bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract C60: Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of pancreatic cancer
Authors: Wasko Urszula N. , Sastra Stephen A. , Palermo Carmine F. , Olive Kenneth P.
Published: March 2020

Activating mutations of Kras are the main genetic drivers of pancreatic ductal adenocarcinoma (PDA) and are essential for its initiation and maintenance. It was recently shown that suppression of the Kras effectors Raf/Mek/Erk in the context of Kras-mutant pancreatic tumors leads to the increase of autophagic flux, suggesting that this inhibition may be enhancing PDA dependence on autophagy. Autophagy, a lysosome-mediated process, allows cells to degrade organelles and macromolecules and recycle the intermediates to sustain cell metabolism, critical for tumor growth. This discovery, made recently by two independent research teams, led to the development of a two-drug regimen that blocks MEK/ERK and autophagy pathways and produces consistent synergistic responses in cell lines, in several transplantation models, and in a human PDA patient. Here we present results from an intervention study performed in the K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cre (KPC) mice, a highly chemoresistant genetically engineered model of PDA. We found that a two-drug regimen of trametinib (MEK inhibitor) and hydroxychloroquine (autophagy inhibitor) induced frank regressions in all six animals treated to date—an unmatched response in this model. Tumor regressions ranging from 30% to 95% following treatment were sizable, as measured by longitudinal 3D high-resolution ultrasound, and these mice survived significantly longer than historical controls treated with saline under identical conditions. IHC performed on tumor tissues from treated mice showed decreased proliferation and increased apoptosis relative to untreated KPC pancreatic tumors. Some tumors exhibited substantially reduced phospho-ERK expression by IHC. Interestingly, some tumors that underwent large regressions exhibited positive staining for phospho-ERK in the residue tumor tissues, suggesting a mechanism of resistance through the reactivation of this downstream effector. Studies focused on mechanisms of acquired resistance are ongoing.

Citation Format: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, Kenneth P. Olive. Combination of MEK and autophagy inhibition promotes tumor regression in the KPC mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C60.
Abstract I01: Mechanisms and consequences of pancreatic cancer stromal evolution
Authors: Sherman Mara
Published: March 2020

The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. Pancreatic ductal adenocarcinoma (PDAC) is the archetype of a fibroinflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type driving the stromal reaction in PDAC. Recent reports suggest that PDAC CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types that support and others that suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas that can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of CAFs in the PDAC microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. We have taken advantage of a novel mouse model we developed to track PSC differentiation and function during pancreatic tumor progression in vivo. This model leverages the unique lipid-storing origin of PSC-derived CAFs, and enables their distinction from CAFs of non-PSC origin for the first time. We hypothesized that PSC-derived fibroblasts in the PDAC microenvironment are a proinflammatory and tumor-supportive subset of PDAC CAFs, and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct populations are entirely unknown. Our data also highlight a potential role for genetic alterations in the epithelial compartment in orchestration of stromal fibroblast evolution. Using our model, we have interrogated PDAC stromal heterogeneity and functional significance, analyzed the distinguishing features of CAF subpopulations from disparate origins, and determined the significance of genetic alterations in the epithelial compartment on stromal cell fate and function. Together, these studies have the potential to lay the foundation for development of stroma-targeted therapies based on careful lineage tracing and molecular data. These findings shed light on mechanisms of stromal evolution during pancreatic tumorigenesis, and potentially identify distinct CAF populations of relevance in additional solid tumors.

Citation Format: Mara Sherman. Mechanisms and consequences of pancreatic cancer stromal evolution [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I01.
Abstract I02: Targeting Innate immunity in pancreatic carcinoma
Authors: Miller George
Published: March 2020

Pancreatic carcinoma has proven largely resistant to immunotherapies as strategies directly targeting T cells or their receptors have failed in early clinical trials. Basic research has shown that effector T-cell infiltration and phenotype in pancreatic cancer is controlled by diverse innate immune elements including dendritic cells, macrophages and other myeloid cells, and subsets of innate-like T cells. However, the phenotype of macrophages and myeloid cells infiltrating pancreatic carcinoma is, for the most part, highly suppressive of effective adaptive antitumor immunity. Therefore, rather than directly targeting T cells in isolation, immunotherapeutic strategies addressing toleorogenic innate immune cell populations hold greater promise. New potential avenues for immunotherapy include activating or blockade of select innate immune receptors on tumor-associated macrophages to reprogram their suppressive phenotype, targeting the microbiome to modulate the intratumoral inflammatory environment toward a more favorable phenotype, or deleting select subsets of tolerogenic T cells such as delta1 cells. These type of approaches have the potential to enable efficacy for more traditional immunotherapies that target checkpoint or costimulatory receptors, and these strategies can also potentiate the effects of systemic chemotherapy or radiation therapy.

Citation Format: George Miller. Targeting Innate immunity in pancreatic carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I02.
Abstract I04: Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis
Authors: Zhang Yaqing , Lazarus Jenny , Steele Nina , Lee Ho-Joon , Yan Wei , Halbrook Cristopher J. , Menjivar Rosa , Kemp Samantha B. , Sirihoracai Veerin , Carpenter Eileen S. , Nevison Anna C. , Vinta Alekya , Anderson Michelle A. , Crawford Howard C. , Lyssiotis Costas A. , Frankel Timothy L. , Bednar Filip , Magliano Marina Pasca di
Published: March 2020

In human patients and in mouse models, immunosuppressive regulatory T cells (Tregs) accumulate in pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Using a genetically engineered mouse model of pancreatic cancer, we determined that—unlike in other malignancies—Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumor progression. We show that Tregs are a key source of TGFb ligands both in human samples and in mouse models. Accordingly, their depletion reprograms the fibroblast population, exemplified by loss of smooth muscle actin expression and an increase in the myeloid-recruiting chemokines Ccl3, Ccl6, and Ccl8. Our findings point to a dual role of Tregs in pancreatic cancer, with their immune-suppressive function being balanced by their induction of a SMA-high (tumor-restraining) fibroblast phenotype. Further, our data point to a compensatory immunosuppression mechanism that confers resistance to Treg depletion in pancreatic cancer. Finally, blockade of the common CCL3/6/8 receptor CCR1 combined with Treg-depletion successfully inhibited tumorigenesis, a finding with potential therapeutic implications.

Citation Format: Yaqing Zhang, Jenny Lazarus, Nina Steele, Ho-Joon Lee, Wei Yan, Cristopher J. Halbrook, Rosa Menjivar, Samantha B. Kemp, Veerin Sirihoracai, Eileen S. Carpenter, Anna C. Nevison, Alekya Vinta, Michelle A. Anderson, Howard C. Crawford, Costas A. Lyssiotis, Timothy L. Frankel, Filip Bednar, Marina Pasca di Magliano. Regulatory T-cell depletion causes compensatory immune suppression and accelerates pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I04.
Abstract I05: Heterocellular interactions in the tumor microenvironment
Authors: Jorgensen Claus
Published: March 2020

Pancreatic ductal adenocarcinoma (PDA) is characterized by a heterocellular microenvironment, exhibiting tumor-promoting as well as tumor-restrictive effects. Tumor cells coerce host cells, such as fibroblasts and myeloid cells, to remodel the stroma, which results in altered stiffness, cell-cell signaling, and modified tumor cell function. The rules governing tumor-stromal interactions are currently not clearly defined. To demark and characterize the cellular components of the tumor microenvironment we devised protein-based marker panels for single-cell analysis by cytometry by time of flight (CyTOF), specifically aimed at defining populations of cancer-associated fibroblast (CAFs). Importantly, we employed cell surface markers, enabling isolation and functional characterization of identified stromal populations. Using these panels, we interrogated tumors from the pdx1-cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ (KPC) genetic engineered model of pancreatic cancer. We observe previously defined CAF populations expressing markers for myofibroblastic CAFs (myCAF); inflammatory CAFs (iCAF) and antigen presenting CAFs (apCAF). In addition to these CAF populations, we observe that differential expression of the auxiliary receptor for the TGFβ receptor complex, endoglin (CD105), demarks two distinct fibroblast populations that are present in murine and human PDA. In addition, we observe CD105-positive (CD105+) and -negative (CD105-) fibroblasts in normal healthy pancreas, liver, and lung, indicating that the presence of these CAFs in tumors is likely due to local expansion. Isolated fibroblasts preserve differential expression of CD105+ and CD105- throughout extended in vitro culture, co-culture, and treatment with regulators of fibroblast function, indicating that CD105 may act as a bona fide lineage marker. We find that while both CD105+/- lineages are able to adapt a general myCAF or iCAF polarization, they show distinct regulation of specific genes. Using a syngeneic subcutaneous co-transplant model, we demonstrate that CD105+ fibroblasts are tumor-promoting, while CD105- fibroblasts are highly tumor-restrictive. Interestingly, both mechanisms are mediated by differential regulation of CD8 T cell-dependent adaptive immunity. Together these data define two novel, functionally distinct fibroblast populations in PDA with pro- or antitumorigenic effects.

Citation Format: Claus Jorgensen. Heterocellular interactions in the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I05.
Abstract I06: Clonal evolution and progression of pancreatic cancer precursor lesions
Authors: Wood Laura D.
Published: March 2020

Pancreatic cancer arises from noninvasive precursor lesions that are curable if detected and treated early enough. These precursor lesions include microscopic pancreatic intraepithelial neoplasia (PanIN) and cystic intraductal papillary mucinous neoplasm (IPMN). Interrogation of these lesions can provide critical insights into the earliest stages of pancreatic tumorigenesis and provide a rational foundation for early detection approaches. We have performed comprehensive genomic analyses of PanINs, IPMNs, and associated invasive carcinomas, highlighting several unique features of initiation and progression of pancreatic neoplasms. We show that early-stage precursor lesions contain multiple independent clones, each with distinct mutations, indicating their polyclonal origin. In addition, we identify convergent evolution of tumor suppressor gene loss at later stages of tumorigenesis, as well as subclonal complexity of driver gene mutations and mutations in specific genes limited to invasive cancers. Taken together, these data challenge the traditional monoclonal origin of pancreatic tumors, highlight distinct evolutionary features of precancerous lesions, and transform our understanding of the clonal evolution of pancreatic neoplasia.

Citation Format: Laura D. Wood. Clonal evolution and progression of pancreatic cancer precursor lesions [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I06.
Abstract I10: Immune cell signaling in human and mouse pancreas cancer
Authors: Habtezion Aida
Published: March 2020

Acute pancreatitis (AP) is the most common gastrointestinal disorder leading to hospital admission in the United States. Patients who present with recurrent acute pancreatitis are at a very high risk of developing chronic pancreatitis (CP). Patients with CP experience intractable, difficult to treat abdominal pain and the disease is associated with pancreatic acinar cell loss and fibrosis, and can result in exocrine and endocrine insufficiency. CP is also a risk factor for developing pancreatic ductal adenocarcinoma (PDAC). In AP, initial injury signals likely start at the acinar cell level, where injured acinii produce proinflammatory cytokines and chemokines leading to the recruitment of inflammatory leukocytes into the pancreas. One of the initially recruited leukocytes includes neutrophils, which play pathogenic role locally within the pancreas and in distant organs such as the lung. Soon after, inflammatory monocytes follow into the pancreas and differentiate into macrophages with pro-inflammatory properties and exacerbate the pancreatic injury. Earlier and recent studies show that T cells and macrophages are the predominant immune cell infiltrates in CP. Macrophages in CP are found in close proximity to key pro-fibrogenic pancreatic stellate cells. Experimental studies suggest an interaction between the stellate cells and macrophages to promote fibrosis in CP. In contrast to AP, macrophages in CP display alternate activation consistent with immunosuppressive environment associated with CP. Immune cells also play a critical and differential role of anti- and pro-tumor functions in PDAC. For example, immune signals such as IL-22/IL-22R axis are involved in AP, CP, and PDAC but play differential role between the diseases. To get insight into the inflammatory processes involved, we use multiplex based assays to profile immune cells isolated from the pancreas as well as in situ to determine functional and geographic localization.

Citation Format: Aida Habtezion. Immune cell signaling in human and mouse pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I10.
Abstract I13: Modulating the immune response with epigenetic agents
Authors: Azad Nilofer S.
Published: March 2020

Epigenetic modulation offers the potential of altering key tumor-immune interactions to allow for more effective therapeutic targeting. Epigenetic abnormalities in cancer in the tumor-immune response will be discussed, as well as data that support the reversibility of these lesions with epigenetic modulators. Preclinical and emerging clinical data in solid tumors will be surveyed, with an eye towards how these data support the rationale of epigenetic-immunotherapy combinations in pancreatic cancer.

Citation Format: Nilofer S. Azad. Modulating the immune response with epigenetic agents [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I13.
Abstract I15: Deciphering the origins of PDAC development
Authors: Flowers Brittany , Xu Hang , Hanson Kathryn , Curtis Christina , Vogel Hannes , Wood Laura D. , Attardi Laura D.
Published: March 2020

The TP53 gene, encoding the p53 transcription factor, is mutated in the majority of human pancreatic cancers, underscoring its critical role as a barrier to PDAC development. Despite this essential function, however, the cellular and molecular pathways through which p53 acts in pancreatic cancer suppression have remained elusive. To gain a better understanding of the programs through which p53 suppresses PDAC development, which will provide key insight into how the disease develops, we have taken combined mouse genetic and genomic approaches. First, we have sought to understand whether p53 acts in acinar and/or ductal cells to restrain PDAC development. For these studies we have used adult mice to more accurately mimic the development of PDAC in humans. Second, we have sought to systematically deconstruct the role of p53 loss-of-function and gain-of-function mutations in driving cancer from these different cells of origin. In addition, we have characterized the trajectory of cancer development in these models through histologic analysis of lesions at different time points and through lineage tracing. This comprehensive analysis of large adult mouse cohorts has helped to define the role for p53 in restraining spontaneous PDAC development, an essential first step for understanding p53 programs involved in tumor suppression. To gain insight into the programs that become dysregulated during pancreatic cancer development, we have performed transcriptomic analysis on tumors arising from different compartments and driven by different genetic lesions. These studies have revealed the molecular profiles of tumors arising from acinar versus ductal cells as well those driven by different types of p53 mutations. Through comparison to human pancreatic cancer data, our studies will reveal the paths to PDAC development in humans and the underlying origins of different subtypes of this disease.

Citation Format: Brittany Flowers, Hang Xu, Kathryn Hanson, Christina Curtis, Hannes Vogel, Laura D. Wood, Laura D. Attardi. Deciphering the origins of PDAC development [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I15.
Abstract I17: Genomic loss of the wild-type KRAS allele in pancreatic tumor progression and metastasis
Authors: Yan Han , Yu Chih-Chieh , Fine Stuart , Lee Ayman , Yang Ye-Ran , Yan Juan , Garcia-Carracedo Dario , Karg Dillon , Cheung Edwin , Friedman Richard , Chen Emily , Luo Ji , Miao Yi , Qiu Wanglong , Su Gloria
Published: March 2020

KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). Intriguingly, human tumors with RAS mutations often display loss of the remaining wild-type (WT) allele, including PDAC. We previously reported that selective loss of WT Kras allele is associated with PDAC progression to metastasis in both mice and humans. These data suggest that WT KRAS functions as a tumor suppressor in the context of mutant KRAS and loss of WT KRAS offers growth advantage in clonal evolution and tumor progression to metastasis. To investigate the underlying mechanism, we have examined the impact of inducible WT KRAS expression on human PDAC cell lines that had spontaneously lost the WT allele. We observed re-expression of WT KRAS significantly attenuated the malignancy of pancreatic cancer cells in vitro and in vivo. RNA-Seq and proteomic analyses identified HIPPO signaling, specifically YAP1 activation, is inhibited by WT KRAS restoration. We observed a marked reduction of YAP1 nuclear localization and a consequent inhibition of YAP1 transcriptional activity upon restoration of WT KRAS. Expression of constitutively activated YAP1 mitigated the growth-inhibitory effects of WT KRAS, confirming that YAP1 is a downstream effector of the pathway. Furthermore, YAP1 nuclear localization was found to be associated with poor prognosis in PDAC patients. Together, these results offer a novel mechanism that WT KRAS suppresses tumor metastasis via inhibition of YAP1 activation and further demonstrate that genomic loss of the WT KRAS allele is not a mere consequence of genomic instability but rather a selective event that promotes pancreatic tumor progression to metastasis.

Citation Format: Han Yan, Chih-Chieh Yu, Stuart Fine, Ayman Lee, Ye-Ran Yang, Juan Yan, Dario Garcia-Carracedo, Dillon Karg, Edwin Cheung, Richard Friedman, Emily Chen, Ji Luo, Yi Miao, Wanglong Qiu, Gloria Su. Genomic loss of the wild-type KRAS allele in pancreatic tumor progression and metastasis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I17.
Abstract I21: Understanding metabolic limitations in pancreatic cancer
Authors: Heiden Matthew G. Vander
Published: March 2020

Complex regulatory mechanisms enable cell metabolism to match physiologic state. The major pathways cells use to turn nutrients into energy and to synthesize macromolecules have been elucidated; however, there remain many unanswered questions regarding how metabolism supports cancer cell proliferation and thus how best to target metabolism for pancreatic cancer treatment. Of note, some therapies for pancreas cancer target metabolic processes that are thought to be essential in all cells. This raises a key question of how drugs that target otherwise essential processes like nucleotide metabolism show differential effectiveness to treat cancers. We have characterized the factors that drive sensitivity to disruption of specific metabolic processes, including nucleotide metabolism, and find that both cancer cell extrinsic and intrinsic factors dictate metabolic vulnerabilities. Further, this leads to different cells being more reliant on limiting nutrients for different metabolic processes, creating a framework to understand how specific cancer cells becomes sensitive to agents that target otherwise essential pathways.

Citation Format: Matthew G. Vander Heiden. Understanding metabolic limitations in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I21.
Abstract I26: Investigating the immune microenvironment in mouse models of pancreatic cancer
Authors: Pickering Karen , Lapienyte Laura , Karim Saadia , Strathdee Douglas , Sansom Owen , Morton Jen
Published: March 2020

Pancreatic cancer is predicted to become the second most common cause of cancer death in the Western world by ~2025. The focus of our research has been to better understand the disease and identify more effective and targeted therapies, in particular, using genetically engineered mouse models, which develop pancreatic tumors reminiscent of the human disease including development of a complex microenvironment. The pancreatic cancer microenvironment is characterized by significant infiltration of immune cells, but a distinct lack of T cells. Thus, immunotherapies have had little efficacy in PC despite promise in other cancers. Recent data have suggested that genomic instability and increased mutation burden may predict the efficacy of immune checkpoint inhibitors. To investigate this, we have generated a model of APOBEC mutagenesis in pancreatic cancer. The APOBEC family of cytidine deaminase enzymes, whose normal function is to protect from viral infections, have been revealed as drivers of mutation in a variety of human tumors, including pancreatic cancer. We have engineered mice to express Cre-inducible APOBEC3B and crossed these with the KPC genetically engineered mouse model of pancreatic cancer. We find that overexpressing APOBEC3B results in a poorer prognosis in these animals and some changes in the immune microenvironment. We are currently performing genomic and transcriptomic analyses to determine mutational burden and tumor subtype in an effort to identify therapeutic opportunities in patients bearing this signature. In contrast with T cells, recent studies have suggested that B cells may be tumor promoting in pancreatic cancer. However, clinical trials targeting B cells have been conducted recently and the results have been very disappointing. We have now generated an autochthonous model of B-cell depletion and find that B cells are not tumor promoting in this setting. We are now investigating the mechanisms behind this and the microenvironmental differences that are observed in spontaneous versus allograft models.

Citation Format: Karen Pickering, Laura Lapienyte, Saadia Karim, Douglas Strathdee, Owen Sansom, Jen Morton. Investigating the immune microenvironment in mouse models of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I26.
Abstract I27: Pancreatic cancer immunotherapy: Moving forward
Authors: Le Dung T.
Published: March 2020

As immunotherapy becomes a pillar of therapy for some of our patients with solid tumors, the role in pancreatic cancer remains limited despite a multitude of studies testing combinations of novel agents. The landscape of effective systemic therapies to date is limited to combination chemotherapy and PARP inhibitors in a small subset of patients with germline BRCA mutations. We also currently await the phase 3 data testing PEGPH20, a recombinant hyaluronidase, in combination with gemcitabine and nab-paclitaxel. These more recent studies were developed from studying and targeting the unique characteristics of pancreatic cancer based on the genomics, chemotherapy sensitivity, and tumor microenvironment characterization. Research in combination strategies that include immunotherapy agents is continuing to build on what we are actively learning about the genomics, epigenetics, RNA expression, and tumor microenvironment characterization specific to pancreatic cancer biology. Historically, studies involving single-agent immunotherapy approaches to pancreatic cancer have yielded responses in 0 or 1 patient. More recent studies with combination immunotherapy approaches with and without chemotherapy have increased the number of responders, but responses still occur in only a handful of patients except in studies where the agents are combined with chemotherapy, which may be the driver of the responses. Further characterization of the responders may help us to identify predictive biomarkers, and further understanding of the nonresponders can help drive future directions. This lecture will review the current strategies that have made it into clinical trials or strategies being proposed for further study and preliminary data that are available to support continued development. Advances in increasing T-cell delivery such as cell-based or neoantigen vaccines, modified T cells, viral and bacterial vectors, or bispecific antibodies may increase immune cell infiltration into tumors while new agonist agents promoting immune cell activation or antagonist targeting negative checkpoints or immune cell populations can increase the probability of success. The combination of increasing the number of responders and better understanding those subsets will eventually lead to additional treatment options for our patients.

Citation Format: Dung T. Le. Pancreatic cancer immunotherapy: Moving forward [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I27.
Abstract PR04: STING and TLR-independent activation of T-cell responses against pancreatic cancer using agonistic CD40 antibody
Authors: Byrne Katelyn T. , Morrison Alexander H. , Vonderheide Robert H.
Published: March 2020

Immunotherapy is increasingly used in combination with current standard-of-care treatments such as chemotherapy that likely provides danger signals via immunogenic tumor cell death and activation of STING or TLR pathways. However, both the toxicity and immunosuppressive effects of chemotherapy risks hindering clinical benefit. Agonistic CD40 antibody is a potent activator of immune responses, acting upstream of immune checkpoint blockade (ICB) by driving T-cell priming. Here, we show that anti-CD40 is sufficient to drive potent T-cell responses against murine KPC (KrasG12D;Trp53R172H;Pdx-Cre) pancreatic tumors if combined with ICB. CD40/ICB was more effective than CD40/ICB/chemotherapy (median overall survival 76 days vs. 44 days in CD40/ICB vs. CD40/ICB/chemotherapy-treated mice, p<0.01). Therapeutic efficacy of CD40/ICB was fully independent of the STING, MyD88, and IFNAR pathways, requiring instead host expression of CD40, cross-presenting dendritic cells, and an intact T-cell compartment. Therapy-induced CD4 and CD8 T cell responses displayed enhanced polyfunctional cytokine secretion (48.9% vs. 29.5% of CD8+ T cells in vehicle control treated mice), cleared established primary tumors (43% vs. 0% in vehicle control or single-treatment cohorts p<0.0001), and formed protective memory responses in 57% of CD40/ICB cured mice. Immunosuppressive regulatory T cells were noticeably absent from the tumor site after CD40 treatment (7% of CD4+ T cells vs. 33% in mice treated with ICB alone, p<0.01), concomitant with improved T-cell activation and proliferation, whereas ICB was needed to potentiate the full activation and reinvigoration of the T-cell response both locally and systemically. The efficacy of CD40/ICB in in this ICB-resistant KPC model opens the possibility of optimized immunotherapy regimens free of the toxicity and immunosuppressive effects of cytotoxic therapy.

This abstract is also being presented as Poster B08.

Citation Format: Katelyn T. Byrne, Alexander H. Morrison, Robert H. Vonderheide. STING and TLR-independent activation of T-cell responses against pancreatic cancer using agonistic CD40 antibody [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR04.
Abstract PR07: Phase I/II study of mesothelin-targeted immunotoxin LMB-100 with nab-paclitaxel for patients with advanced pancreatic adenocarcinoma
Authors: Alewine Christine C. , Ahmad Mehwish , Peer Cody J. , Hu Zishuo , Lee Min-jung , Yuno Akiro , Kindrick Jessica , Thomas Anish , Steinberg Seth , Trepel Jane B. , Figg William D. , Hassan Raffit , Pastan Ira
Published: March 2020

Purpose: LMB-100 recombinant immunotoxin (iTox) consists of a mesothelin-binding Fab for targeting and a modified Pseudomonas exotoxin A payload. Preclinical studies showed that combining taxanes with iTox results in synergistic antitumor activity. The primary objectives of this phase I/II study were to determine the maximum tolerated dose (MTD) of LMB-100 when given with nanoalbumin bound (nab)-paclitaxel to participants with previously treated advanced pancreatic adenocarcinoma and to assess the objective response rate.

Patients and Methods: Patients (n = 20) received fixed-dose nab-paclitaxel (125 mg/m2 on Days 1 and 8) with LMB-100 (65 or 100 mcg/kg on Days 1, 3, and 5) in 21-day cycles. Treatment was limited to 2-3 cycles by protocol. Safety and tolerability, pharmacokinetics, immunogenicity, and relationship of activity to tumor mesothelin expression were assessed.

Results: Dose-limiting toxicity (DLT) of Grade 3 myalgia was observed in 2 of 5 patients treated with 100 mcg/kg. DLT of Grade 3 edema from capillary leak syndrome (CLS) was observed in 1 of 6 patients at MTD of 65 mcg/kg. Severe toxicities of Grade 4 left ventricular dysfunction and hypotension from CLS were observed in 1 patient in the phase II expansion, resulting in study closure. LMB-100 anti-drug antibody formation limited LMB-100 exposure in 5 of 13 patients during cycle 2. Seven of 17 patients with evaluable CA19-9 experienced >50% decrease of this tumor marker, and one patient developed a partial response. Response was associated with higher tumor mesothelin expression and Cycle 2 LMB-100 exposure.

Conclusions: The combination caused serious toxicity. Despite some observed clinical activity, further testing of this combination will not be pursued.

This abstract is also being presented as Poster B01.

Citation Format: Christine C. Alewine, Mehwish Ahmad, Cody J. Peer, Zishuo Hu, Min-jung Lee, Akiro Yuno, Jessica Kindrick, Anish Thomas, Seth Steinberg, Jane B. Trepel, William D. Figg, Raffit Hassan, Ira Pastan. Phase I/II study of mesothelin-targeted immunotoxin LMB-100 with nab-paclitaxel for patients with advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR07.
Abstract PR08: Intratumoral T-cell distribution in murine and patient pancreatic cancer correlates with tissue heterogeneity and survival
Authors: Carstens Julienne L. , Sampaio Pedro Correa de , Barua Soutik , Wang Huamin , Burks Jared K. , Rao Arvind , LeBleu Valerie S. , Kalluri Raghu
Published: March 2020

The complex microenvironment characteristic of pancreatic ductal adenocarcinoma (PDAC) has been implicated as a critical mediator of tumor progression and therapeutic response. Spatial relationships of individual cellular and acellular components within tumors may offer novel insights into the dynamic and complex functions of PDAC. Using eight-color multiplex immunohistochemistry and novel spatial analysis algorithms, we report a heterogeneous and increased population of infiltrating T lymphocytes in the tumors compared to uninvolved pancreatic tissues of treatment-naïve PDAC patients. Spatial distribution of cytotoxic T cells in proximity to cancer cells independently correlates with increased overall patient survival. Collagen-I and aSMA-positive fibroblasts do not correlate with a paucity of T-cell accumulation around cancer cells, suggesting that PDAC desmoplasia may not be a simple physical barrier. However, T-cell infiltration was reduced in proximity to specific cancer cell subpopulations, supporting cancer-cell intrinsic mechanisms for immune avoidance. Further expansion of this technology using early and late primary tumors and metastatic tissue of genetically engineered mouse models (KrasLSL-G12D; p53R172H; PDX1-Cre; EYFPLSL) demonstrates similar T-cell heterogeneity and spatial associations. These data support the validity of multiplex and spatial analysis platforms for exploring the structure-function relationships in the PDAC microenvironment and suggest differential spatial relationships between cancer subtypes and the surrounding microenvironment may be a determining factor in PDAC progression.

This abstract is also being presented as Poster A04.

Citation Format: Julienne L. Carstens, Pedro Correa de Sampaio, Soutik Barua, Huamin Wang, Jared K. Burks, Arvind Rao, Valerie S. LeBleu, Raghu Kalluri. Intratumoral T-cell distribution in murine and patient pancreatic cancer correlates with tissue heterogeneity and survival [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR08.
Abstract PR13: Macrophage metabolism inhibits pancreatic cancer therapy
Authors: Halbrook Christopher J. , Menjivar Rosa , Thurston Galloway , Magliano Marina Pasca di , Lyssiotis Costas
Published: March 2020

Pancreatic ductal adenocarcinoma (PDA) is projected to become the 3rd most prevalent cancer-related death in the United States in 2016, contrasting a relatively low incidence rate. The lethality of PDA is largely due to a lack of effective treatment options. A principal barrier in PDA treatment is the physiology of the tumors, characterized by a densely fibrotic stroma, rich with immune cell infiltration. The majority of these immune cells are immunosuppressive myeloid cells, including macrophages. These macrophages within the tumor, termed tumor-associated macrophages (TAMs), are strongly immunosuppressive, inhibiting both infiltration and activation of cytotoxic T cells. While immunotherapy has emerged as a promising strategy to treat other solid tumors, immune suppression has rendered PDA refractory to such approaches. Accordingly, much effort has been made to understand the role of TAMs in pancreatic tumorigenesis and tumor maintenance. Several studies have identified pathways by which PDA cells recruit and polarize macrophages into TAMs and the effects that TAMs have on the tumor microenvironment. Depletion of TAMs leads to the inhibition or regression of tumor growth, mediated largely by increased infiltration of cytotoxic T cells into the tumor. In addition to signaling proteins, metabolic byproducts can also influence cellular crosstalk in the tumor microenvironment; however, this has not been described in the context of PDA. Utilizing reciprocal conditioned media approaches combined with LC/MS metabolomics, we have profiled the metabolic crosstalk between cancer cells and macrophage cultures and found TAMs release metabolites that can regulate the response of PDA cells to chemotherapy. We further noted several additional metabolic pathways by which TAMs can deplete important nutrients in the microenvironment to directly inhibit T-cell activity. Taken together, these data provide mechanistic insight into previous reports that macrophages can drive immune and chemoresistance in PDA. Furthermore, these results also suggest that further development of interventions that target either PDA-mediated polarization of TAMs or TAM-mediated inhibition of therapy represent opportunities to improve the efficacy of currently available treatment options.

This abstract is also being presented as Poster A36.

Citation Format: Christopher J. Halbrook, Rosa Menjivar, Galloway Thurston, Marina Pasca di Magliano, Costas Lyssiotis. Macrophage metabolism inhibits pancreatic cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR13.
Abstract BS1-1: RNA Methylation in human cancer
Authors: He C
Published: March 2020

Over 150 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have discovered the first two RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of the most prevalent modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N6-methyladenosine (m6A). These findings indicate that reversible RNA modification could impact biological regulation analogous to the well-known reversible DNA and histone chemical modifications. We have also characterized proteins that selectively recognize m6A-modified mRNA and affect the translation status and lifetime of the target mRNA, as well as molecular machines that deposit the m6A methylation on mRNA. Functional studies reveal m6A methylation as a critical mechanism to synchronize groups of transcripts for coordinated metabolism, translation, and decay, allowing timely and coordinated protein synthesis and transcriptome switching during cell differentiation and development. Misregulations of these processes lead to embryo lethality and human diseases such as cancer. I will focus on our discoveries of how aberrant expressions of m6A regulators could contribute to human cancer. I will also present effects of m6A regulation on immune response related to cancer progression.

Citation Format: C He. RNA Methylation in human cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr BS1-1.
Abstract CS1-1: Origins and Clinical Implications of HER2 Heterogeneity
Authors: Richardson A
Published: March 2020

The presentation will describe the types of HER2 heterogeneity and how it is identified pathologically including case examples and molecular studies. The implications for treatment decisions and for its possible role in patient outcomes will also be discussed.

Citation Format: A Richardson. Origins and Clinical Implications of HER2 Heterogeneity [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr CS1-1.
Abstract ES1-3: Assessment of PD-L1 in Breast Cancer to Predict Response to Immunotherapy
Authors: Rimm DL
Published: March 2020

Many tumors showed promise in phase one trials of immunotherapy, but breast cancer was not high on the list. Since then, focus in breast cancer has shifted to Triple Negative Breast Cancer (TNBC) which has shown promise in both the metastatic and neo-adjuvant setting. This presentation will provide a history of the PD-L1 assay to select response to therapy in lung cancer where it was most successful and then discuss its transition to breast cancer. In TNBC, there are successful trials and even FDA approval, but there is also deep concerns related to the IHC-based patient selection assay. This presentation will discuss the breast cancer PD-L1 assay(s) and the controversy surrounding its implementation.

Citation Format: DL Rimm. Assessment of PD-L1 in Breast Cancer to Predict Response to Immunotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES1-3.
Abstract ES11-2: Neoadjuvant Systemic Treatment (NST): Tailoring Response by Sub-type
Authors: Chang JC
Published: March 2020

Achieving a pathologic complete response (pCR) after neoadjuvant systemic treatment (NST) is clearly associated with improved survival in breast cancer patients, especially with HER2 and triple negative subtypes. In HER2-positive breast cancer patients, the neoadjuvant platform has allowed for the unprecedented accelerated approval for pertuzumab based on improved pCR rates. The KATHERINE trial, in patients who did not achieve pCR following standard trastuzumab/pertuzumab/chemotherapy, demonstrated for the first time that switching to trastuzumab-emtansine (TDM1) led to significant benefit, creating an interesting research paradigm for these high-risk patients with residual disease. For patients with residual disease, the CREATE-X trial demonstrated survival improvement with capecitabine, especially in patients with triple negative disease. New promising agents in the metastatic setting that are being incorporated into NST include immune-check-point inhibitors and cyclin-dependent kinase inhibitors. Evolving technologies like next generation sequencing and gene expression profiles have improved our knowledge regarding the biology of residual disease, and the mechanisms behind treatment resistance, and potentially, metastases. NST allows for testing of new promising treatment regimens - both escalation and de-escalation - depending on sub-types, before surgery. The management and strategies post-NST and the management of residual disease will be discussed.

Citation Format: JC Chang. Neoadjuvant Systemic Treatment (NST): Tailoring Response by Sub-type [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES11-2.
Abstract ES11-3: Local treatments in patients who achieve pathologic complete response
Authors: White J
Published: March 2020

Local regional treatment of breast cancer has been historically based on anatomic extent of disease in the breast and ipsilateral axilla at presentation. An adjustment in this paradigm is evolving as more breast cancer patients receive neoadjuvant systemic therapy with increasingly more effective agents leading to higher rates of pathologic complete response. In the neoadjuvant setting, breast cancer subtype and pathologic complete response (pCR) may prove to have similar influence on local regional treatment as anatomic stage at presentation. In the ALLIANCE-ACOSOG 1071 clinical trial, rates of pCR (breast and axilla) were highest in the triple-negative (38.2%) and HER2-positive (45.4%) cases and similarly had the highest breast conservation rates of 46.3% and 43.8%, respectively. In addition, breast cancer patients that present with clinical N1 axillary involvement and have complete pathologic response can potentially avoid axillary node dissection with careful use of sentinel node biopsy based on the Sentina and SN FNAC trials. It may be that surgical resection will prove unnecessary for breast conservation in select cases with complete clinical and imaging response when breast radiation is intended and clinical trials are underway. Radiation therapy indications have likewise been established from extent of disease when surgery is the first line of therapy. Retrospective analyses of local regional recurrence incidence in neoadjuvant chemotherapy clinical trials demonstrates it is lowest in those with pathologic compete response in the breast and axillary nodes; as shown in a combined analysis of the NSABP B18 and 27 trials and again seen from analysis of the EORTC 10994/ BIG 1-00 trial. The ongoing NRG NSABP B51 RTOG 1304 clinical trial will determine if regional nodal irradiation is beneficial if positive axillary nodes at presentation convert to negative by neoadjuvant chemotherapy. Complete pathologic response may allow complete omission of post mastectomy radiation in some settings as well reduced extent of breast radiation following breast-conserving surgery.

Citation Format: J White. Local treatments in patients who achieve pathologic complete response [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr ES11-3.