bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B56: Breaching endosomal barriers for carried-mediated intracellular delivery of messenger RNA
Authors: Patel Siddhrath , Sahay Gaurav 
Published: March 2017

Abstract
RNA therapeutics represents a new class of modern medicine for targets considered undruggable. Lipid based nanoparticles (LNPs) based platforms remain the most advanced in clinical trials for RNA based drugs. Yet, the lack of mechanistic insights into the cellular trafficking and endosomal escape of nanoparticles has become a major hurdle for efficient intracellular delivery. We have 1) Dissected the productive sites for endosomal escape by utilizing an CRISPR/Cas9 based genetically altered cells targeted against endosomal proteins, that direct nanoparticles towards the early, recycling, late or lysosomal delivery. The disruption of key steps in endocytic trafficking revealed the active sites for endosomal escape 2) Identified novel compounds that improve escape from productive endocytic compartments. These molecules were selected based on their properties of influencing endo/lysosomal system that can trigger endosomal escape. Our investigation reveals that endo/lysosomal transport drives intracellular delivery of LNP delivered mRNA and we were able to pinpoint key stages of endosomal escape using genetically altered cells. Novel compounds that can improve cytosolic delivery of mRNA have been identified and are being further interrogated for their ability to breach endosomal barriers. Our goal is to unlock the mechanisms of carrier-mediated intracellular delivery, unravel productive sites of endosomal escape and identify compounds that enable intracellular mRNA delivery for the treatment of various devastating disorders including cancer.
Citation Format: Siddhrath Patel, Gaurav Sahay. Breaching endosomal barriers for carried-mediated intracellular delivery of messenger RNA. [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 B56.
Abstract PR09: Polymeric mechanical amplifiers of tumor apoptosis
Authors: Mitchell Michael John , Langer Robert 
Published: March 2017

Abstract
Regulation of receptor-mediated phenomenon at the nanoscale in a controlled manner remains a challenge for a broad range of fields, including cell biology, medicine, and bioengineering. Fluid forces play a crucial role in receptor-mediated signaling necessary for physiological function, while materials such as nanoparticles have demonstrated potential for spatiotemporal control of cellular signaling. Here, we have developed polymeric mechanical amplifiers that tether to the cell surface and increase receptor-mediated apoptosis in the presence of physiological fluid flow. The mechanical amplifiers consist of both non-degradable and biodegradable polymer nanoparticles that are tethered to the surface of tumor cells via polyethylene glycol (PEG) linkers. Tethered nanoparticles, in the presence of fluid shear forces observed in vivo, increased the therapeutic effect of a TNF superfamily death ligand (TRAIL) on colon and prostate tumor cells by as much as 50% compared to soluble TRAIL treatment alone, while exerting negligible toxic effects on normal cells. Increasing the number of nanoparticles conjugated to the tumor cell surface enhanced TRAIL-mediated apoptosis under fluid shear exposure, while the therapeutic effect under static conditions was not altered. Our results suggest that the enhanced therapeutic response using polymeric nanoparticles is both receptor-mediated apoptosis-specific and does not affect doxorubicin efficacy. Inhibition studies indicate the response is caspase signaling-dependent, and increased tumor cell death receptor expression in the presence of shear forces is also observed. We show that targeted polymeric nanoparticles delivered to tumor cells in vivo mechanically amplified a subsequent treatment of soluble TRAIL, and reduced both circulating tumor cells in blood and overall tumor cell burden in vivo by over 90%. We conclude that surface-bound polymeric nanoparticles enhance receptor-mediated apoptosis in the presence of physiological shear forces, and represents a potentially new application for a broad range of nanotechnologies to maximize the capacity of receptor-mediated signaling and function in the presence of a ligand.
This abstract is also being presented as Poster B35.
Citation Format: Michael John Mitchell, Robert Langer. Polymeric mechanical amplifiers of tumor apoptosis. [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 PR09.
Abstract BS2-2: PTEN loss by exosomal microRNA primes brain metastasis outgrowth
Authors: Yu D 
Published: March 2017

Abstract
Of 1.6 million newly diagnosed breast cancer patients per year, about 10-16% will develop brain metastases. Among the different subtypes of breast cancer, HER2-overexpressing (HER2+) and triple-negative breast cancers (TNBC) have the highest incidence of brain metastasis. Recently, advances in targeted therapies for breast cancer (e.g., trastuzumab, T-DM1, and lapatinib) have prolonged patient survival through better control of the systemic disease. However, when patients have disease recurrence, their brain metastasis incidence doubles, which represents an imposing challenge. Current treatment options are limited and merely palliative for those patients with brain-metastatic breast cancer, and their one year survival is less than 20%. To develop effective treatments for brain metastasis, we strived to gain global understanding of the mechanisms of brain metastasis to guide rapid development of novel and clinically applicable targeted therapies.
We recently found that the brain astrocytes secrete exosomes that contain PTEN-targeting miR-19a, among other biomolecules. After brain metastatic tumor cells uptake these astrocytes-derived exosomes, miR-19a reversibly downregulates PTEN expression in metastatic tumor cells, thereby increasing Akt and NF-kB signaling, leading to an increased secretion of CCL2 cytokine. CCL2 then recruits CCR2 positive and Iba1 positive myeloid cells that promote proliferation and inhibit apoptosis of brain metastatic tumor cells and facilitate metastatic tumor outgrowth to symptomatic brain metastasis. Importantly, inhibition of exosome secretion or stable ablation of CCL2 inhibits brain metastasis outgrowth in vivo, demonstrating the potential of exosome- and CCL2-targeting for therapeutic intervention of life-threatening brain metastases (Nature, 11/2015). Currently, we are exploring the clinical potential by systematic preclinical testing in animal models.
Citation Format: Yu D. PTEN loss by exosomal microRNA primes brain metastasis outgrowth [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 BS2-2.
Abstract CS1-1: The genomics of metastatic breast cancer: What are we learning?
Authors: Wagle N 
Published: March 2017

Abstract
Over the past decade, genomic characterization of tumors from cancer patients obtained through large-scale sequencing projects has shed enormous light on the molecular underpinnings of cancer. These discoveries have, in turn, led to the development of novel therapies and preventive measures that have already revolutionized cancer care. Despite this tremendous progress, our understanding of the genomics of metastatic breast cancer – and in particular cancers that have developed resistance to therapies – remains incomplete. In this presentation, we will discuss recent and ongoing studies that focus on the genomics of metastatic breast cancer, and how the learnings from these studies are influencing precision medicine strategies for patients with advanced breast cancer. We will focus on how genomic and molecular characterization of metastatic tumor samples from patients can shed light on the biology of metastatic breast cancer and can enable the development of strategies to overcome or prevent drug resistance. We will discuss the landscape of mutations in metastatic breast cancer, the potential clinical impact of genomic profiling, and the incorporation of genomic information into clinical care and clinical trials. We will also discuss how partnering directly with patients, in projects such as The Metastatic Breast Cancer Project (mbcproject.org), enables rapid identification of large numbers of patients willing to share tumors, saliva, and medical records to accelerate this research.
Citation Format: Wagle N. The genomics of metastatic breast cancer: What are we learning? [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 CS1-1.
Abstract ES4-2: Ex vivo and in vivo approaches to studying the immune tumor microenvironment
Authors: Lee PP 
Published: March 2017

Abstract
Tumors consist not only of cancer cells, but also stromal and immune cells that constitute the tumor microenvironment (TME). Clinical outcome and response to therapy depend on the complex interplay between these cell populations within the TME. Cancer drug development has traditionally relied on screening against cancer cell lines on plastic dishes before in vivo testing. It is increasingly clear that cancer cell lines in 2D do not fully reflect the biology of primary cancer cells within the complex 3D TME. In the new era of cancer immunotherapy, models also need to incorporate immune cells. In this educational session, we will discuss new ex vivo and in vivo approaches to studying the immune tumor microenvironment and response to therapy. These include patient-derived tumor organoids (PDO), patient-derived xenografts (PDX), and humanized mouse models to evaluate cancer immunotherapies.
Citation Format: Lee PP. Ex vivo and in vivo approaches to studying the immune tumor microenvironment [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 ES4-2.
Abstract ES9-2: ES9-2 Metastatic TNBC: New targets/new strategies
Authors: Moulder SL 
Published: March 2017

Abstract
Triple negative breast cancer (TNBC) is a diagnosis of exclusion as these tumors lack ER, PR and HER2. Through advances in molecular profiling, the heterogeneity of TNBC has been revealed as subsets with molecular features targetable with either investigational or existing FDA approved drugs. Basal-like TNBCs (BL1 and BL2) are associated with proliferative gene signatures. BL1 tumors demonstrate at higher rate of pCR to standard chemotherapy compared to other subtypes. The BL2 subset demonstrates gene ontologies involving growth factor signaling such as EGFR and IGF1R. Preclinical models demonstrate that basal-like TNBCs have high sensitivity to cisplatin and relative resistance to PI3K inhibitors in cell culture and xenografts. Germ line aberrations in BRCA1 and BRCA2 lead to a defect in DNA repair in cancers harboring such mutationsand these tumors appear to be more sensitive to therapy inducing DNA breaks, such as those induced by platinum based therapies or PARP inhibition. Approximately 30% of TNBCs display mesenchymal features and carry a high rate of molecular aberrations that activate the PI3K/Akt/mTOR axis with clinical data suggesting that this subgroup may be responsive to therapeutic regimens targeting this pathway. Approximately 10-15% of TNBCs are associated with expression of androgen receptor (AR+ or LAR) and are characterized by the expression of luminal genes and a high rate of PI3K activation/mutation. Response to AR and/or PI3K directed therapy has been demonstrated in preclinical models and AR inhibition has demonstrated response in early phase clinical trials. Lastly, though breast cancer is generally considered a non-immunogenic malignancy, some TNBCs have tumor infiltrating lymphocytes. Novel agents to enrich immune response have been associated with durable responses in a subset of patients with metastatic TNBC. In summary, molecular characterization has identified subsets of TNBC that show promising response to existing or emerging targeted agents.
Citation Format: Moulder SL. ES9-2 Metastatic TNBC: New targets/new strategies [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 ES9-2.
Abstract MS1-2: MS1-2 Breast cancer immunotherapy: Building on clinical success
Authors: Emens LA 
Published: March 2017

Abstract
Breast cancer has long been considered immunologically silent, but it is now clear that the immune system is active in this disease. Breast cancers can naturally induce tumor infiltrating lymphocytes (TIL), which represent a biomarker of the endogenous immune response. Increasing data support the association of TIL with a better prognosis for breast cancer patients, and also suggest that the presence of TIL can predict response to standard breast cancer therapies. These observations have stimulated intense interest in harnessing the natural breast cancer-specific immune response for therapeutic benefit. Breast cancer vaccines that activate the breast cancer-specific immune response have been tested for many years, with minimal clinical success to date. This is likely due to both inadequate vaccination platforms and dominant mechanisms of immune suppression active within the breast tumor microenvironment. In the tumor microenvironment, the immune checkpoint pathway governed by the programmed cell death-1 (PD-1) receptor and its ligand PD-L1 has emerged as a significant mechanism of immune resistance in a variety of cancers, including breast cancer. Several monoclonal antibody antagonists of PD-1 or PD-L1 unleash the activity of tumor-specific T cells in multiple types of cancer, resulting in durable clinical responses that translate into an overall survival benefit. Early data in breast cancer reveal that these agents have activity in some patients with triple negative and estrogen receptor-positive breast cancer, with response rates that range from about 5-44%. Antagonists of the PD-1 pathway are typically well-tolerated in breast cancer patients, with unique immune-related adverse events that are quite manageable. Selecting patients for PD-L1 expression appears to enrich for responders to single agent therapies that target PD-1/PD-L1. Based on early clinical data, agents that target the PD-1 pathway are under accelerated clinical development for breast cancer treatment. The challenge moving forward is converting immunotherapy non-responders to responders. Combination immunotherapies that integrate standard breast cancer therapies and/or multiple innovative immune-based therapies to simultaneously promote T cell activity and relieve multiple mechanisms of immune suppression at the tumor site have the greatest potential for enhancing the clinical activity of immunotherapy for breast cancer patients.
Citation Format: Emens LA. MS1-2 Breast cancer immunotherapy: Building on clinical success [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 MS1-2.
Abstract MS2-2: MS2-2 The latest breakthroughs on the translational aspects of DNA repair pathways
Authors: Powell SN 
Published: March 2017

Abstract
Genomic instability exists in the majority of human cancer, and there is an underlying DNA repair defect driving the instability in most cases. There are seven defined DNA repair pathways that, when inactive, can produce genome wide patterns of mutations. Current cancer genomics can provide a significant insight into the underlying DNA repair defect. This information can be used to select targeted therapies or suggest a more likely response to immune checkpoint blockade.
To use acquired homologous recombination (HR) deficiency as an example of this paradigm, we have found that large scale genomic rearrangements and segmental copy number changes are found in breast cancers without a known germline mutation and see a strong link to biallelic alterations in homologous recombination genes. We detected a genetic etiology of HR deficiency in 90% of studied HR-deficient cases, whereas HR-proficient tumors only showed biallelic HR gene mutations in &lt;7% of cases tested. The goal now is to develop genomic biomarkers that could be used to identify cancer patients who would benefit from therapy with PARP inhibitors and other novel agents, such as those identified by studies of synthetic lethality.
Synthetic lethality in human cancer is a developing area of new therapeutic discovery. HR deficiency is thought to be rescued by at least 3 different DNA repair pathways: base-excision repair, translesion synthesis and alternative end joining – all of which are active in proliferating cancer cells. In addition, even the canonical end-joining mechanism of Ku heterodimer binding to any double-stranded end is another component of handling DNA lesion intermediates. The reason for this variety of synthetic lethality has to be different critical DNA lesion intermediates. Knowledge of the DNA damage processing and the proteins involved in the rescue of lesions that would be repaired by HR can provide the basis for the identification of novel targets. I will review our progress in making RAD52 a potential target along with other initiatives for new drug discovery.
Citation Format: Powell SN. MS2-2 The latest breakthroughs on the translational aspects of DNA repair pathways [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 MS2-2.
Abstract OT1-04-03: Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS)
Authors: Lu Y-S , Tseng L-M , Yu J-C , Rau K-M , Chao T-Y , Chen S-C , Chiu C-F , Chang Y-C , Chen TW-W , Lin C-H , Chang D-Y , Chao T-C , Huang S-M , Huang C-S , Cheng A-L 
Published: March 2017

Abstract
Background For breast cancer (BC) patients with brain metastases (BM) who are not suitable for surgery/radiosurgery, whole brain radiotherapy (WBRT) remained the only standard treatment. Recently, we have demonstrated that bevacizumab preconditioning followed by etoposide and cisplatin (BEEP) is a highly effective treatment for BM of BC progressing from WBRT (Clin Cancer Res. 2015;21(8):1851). The CNS objective response rate is 77.1% according to volumetric criteria, and 60% according to RECIST 1.1. It has been demonstrated that enlarged brain tumor size is a predictor of WBRT failure. We hypothesized that, for BC with BM, induction BEEP treatment could decrease the size of brain metastases and thereby enhance effectiveness of WBRT. Methods This is a Phase II, randomized, open-labelled study (NCT02185352). Key inclusion criteria: BC with measurable brain metastatic tumor who had not received WBRT and not suitable for surgery or radiosurgery; KPS ≥30%. Key exclusion criteria: patients who had leptomeningeal metastases; history of disease progression during prior cisplatin treatment. In the experimental arm, patients will be treated by induction BEEP for three cycles followed by WBRT. In the control arm, patients will receive upfront WBRT for brain metastases. The BEEP regimen consist of bevacizumab (15 mg/kg) on Day 1 and, with a 1 day window period, followed by etoposide (70 mg/m2/day, Day 2 to Day 4) and cisplatin (70 mg/m2, Day 2), in a 21-day cycle. Stratification is based on the Graded Prognostic Assessment (GPA) score. Primary endpoint: brain-specific progression free survival (PFS) according to RECIST 1.1; key secondary endpoint: the 2-month brain-specific objective response rate (BS-ORR) of BEEP alone and WBRT alone. Other secondary endpoints include overall survival, extra-CNS tumor PFS, safety, time-to-improvement of neurological function,brain-specific PFS according to volumetric criteria, and BS-ORR. Approximately 126 patients will be 2:1 randomized. Multi-center recruitment is ongoing. To our knowledge this is the first randomized trial investigating a targeted therapy plus chemotherapy as induction regimen followed by WBRT as first line treatment for BC with BM.
Citation Format: Lu Y-S, Tseng L-M, Yu J-C, Rau K-M, Chao T-Y, Chen S-C, Chiu C-F, Chang Y-C, Chen TW-W, Lin C-H, Chang D-Y, Chao T-C, Huang S-M, Huang C-S, Cheng A-L. Randomized phase II study of induction bevacizumab, etoposide and cisplatin followed by whole brain radiotherapy (WBRT) versus WBRT alone in breast cancer with untreated brain metastases (A-PLUS) [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 OT1-04-03.
Abstract OT2-04-02: Comparison of axillary sentinel lymph node biopsy versus no axillary surgery in patients with early-stage invasive breast cancer and breast-conserving surgery: A randomized prospective surgical trial. The Intergroup-Sentinel-Mamma (INSEMA)-trial
Authors: Reimer T , von Minckwitz G , Loibl S , Hildebrandt G , Nekljudova V , Schneider-Schranz C , Gerber B 
Published: March 2017

Abstract
Background:
Currently, axillary surgery for breast cancer is considered as staging procedure that does not seem to influence breast cancer mortality, since the risk of developing metastasis depends mainly on the biological behaviour of the primary. Based on this, the postsurgical therapy should be considered on the basis of biologic tumor characteristics rather than nodal involvement.
Trial design:
The goal of INSEMA is to show that early-stage breast cancer patients with reduced extent of axillary surgery are not inferior regarding invasive disease-free survival (IDFS) outcome. Patients with planned breast-conserving surgery (BCS) will be first randomized (1:4 ratio) to either no axillary surgery or axillary sentinel lymph node biopsy (SLNB). Patients with SLNB and pN+(sn) status will be secondly randomized (1:1 ratio) to either SLNB alone or completion axillary lymph node dissection (ALND) in cases with less than three involved nodes (one or two macrometastases).
Primary objective:
-IDFS after BCS (non-inferiority question)
Inclusion criteria:
-Written informed consent
-Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy)
-Age at least 35 years
-Preoperative imaging techniques with estimated tumor size of maximal 5 cm (iT1/iT2 irrespective of hormone sensitivity or HER2 status)
-Clinically and sonographically tumor-free axilla prior to core biopsy
-In cases with cN0 and iN+, a negative core biopsy or fine needle aspiration biopsy of the suspected lymph node is required
-No clinical evidence for distant metastasis (M0)
-Planned breast-conserving surgery (R0 resection) with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation)
Statistics:
The calculated total case number for per-protocol analyses is 6,740 (5,940 German and 800 Austrian patients), the expected total number of randomized patients is 7,095.
Time lines:
-First patient in: September 2015
-Last patient in: August 2019
-Final analysis: End of 2024
Present accrural: In June 2016, more than 1.000 patients were recruited in Germany and Austria.
Citation Format: Reimer T, von Minckwitz G, Loibl S, Hildebrandt G, Nekljudova V, Schneider-Schranz C, Gerber B. Comparison of axillary sentinel lymph node biopsy versus no axillary surgery in patients with early-stage invasive breast cancer and breast-conserving surgery: A randomized prospective surgical trial. The Intergroup-Sentinel-Mamma (INSEMA)-trial [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 OT2-04-02.