bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR08: Mutant KRAS decouples glycolysis from cell mechanics in non-small cell lung cancer
Authors: Park Jin Suk , Sudderth Jessica , Gao Boning , Bachoo Robert , Danuser Gaudenz 
Published: March 2017

Abstract
Reprogramming of the cellular metabolism is an accepted hallmark of cancer. On the other hand, increasing evidence suggests the importance of the microenvironment, including its mechanical properties, in tumor development and metastasis. Whether cellular metabolism and cell mechanics are interdependent has been relatively unexplored, although recent works from several labs seem to suggest a direct link between microenvironment and metabolic state of cells. My project focuses on this mechano-metabolism in cancer. Using metabolic flux analysis, we show that the metabolism of untransformed human bronchial epithelial cells (HBECs) responds to the stiffness of the extracellular matrix. Relative to the cells on soft substrates, the cells on stiff substrates had elevated rates of glycolysis by 2.8-fold and of oxidative respiration by 1.2-fold. However, this mechano-sensitivity is lost in hTert/p53/myc/Kras-transformed lung epithelial cells, as well as non-small cell lung cancer (NSCLC) that harbors the KRAS mutations. Interestingly, these cells assume overall higher rates of glycolysis and oxidative respiration, independent of cell substrate stiffness. Thus far I have been able to identify that the mechano-desensitization is driven by the Kras mutations, which constitutively activate downstream signal cascades including the MAPK pathway. In addition, isotope tracing shows that mutant KRAS is required to generate citrate from glucose on soft substrates, and the absence of KRAS mutations significantly hinder glycolysis upon the treatment with blebbistatin. This study subsequently establishes the novel insight that the metabolic stabilization due to the mechano-insensitivity of cancer cells is driven by mutant KRAS, which may be advantageous when out-competing the surrounding cells over the course of tumorgenesis.
This abstract is also being presented as Poster A55.
Citation Format: Jin Suk Park, Jessica Sudderth, Boning Gao, Robert Bachoo, Gaudenz Danuser. Mutant KRAS decouples glycolysis from cell mechanics in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR08.
Abstract PR10: Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects
Authors: Metcalf Chester , Poll Derek van der , Zhao Liang , Halo Tiffany , Lazarus Doug , Stockmann Adam , Peters Christian , Brown Donna , Case Roy , Rohde Ellen , Jayaraman Lata , Wang Hongwei , Crowell Tiffany , Senderowicz Adrian , Eliasof Scott 
Published: March 2017

Abstract
Cerulean Pharma Inc.'s Dynamic Tumor Targeting™ Platform creates nanoparticle-drug conjugates (NDCs) designed to significantly mitigate a payload's limitations by providing sustained drug delivery to the tumor and superior therapeutic index through controlled release kinetics. By conjugating drug payloads to our novel β-cyclodextrin-PEG copolymer through linker strategies that allow modulation of release and pharmacokinetics (PK), we provide advantages over entrapped nanoparticle strategies, e.g., polymeric nanoparticles and liposomes. Cerulean has two NDCs in the clinic, CRLX101 and CRLX301, evidencing the translatability of our technology. CRLX101 has been dosed in over 350 patients and CRLX301 is in an ongoing Phase 1/2a trial. Our Dynamic Tumor Targeting Platform is applicable to a diverse range of drug payload possibilities, including small molecules with a host of physiochemical properties, i.e., hydrophobic and hydrophilic payloads, and functional groups with chemical handles for conjugation. To illustrate the capabilities of our platform we will present the biological impact of a series of cabazitaxel-containing NDCs with linkers encompassing a diversity of in vitro release rates. In vivo PK studies showed high and sustained levels of released drug in tumor tissues (&gt;168 hrs), and in vivo mouse tumor model studies demonstrated vastly improved efficacy, i.e., tumor regression and significant tumor growth delay, and survival over separately dosed cabazitaxel including efficacy in a taxane-resistant tumor model. Cerulean continues to expand its platform through the development of new and emerging capabilities to treat patients living with cancer. In this regard, we also will address the future evolution of NDCs, including the conjugation of multiple payloads to a single NDC and the development of antibody-conjugated NDCs.
This abstract is also being presented as Poster B43.
Citation Format: Chester Metcalf, III, Derek van der Poll, Liang Zhao, Tiffany Halo, Doug Lazarus, Adam Stockmann, Christian Peters, Donna Brown, Roy Case, Ellen Rohde, Lata Jayaraman, Hongwei Wang, Tiffany Crowell, Adrian Senderowicz, Scott Eliasof. Significant improvements in therapeutic index for conjugated payloads using a nanoparticle-drug conjugate (NDC) platform to provide sustained drug release and potentially improved anticancer effects. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr PR10.
Abstract BS1-1: Transcription factor stability and stem cell maintenance
Authors: Dixit VM 
Published: March 2017

Abstract
Proto-oncogenes ETV1, ETV4, and ETV5 belong to the PEA3 family of ETS transcription factors and have been identified recently in prostate cancer chromosomal rearrangements that result in their overexpression. Little is known, however, about their post-translational regulation. We previously showed that ETV1, ETV4, and ETV5 interact with the ubiquitin ligase COP1. COP1 together with its binding partner DET1 ubiquitinates ETV1, resulting in its proteasomal degradation. Importantly, truncation of ETV1 by the TMPRSS2:ETV1 translocation found in prostate cancer removes its COP1 binding motif and thereby enhances its stability. Consistent with a critical role for COP1 in regulating PEA3 transcription factors, COP1 deficiency in primary mouse prostate cells produced prostate intraepithelial neoplasia in vivo. The relationship between COP1 and ETV1 was also evident in human prostate cancer samples where loss of COP1 expression correlated with elevated ETV1 protein. I will discuss unpublished work that underscores the importance of COP1 as tumor suppressor.
References:
1. Wertz I, O'Rourke K, Zhang Z, Dornan D, Arnott D, Deshaies R, and Dixit VM (2004). Human De-Etiolated-1 Regulates c-Jun by Assembling a CUL4A Ubiquitin Ligase. Science 303: 1371-1374.
2. Vitari AC, Leong KG, Newton K,Yee C, O'Rourke K, Liu J, Phu L, Vij R, Ferrando R, Couto SS, Mohan S, Pandita A, Hongo J-A, Arnott D, Gao W-Q, French DM, and Dixit V (2011) COP1 is a Tumor Suppressor that Causes Deregulation of Proto-oncogenic ETS Transcription Factors. Nature 474: 403-408.
3. Suriben R, Kaihara KA, Reichelt M, Kummerfeld SK, Modrusan Z, Dugger DL, Newton K, Webster JD, Liu J, Hebrok M, Dixit VM (2015). β-cell insulin secretion requires the ubiquitin ligase COP1. Cell 163: 1457-1467.
Citation Format: Dixit VM. Transcription factor stability and stem cell maintenance [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BS1-1.
Abstract BS2-1: A role of extracellular miRNA in breast cancer metastasis
Authors: Wang SE 
Published: March 2017

Abstract
Extracellular microRNAs (miRNAs) that can be detected in the circulation are novel mediators of intercellular communication and are considered emerging biomarkers for human diseases. Using cell-secreted extracellular vesicles (e.g., exosomes) as vehicles, miRNAs secreted by cancer cells can travel to and enter various types of niche cells in primary and pre-metastatic tumor microenvironments. Upon entering niche cells, miRNAs regulate gene expression to prepare the niche for cancer progression. Our lab focuses on defining the roles of breast cancer secreted miRNAs in adapting local and distal niche cells and tissues in cancer progression and metastasis. Through de novo sequencing and PCR of circulating small RNAs in the pre-treatment sera of stage II-III breast cancer patients we identified circulating miRNAs as biomarkers for cancer progression to metastatic disease. Subsequent mechanistic studies revealed important functions of breast cancer secreted miRNAs in various aspects of cellular behaviours. Our lab is currently exploring additional mechanisms through which breast cancer-derived, extracellular miRNAs contribute to the multifaceted reprogramming of non-cancerous cells in the tumor microenvironment as well as novel therapeutic strategies targeting cancer-derived extracellular miRNAs for their function in cancer-host communication.
Citation Format: Wang SE. A role of extracellular miRNA in breast cancer metastasis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr BS2-1.
Abstract ES1-1: Non-cell-autonomous drivers of tumor growth and progression
Authors: Polyak K 
Published: March 2017

Abstract
Cancer cells even within the same tumor can display startling differences for many features including migratory/invasive potential and sensitivity to therapeutic agents. This intratumor heterogeneity is a major obstacle toward understanding and treatment of cancers. In solid tumors differences in the local microenvironment, in part due to variability in blood supply and topologic differences in the distribution of leukocytes, can lead to high degree of spatial heterogeneity and also select for cancer cells with different properties. While our ability to define intratumor clonal heterogeneity has grown immensely in the past few years due to technologic advances enabling whole genome sequencing studies even at the single cell level, our understanding of the functional relevance of this heterogeneity has been lagging behind. Similarly, our definition of cancer drivers has been based on the relative frequency of the cells within tumors and based on their cell-autonomous function, thus, by definition neglecting the potential relevance of minor clones and non-cell-autonomous (e.g., paracrine and juxtracrine) effects.
In experimental models there is increasing evidence for cooperation among cancer cell clones with different properties, but identifying and characterizing such interactions in clinical samples has been challenging. At the same time, emerging data suggest that intratumor clonal heterogeneity is maintained by non-cell-autonomous drivers and many of these never achieve clonal dominance due to lack of selective advantage. Thus, it is likely that non-cell-autonomous driver clones exist in human tumors and the effects of the microenvironment are mostly non-cell-autonomous as well. Because interactions among clones of cancer cells and between cancer cells and the tumor microenvironment have a major impact on overall therapeutic outcomes, understanding these interactions is necessary for the design of more effective treatment strategies for heterogeneous tumors.
Citation Format: Polyak K. Non-cell-autonomous drivers of tumor growth and progression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES1-1.
Abstract ES1-3: umor-stroma interactions in breast cancer progression
Authors: Isacke CM 
Published: March 2017

Abstract
The interaction of tumor cells with stroma cells and stromal components not only promotes tumor progression and metastasis, but also influences tumor cell responses to chemotherapy, endocrine therapy and targeted agents. As a consequence, there is an urgent need to identify strategies to efficiently target these interaction pathways for the prevention or suppression of metastatic disease and to overcome treatment-resistant tumor progression in advanced breast cancer.
This talk will focus on the tumor-stroma crosstalk pathways underpinning the striking heterogeneity between different breast cancers in their ability to recruit and activate a pro-tumorigenic stroma. In particular (a) the mechanisms involved in the activation of cancer-associated fibroblasts (CAFs), (b) the role of activated pericytes in promoting metastatic dissemination, and (c) the mechanisms by which a productive microenvironmental niche is initiated at metastatic sites.
Citation Format: Isacke CM. umor-stroma interactions in breast cancer progression [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES1-3.
Abstract ES3-2: Optimizing Her2- directed treatment in early stage disease
Authors: Tolaney S 
Published: March 2017

Abstract
Amplification of HER2 is present in approximately 18-20% of all breast cancer, and targeted anti-HER2 therapies have transformed our approach for this subtype of disease. Trastuzumab-based chemotherapy remains the standard therapy for these patients, however, there remain several questions in determining the optimal treatment regimen: (1) What is the role of anthracyclines? ; (2) What is the optimal preoperative regimen?; (3) How do we treat small, node-negative HER2+ breast cancers?; (4) Should all patients receive pertuzumab, and in what setting?; (5)Does Trastuzumab-DM1 have a role in the early stage setting? This educational session will review the available data to address each of these questions, and will provide recommendations for optimizing HER2- directed therapy in the early stage setting.
Citation Format: Tolaney S. Optimizing Her2- directed treatment in early stage disease [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES3-2.
Abstract ES6-3: ES6-3 Radiation implications post neoadjuvant therapy
Authors: Smith BD 
Published: March 2017

Abstract
Neoadjuvant therapy offers unique challenges and opportunities for the radiation oncologist. Classical indications for radiation have been rooted in the pathologic analysis of tissue resected prior to treating the patient with systemic therapy. However, in patients treated with neoadjuvant therapy, pathologic findings are frequently altered by the administration of systemic therapy, and thus classical indications for radiation may be clouded. Nevertheless, the degree of response to neoadjuvant therapy offers a novel prognostic factor which reflects intrinsic tumor biology and affords the opportunity for a new, precision approach to risk stratification and radiation therapy treatment decision making.
To maximally capitalize on the information gained from treating a patient with neoadjuvant chemotherapy, patients must be meticulously staged, preferably by a multidisciplinary team, prior to initiation of systemic therapy. Ultrasound of the regional nodal basins including the low axillary, infraclavicular, supraclavicular, and internal mammary nodal chains with ultrasound-guided fine needle aspiration of radiographically abnormal nodes enables detailed mapping of the local-regional disease extent. Cross-sectional imaging with CT and/or PET/CT is also helpful to permit customized radiation field design after systemic therapy and surgery. These imaging studies are invaluable to the radiation oncologist and allow for optimal field design to facilitate cure. Additionally, nodal surgery prior to administration of systemic therapy, while helpful in documenting pre-treatment nodal status, results in loss of ability to accurately assess response to chemotherapy in the lymph nodes and is thus avoided in our practice.
The available evidence indicates that patients experiencing a pathologic complete response have exceptional local-regional control. Accordingly, current randomized trials are exploring whether either radiation or surgery can be de-escalated within this context. In contrast, for patients with significant residual tumor burden following neoadjuvant chemotherapy, local-regional control outcomes are suboptimal for those with triple negative or HER2 positive disease. Novel strategies to escalate therapy with radiosensitizers or other biologic agents are needed for this population.
Citation Format: Smith BD. ES6-3 Radiation implications post neoadjuvant therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES6-3.
Abstract ES8-1: ES8-1 Managing the aftermath of estrogen deprivation in survivors
Authors: Partridge AH 
Published: March 2017

Abstract
Endocrine therapy is the most important systemic treatment for women with hormone receptor-positive breast cancer, resulting in substantial risk reduction and improvements in survival. Yet, the strategies to reduce or block estrogen including ovarian suppression or ablation, aromatase inhibition or tamoxifen can all lead to symptoms and long-term toxicities associated with estrogen deprivation. The effect of long-term estrogen deprivation on bone, heart and brain health may lead to substantial morbidity and should be considered when making treatment decisions and managed in follow-up. However, even less serious daily symptoms including hot flashes, mood changes, insomnia, weight gain, vaginal dryness and sexual dysfunction can lead to profound negative long term effects on a patient and her relationships. Thus even these more minor concerns should be considered and managed proactively for patient overall health and well-being. For serious co-morbidity risks, attention to optimizing risk factors and monitoring when appropriate (e.g., DEXA scan) is prudent. For symptom management, it is generally recommended that survivors forgo estrogen replacement therapy although sometimes a low dose, short course of replacement therapy is necessary. Otherwise, strategies include a multi-prong approach focusing not only on improving particular symptoms, but also on mitigating the downstream effects and emotional impact. Evidence-based strategies for management of vaginal dryness, hot flashes and other problems will be discussed
Citation Format: Partridge AH. ES8-1 Managing the aftermath of estrogen deprivation in survivors [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES8-1.
Abstract ES8-2: ES8-2 Energy balance: The new adjuvant therapy?
Authors: Irwin ML 
Published: March 2017

Abstract
Obesity affects the risk of breast cancer development and the risk of recurrence and death from breast cancer. Furthermore, weight gain after diagnosis of breast cancer (independent of BMI at diagnosis) is associated with higher all-cause mortality rates compared with maintaining body weight. The American Cancer Society (ACS) recommends cancer survivors achieve and maintain a healthy weight, follow a dietary pattern high in vegetables, fruits, and whole grains, engage in 150 minutes per week of aerobic exercise plus two strength training sessions per week, and avoid physical inactivity. Despite these recommendations, over 65% of breast cancer survivors are overweight or obese, and fewer than 30% engage in recommended levels of physical activity. Recently, the American Society of Clinical Oncology (ASCO) published a position statement on obesity and cancer with a multipronged initiative to reduce the impact of obesity on cancer, with one of the initiatives focused on determining best methods to help cancer survivors make effective changes in lifestyle behaviors. The impact of weight loss and exercise trials on breast cancer outcomes, as well as future research opportunities and the role of clinical and community-based weight management programs, will be discussed.
Citation Format: Irwin ML. ES8-2 Energy balance: The new adjuvant therapy? [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES8-2.
Abstract MS2-1: MS2-1 Targeting the ATR checkpoint in cancer therapy
Authors: Zou L 
Published: March 2017

Abstract
Rémi Buisson1, Michael S. Lawrence2, Cyril H. Benes1 & Lee Zou1,3
1. Massachusetts General Hospital Cancer Center & Harvard Medical School, Boston, MA. 2. Broad Institute of Harvard and MIT, Cambridge, MA. 3. Department of Pathology, Massachusetts General Hospital & Harvard Medical School, Boston, MA.
Recent cancer genomics studies have revealed that the mutation signatures of APOBEC3A/B are commonly detected in several cancer types, such as bladder, breast, head and neck cancers, lung adenocarcinoma, and lung squamous cell carcinoma. APOBEC3A/B are members of the APOBEC family of cytosine deaminases. While APOBEC3 proteins are important for the innate immunity against viral infection, they are not expressed in normal tissues. When APOBEC3A/B are aberrantly expressed in cancer cells, they become potent “mutators”, which may promote genomic instability and contribute to tumor evolution. Interestingly, recent studies have suggested that APOBEC3A/B may act during DNA replication. However, whether the APOBEC3A/B activity in cancer cells induces DNA replication stress, and whether this activity creates a vulnerability in cancer cells that can be exploited therapeutically, remains unknown.
In this study, we show that APOBEC3A imposes a unique type of mutator-driven DNA replication stress, and that the ATR kinase plays a crucial role in antagonizing this stress. APOBEC3A expression activates ATR during DNA replication through UNG2-generated abasic sites. Surprisingly, ATR inhibition in APOBEC3A-expressing cells results in a drastic surge of abasic sites at replication forks, revealing an ATR-mediated feedback loop countering the action of APOBEC3A during replication. Mechanistically, ATR inhibition unleashes APOBEC3A-driven ssDNA accumulation at replication forks, which propagates the substrate of APOBEC3A and ultimately drives cells into replication catastrophe. In a panel of cancer cell lines, ATR inhibitor selectively induces replication catastrophe in those harboring high APOBEC3A/B activity, showing that the APOBEC3A/B activity in cancer cells confers susceptibility to ATR inhibition. Together, these results suggest that the unique APOBEC-driven replication stress in cancer cells may offer a new opportunity for ATR-targeted therapy.
Citation Format: Zou L. MS2-1 Targeting the ATR checkpoint in cancer therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr MS2-1.