori Abe, Tsuyoshi Akagi, Hiroshi Shirota, Satoshi Kawano, Makoto Asano, Osamu Asano, Akira Yokoi, Junji Matsui, Izumi O. Umeda, Hirofumi Fujii. Eribulin modulates tumor microenvironment through vascular remodeling for antitumor effect in multiple mouse 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 5927. doi:10.1158/1538-7445.AM2017-5927
Abstract 5937: Obesity-induced destabilization of p16INK4A promotes the procarcinogenic effects of breast stromal adipocytes through miR-141/miR-146b-5p-dependent inhibition of leptin
Authors: Alkhalaf Huda H. , Aboussekhra Abdelilah 
Published: July 2017

Abstract
Obesity, a disease linked to increased number of adipocytes in various tissues, is increasingly recognized as a risk factor for the development of breast cancer. However, the molecular basis of adipocyte-related breast carcinogenesis remains elusive. In this study, we established and characterized normal stromal adipocytes from post-plastic surgery of breast tissues from obese and lean women. We have shown that adipocytes from obese women express low level of the tumor suppressor p16 protein, have higher secretion of various adipokines and higher invasion and migration capabilities as compared to adipocytes from lean women. In addition, down-regulation of p16INK4A by shRNA in adipocytes from lean women increased the expression/secretion levels of various adipokines including leptin, activated breast adipocytes and enhanced their migration/invasion abilities. Consequently, media conditioned with p16-deficient adipocytes or adipocytes from obese women promote epithelial-to-mesenchymal-transition in normal breast luminal cells in a leptin-dependent manner and induced tumor growth in vivo. Indeed, p16INK4A suppresses Leptin at the mRNA level through miR-141 and miR-146b-5p, which inhibits Leptin expression through a specific sequence at the Leptin 3’UTR. These results show the existence of active adipocytes in the mammary gland of obese women in absence of breast cancer cells and provide the first indication that p16INK4A through targeting miR-141 and miR-146b-5p suppresses Leptin and its procarcinogenic effects. This indicates that p16 pathway has non-cell-autonomous tumor suppressor function in breast stromal adipocytes.
Note: This abstract was not presented at the meeting.
Citation Format: Huda H. Alkhalaf, Abdelilah Aboussekhra. Obesity-induced destabilization of p16INK4A promotes the procarcinogenic effects of breast stromal adipocytes through miR-141/miR-146b-5p-dependent inhibition of leptin [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 5937. doi:10.1158/1538-7445.AM2017-5937