bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A36: Assessment of effectiveness and molecular markers of CDK4/6 inhibitor Palbociclib in Pancreatic Ductal Adenocarcinomas
Authors: Salvador Beatriz , López-Casas Pedro P. , Menéndez Camino , Baños Natalia , Sarno Francesca , Min-Jean Yin , Olson Peter , VanArsdale Todd , Shields David J. , Hidalgo Manuel 
Published: March 2017

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) continues to be the deadliest human cancer with a 5-year survival rate of 7%. One of the current standards of care for advanced PDAC is gemcitabine plus nab-paclitaxel, a regimen our group helped develop. Finding new agents to combine with this regimen remains necessary, particularly using drug targeting strategies. At the molecular level, genetic and genomic profiling identified CDKN2A as a very frequently disrupted gene in PDAC (&lt;90%). This gene encodes the tumor suppressor p16, a cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor, that controls cell cycle progression. Recently, the selective CDK4/6 inhibitor palbociclib was approved by the FDA for certain types of breast cancer patients. Whether palbociclib can also benefit patients with PDAC is unknown.
In the current study, we aimed to evaluate the effectiveness of palbociclib monotherapy and in combination with nab-paclitaxel and gemcitabine/nab-paclitaxel in a cohort of PDACs patient derived xenograft (PDX) models.
PDX models obtained from late stage PDAC patients were treated with palbociclib alone and in combination with gemcitabine/nab-paclitaxel. The majority of models displayed &gt;50% tumor growth inhibition (TGI) following treatment with single agent palbociclib. Treatment with palbociclib plus nab-paclitaxel or palbociclib plus gemcitabine/nab-paclitaxel increased TGI to a greater degree than the gemcitabine/nab-paclitaxel combination and also increased the duration of response as compared to the standard of care therapy.
Moving forward, the palbociclib/nab-paclitaxel combination will be evaluated in a clinical trial for PDAC patients. We are currently expanding our analyses to a larger cohort of PDX models and performing molecular characterization of these models in order to gain insights on biomarkers and mechanism of action of the drug combinations in PDAC.
Citation Format: Beatriz Salvador, Pedro P. López-Casas, Camino Menéndez, Natalia Baños, Francesca Sarno, Yin Min-Jean, Peter Olson, Todd VanArsdale, David J. Shields, Manuel Hidalgo. Assessment of effectiveness and molecular markers of CDK4/6 inhibitor Palbociclib in Pancreatic Ductal Adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A36.
Abstract B30: Establishment and maintenance of a PDX Core Facility
Authors: Mattar Marissa , Uthamanthil Rajesh K. , Stanchina Elisa de 
Published: March 2017

Abstract
Patient Derived Xenografts (PDX) are a powerful technology with the potential to unlock key mechanisms of disease for a variety of difficult to treat cancers and cancers with no applicable laboratory models. These models have a wealth of potential applications in tumor genetics, biomarker discovery, progression of metastasis, fate of circulating tumor cells, and in drug development of novel therapies for advanced and drug-resistant tumors. While several individual laboratories can excel at establishing such models, there are challenges, both procedural and technical, which present serious obstacles for established investigators as well as new investigators without prior experience with PDX models. Therefore, for some Institutions it is preferable to designate a centralized “PDX Core” to streamline the workflow that is required for the success of such program.
Here we describe and analyze the key components of a successful Academic PDX program. The PDX coordination branch carries out administrative duties to guarantee that the multiple components involved in generating PDXs are seamlessly integrated. In particular, it deals with logistical tasks including regulatory requirements (IRB, patient consent forms, IACUC), and sample accrual (patient selection, coordination with surgery schedules, specimen collection). In addition, it takes care of database maintenance and interface with clinical applications. The PDX laboratory branch meanwhile devises and implements standard operating procedures for sample processing, storage and implantation, and model maintenance, PDX characterization and distribution, and takes care of training of specialized personnel.
The establishment of such centralized PDX core at MSKCC resulted in a tenfold increase in the Institution's ability to generate PDX models within a year of inception of the program. In particular, for ongoing projects, we observed an increase not just in sample accrual but also in tumor take rate. In addition, the number of different tumor types implanted expanded substantially, from six to over twenty.
PDXs have the potential to be invaluable tools in understanding cancer and developing novel treatments. In our experience, the establishment of a centralized PDX core is both the most cost effective and efficient way for academic investigators to generate and gain access to novel, well characterized, and clinically annotated PDX models.
Citation Format: Marissa Mattar, Rajesh K. Uthamanthil, Elisa de Stanchina. Establishment and maintenance of a PDX Core Facility. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B30.
Abstract B45: Huntsman Cancer Institute Preclinical Research Resource (PRR) Core
Authors: Smith Brittni , Kavetska Oksana , Wang Guoying , Lum David Henry 
Published: March 2017

Abstract
Accumulating evidence from recent genomics data has reinforced the view that tumors can display exceptional heterogeneity between patients, between tumors from the same patient and even within a single tumor. These findings, together with decades of clinical experience with varied drug responses, strongly suggest that personalized approaches to assess cancer risk and treatment will be essential to reduce mortality.
New experimental models of human tumor initiation, progression, metastasis, and therapeutic response/resistance are critical to improve cancer treatments. Current models often fail to predict the efficacy of drugs in the clinical setting. This disconnect leads to disappointing clinical trial results that do not considerably improve patient survival, to failure of the FDA to approve new therapies, and to the loss of time and money. The ideal cancer model(s) would: 1) replicate the spectrum of tumor pathologies and subtypes, 2) reproduce genetic and epigenetic alterations found in human tumors, 3) grow in the correct developmental and anatomic context, 4) have an appropriate tumor microenvironment and an intact immune system, and 5) exhibit patterns of metastasis observed in patients.
Dr. Alana Welm (HCI) has established a collection of patient-derived orthotopic breast xenografts by implanting patient tumor tissue into mice. Significant evidence demonstrates that patient-derived xenografts (PDX) recapitulate the genomic and phenotypic features of their corresponding patient tumors, and that tumor graft growth and metastasis mirrors clinical outcome in the corresponding patients. We believe that PDXs may provide a remarkable opportunity to predict the best therapy regimens for individuals, a concept termed “personalized” or “precision” medicine.
The Preclinical Research Resource (PRR) Core will provide high-quality services for basic and translational cancer research, drug discovery and personalized cancer therapy.
The mission of the core will be to: generate the most current and sophisticated patient-derived in vivo cancer models; bridge the gap between basic scientists and clinicians to facilitate seamless bench-to-bedside research; and improve pre-clinical drug efficacy evaluation and examine personalized chemotherapy with patient-derived xenografts.
Citation Format: Brittni Smith, Oksana Kavetska, Guoying Wang, David Henry Lum{Authors}. Huntsman Cancer Institute Preclinical Research Resource (PRR) Core. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B45.
Abstract IA17: Application of PDX models to pancreas cancer research
Authors: Hidalgo Manuel 
Published: March 2017

Abstract
Pancreatic cancer remains one of the most deadly cancers. Very few therapeutics advanced have been achieved in this disease. Over the last few years, several studies have started to elucidate the molecular biology of PDAC including the genomic landscape of the disease, the importance of the stroma and the immunesuppressive environment characteristic of PDAC. One important development in translational research in PDAC is the availability of preclinical models of the disease. This includes genetically engineered mouse models of cancer, patient derived xenografts (aka Avatar models) and organoids. These models are becoming useful for drug screening, biomarker development and personalize medicine. Using Avatar models we identified Nab-paclitaxel as an effective agent in pancreas cancer in contrast to paclitaxel that does not result antitumor effects. We also showed that Nab-paclitaxel disrupts PDAC stroma, an observation, however, has not been confirmed by others. In addition, studies in mouse models revealed the lack of predictability of SPARC expression for clinical outcome. More recently, we have identified demcizumab and palbociclib as potentially effective agents in PDX models as the basis for their clinical development. PDX models have also de potential to be used as a platform for personalizes cancer treatment. In this regard, we are now conducting the AVATAR clinical trial in which patients with advanced cancer are randomized to receive either a conventional treatment or a treatment based on integrating genomic data with AVATAR mouse mode development.
Citation Format: Manuel Hidalgo. Application of PDX models to pancreas cancer research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA17.
Abstract IA21: Opportunities for integration of PDX models into clinical trials
Authors: Kopetz Scott 
Published: March 2017

Abstract
Patient-derived xenograft models (PDX) provide opportunities to evaluate efficacy, pharmacodynamics, response durability, and resistance mechanisms in greater details than traditionally possible with sampling of patient tumors. When PDX models are integrated with patients enrolled in clinical trials, or treated with novel agents, there are opportunities to interrogate aspects of cancer biology not traditionally evaluable, while maintaining clinical relevance. This presentation will explore the strengths and limitations of the models, with examples on how these models are being integrated into clinical trials, validation efforts, and novel insights derived from this approach.
The concept of a co-clinical trial has been variously defined, including a definition proposed by the NCI as parallel or sequential trials of combination therapy in patients and in mouse and human-in-mouse models of appropriate genotypes to represent the patients. This concept is being extended for PDX models to incorporate tumor models derived from the same patients participating in the clinical trial, both with a goal of improving translational interrogation of the novel agent efficacy as well as emerging efforts to use the PDX models to guide patient therapy.
Validation of the PDX models for treatment response/regression will be demonstrated, including recently completed clinical trials utilizing inhibitors of BRAF and MEK with a comparison of the response of the matched PDX models to radiographic measurements from the treated patients. Cohort based validation will be demonstrated through examples with EGFR targeted therapy and comparison to randomized clinical trial results. Limitations of these approaches will be described.
PDX models from clinical trials have been demonstrated to model and replicate mechanisms of resistance in some settings, and examples from colorectal and lung cancer will be used to demonstrate this. Resistance of lung cancer to EGFR tyrosine kinase inhibitors is being explored on PDXs obtained from post-progression biopsies. Tumor heterogeneity as a mechanism of resistance has been successfully modeled in BRAF-mutant colorectal cancer, and has been integrated into prospective clinical trials.
Finally, efforts to integrate PDX models as predictors of treatment response are described. These include efforts to use matched PDX models to guide treatment decisions in patients as part of prospective clinical trials. Regulatory, logistic, and biologic limitations of such efforts will be discussed.
Citation Format: Scott Kopetz. Opportunities for integration of PDX models into clinical trials. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA21.
Abstract IA26: Conditionally Reprogrammed Cells (CRCs): A simple, two-component cell system for basic and clinical cancer research
Authors: Schlegel Richard 
Published: March 2017

Abstract
Conditional reprogramming (CR) is a new cell biology technique that allows for the rapid and efficient outgrowth of matched normal and tumor epithelial tissue from patient samples. This approach combines the use of a ROCK inhibitor and irradiated feeder cells to induce and select for stem-like cells from adult tissues. While normal CR cells can be maintained for prolonged periods in vitro (in most cases they are conditionally immortalized), they retain their potential to differentiate normally when returned to an appropriate in vivo or in vitro environmental niche. Tumor cells can also be readily established in culture, although they can exhibit reduced dependence upon feeder cells and ROCK inhibitor for continued proliferation. The high efficiency of this system makes it feasible to establish cell cultures from rare tumor specimens. Minor modifications of the CR method also allow for the outgrowth of neuroendocrine and mesenchyme-like cells, possibly including cells that have undergone epithelial/mesenchymal transition. Biobanking using the CR method is now standardly applied in our pathology department in order to generate a renewable resource of patient samples for scientific investigation. The greatest challenge for routine application of this method is the selection of tumor cells from surgical biopsy specimens. Since both normal and tumor cells proliferate under these conditions, it is critical to evaluate the histologic composition of the biopsies and to validate the outgrowth of tumor cells using molecular biomarkers. Modified growth conditions are being developed to facilitate the selective outgrowth of tumor cells from mixed normal/tumor samples. This cell culture system has been used to identify new therapies for rare tumors (1) and characterize patient biopsies (2), and is now being applied broadly in new NCI initiatives for second-generation cancer cell models.
1. N Engl J Med 367:1220, 2012
2. Science 346:1480, 2014
Citation Format: Richard Schlegel. Conditionally Reprogrammed Cells (CRCs): A simple, two-component cell system for basic and clinical cancer research. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr IA26.
Abstract PR02: Humanized mouse melanoma model using patient-derived xenografts
Authors: Krepler Clemens , Perego Michela , Kalabis Mizuho , Beqiri Marilda , Hristova Denitsa , Xiao Min , Petrelli Nicholas J. , Somasundaram Rajasekharan , Herlyn Meenhard 
Published: March 2017

Abstract
Melanoma patients develop resistance to both chemo- and targeted-therapy drugs. Promising pre-clinical and clinical results with immune checkpoint inhibitors using antibodies directed against CTLA4 and PD1 have re-energized the field of immune-based therapies in melanoma. However, similar to chemo- or targeted-therapies only subsets of melanoma patients respond to immune checkpoint blockade. Currently available immunodeficient mouse xenograft and transgenic mouse melanoma models have a number of short comings and are unable to address the basis of drug resistance and immune non-responsiveness frequently observed in melanoma patients treated either with chemo- and targeted-therapy drugs or immune checkpoint inhibitors. Thus there is an urgent need to establish a mouse model with an immune microenvironment that can address the above issues encountered in melanoma patients. For this, our laboratory has developed a humanized mouse melanoma model using patient-derived xenograft (PDX). Immunodeficient (NOD/Shi-SCID/IL-2Rgnull [NOG; Taconic]/ NOD.Cg-Prkdcscid IL2rgtm1Wjl/SzJ [NSG; Jackson Laboratory]) mice were reconstituted with human CD34+ cells and after 12 weeks, mature human CD45+ cells are observed in mouse peripheral blood and in the lymphoid organs. Humanized mice with optimum number of mature human CD45+ cells in peripheral blood were challenged with HLA-matched melanoma PDX and the immune response to melanoma associated antigens were monitored. Lymphoid cells derived from humanized mice that are challenged with human leukocyte antigen (HLA) matched melanoma cells in vivo showed enhanced cytokine expression to in vitro stimulation with peptides derived from melanoma antigens. In addition, cytotoxic T-cells were able to functionally lyse tumor cells in vitro, infiltrate and restrict in vivo tumor growth. We are currently refining our model to establish an autologous mouse melanoma model. Our innovative humanized mouse melanoma model will enable one to understand the causes of therapy resistance and immune non-responsiveness in patients.
This abstract is also being presented as Poster B33.
Citation Format: Clemens Krepler, Michela Perego, Mizuho Kalabis, Marilda Beqiri, Denitsa Hristova, Min Xiao, Nicholas J. Petrelli, Rajasekharan Somasundaram, Meenhard Herlyn. Humanized mouse melanoma model using patient-derived xenografts. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr PR02.
Comprehensive Meta-analysis of Key Immune-Related Adverse Events from CTLA-4 and PD-1/PD-L1 Inhibitors in Cancer Patients
Authors: De Velasco Guillermo , Je Youjin , Bossé Dominick , Awad Mark M. , Ott Patrick A. , Moreira Raphael B. , Schutz Fabio , Bellmunt Joaquim , Sonpavde Guru P. , Hodi F. Stephen , Choueiri Toni K. 
Published: March 2017

Abstract
Immune-related adverse events (irAE) have been described with immune checkpoint inhibitors (ICI), but the incidence and relative risk (RR) of irAEs associated with these drugs remains unclear. We selected five key irAEs from treatments with approved cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed death ligand 1 (PD-L1) inhibitors (ipilimumab, nivolumab, or pembrolizumab, and atezolizumab, respectively) to better characterize their safety profile. We performed a meta-analysis of randomized phase II/III immunotherapy trials, with non-ICI control arms, conducted between 1996 and 2016. We calculated the incidence and RR of selected all-grade and high-grade gastrointestinal, liver, skin, endocrine, and pulmonary irAEs across the trials using random-effect models. Twenty-one trials were included, totaling 11,454 patients, of whom 6,528 received an ICI (nivolumab, 1,534; pembrolizumab, 1,522; atezolizumab, 751; and ipilimumab, 2,721) and 4,926 had not. Compared with non-ICI arms, ICIs were associated with more all-grade colitis (RR 7.66, P &lt; 0.001), aspartate aminotransferase (AST) elevation (RR 1.80; P = 0.020), rash (RR 2.50; P = 0.001), hypothyroidism (RR 6.81; P &lt; 0.001), and pneumonitis (RR 4.14; P = 0.012). Rates of high-grade colitis (RR 5.85; P &lt; 0.001) and AST elevation (RR 2.79; P = 0.014) were higher in the ICI arms. Ipilimumab was associated with a higher risk of all-grade rash (P = 0.006) and high-grade colitis (P = 0.021) compared with PD-1/PD-L1 ICIs. Incidence of fatal irAE was &lt; 1%. This meta-analysis offers substantial evidence that ICIs are associated with a small but significant increase in risk of selected all-grade irAEs and high-grade gastrointestinal and liver toxicities. Although fatal irAEs remain rare, AEs should be recognized promptly as early interventions may alleviate future complications. Cancer Immunol Res; 5(4); 312–8. ©2017 AACR.
Abstract A03: A role for Macrophage Migration Inhibitory Factor (MIF) in breast cancer growth and metastasis
Authors: Balogh Kristen N. , Cross Janet V. 
Published: March 2017

Abstract
The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that has been well-characterized as a mediator of numerous inflammatory disease processes. We have previously demonstrated that expression of MIF in the primary tumor promotes growth and metastasis in the 4T1 murine model of breast cancer. MIF is overexpressed in many cancer types, including breast cancer, and the degree of MIF expression correlates with tumor aggressiveness. We therefore sought to understand the link between primary tumor expression of MIF and increased tumor growth and metastasis. As a cytokine, we hypothesized that MIF would function by controlling some aspect of the interaction between tumor and host immune system. This was supported by our observation that MIF expression was no longer required for growth and metastasis in an immunodeficient SCID/bg host. Using flow cytometry, we discovered that MIF expression in the primary tumor decreased the abundance of intra-tumoral CD8+ T cells, as well as inhibited those cells' ability to produce the cytokine IFNgamma. We also found that depletion of T cells from MIF KD tumor bearing mice restored tumor growth to the level of WT tumors, while this depletion had no effect on the growth of WT tumors. This suggests that T cells are playing an important role in the control of tumor growth seen in MIF KD tumors. Previous work in the lab has also shown that MIF expression in the primary tumor increased the abundance of an immunosuppressive cell subset known as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We hypothesize that this population of cells is responsible for the reduced T cell infiltration and activity seen MIF-expressing tumors, and we aim to determine the mechanisms by which MIF promotes MDSC accumulation and/or function, and how the MDSCs are inhibiting T cell activity in the tumor.
Citation Format: Kristen N. Balogh, Janet V. Cross. A role for Macrophage Migration Inhibitory Factor (MIF) in breast cancer growth and metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A03.