bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A060: Metabolic patterns in pancreatic cancer cachexia
Authors: Mathur Deepti , Majem Blanca , Kalaany Nada
Published: January 2024

Cachexia is a multi-organ pathological state characterized by physical wasting and tissue catabolism. It occurs in 80% of pancreatic cancer patients, and to date there are no preventative or early detection methods. Cachexia leads to limited tolerance to anti-cancer therapy and is a lethal disease. Here, we have characterized a mouse model of cachexia in pancreatic ductal adenocarcinoma (PDAC) in order to better understand disease progression: the physiology across stages of cachexia in the model recaptures well the progressive disease in humans. We present the first-of-its-kind systemic metabolomic analysis across cachectic stages in the tumor, interstitial fluid, liver, fats, muscles, and blood plasma. The primary source of variation in the data is the tissue type, indicating that each tissue has a unique metabolome and trajectory across cachexia stages. We use mathematical modeling to identify metabolites that may be participating in cross-tissue networks in pre-, early-, and late-stage cachexia. Pathway analysis shows a particular emphasis on lipid alterations. Strikingly, we find systemic metabolic changes prior to weight loss or other disease symptoms, and use feature selection algorithms to identify potential predictive markers of cachexia progression. Overall, we hope our work is a valuable resource for the field and will lay the foundation for metabolic insights into pancreatic cancer cachexia and its prevention and treatment.

Citation Format: Deepti Mathur, Blanca Majem, Nada Kalaany. Metabolic patterns in pancreatic cancer cachexia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A060.
Abstract A079: A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2-deficient pancreatic cancer
Authors: Archasappawat Suyakarn , Lee EunJung , Ji Keely , Pena Jocelyn , Fernandez-Vega Virneliz , Gangaraju Ritika , Beesabathuni Nitin Sai , Kim Martin Jean , Tian Qi , Shah Priya , Scampavia Louis , Spicer Timothy , Hwang Chang-Il
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the United States, with the lowest five-year survival rate of all cancers. Around 10% of pancreatic cancer diagnoses are thought to be familial pancreatic cancer (FPC). BRCA2 pathogenic variants have been identified to be closely associated with FPC. Personalized medicine approaches that are tailored to FPC patients based on their mutation profiles could improve patient outcomes and minimize adverse effects. This study aims to identify novel potential drug candidates for BRCA2-deficient PDAC and dissect its underlying molecular mechanisms. To discover new vulnerabilities for BRCA2-deficient pancreatic cancer, we performed high-throughput drug screening (HTS) using isogenic murine Brca2 knockout (KO) and control PDAC cells. The HTS assay revealed that JQ1, a small molecule inhibitor of the bromodomain and extra-terminal domain protein (BET) family, selectively induced cytotoxicity in Brca2 KO cells. JQ1 significantly decreased the cell viability of Brca2 KO cells in vitro and suppressed the growth of Brca2 KO tumors in vivo compared to the controls. The transcriptomic analyses showed that JQ1 treatment resulted in upregulation of the gene sets associated with macroautophagy. Multi-orthogonal autophagy assays, including live cell imaging of fluorescence-based autophagy reporter, also supported that Brca2 KO cells had a constitutively higher basal level of autophagic activities compared to the controls, and JQ1 further induced autophagic flux in Brca2 KO cells. Moreover, blocking the autophagy process by pharmacological inhibition or knocking down essential autophagy genes rescued JQ1-induced cell death in Brca2 KO cells, indicating that the increased autophagy is responsible for JQ1-mediated cell death in Brca2 KO cells. In conclusion, we found that BRCA2 deficiency elevated autophagic flux, and extensive autophagy was further activated by BET inhibition, culminating in autophagy-dependent cell death in Brca2-deficient pancreatic cancer cells. Our findings suggest that BET inhibition could be a promising therapeutic strategy for treating BRCA2-deficient pancreatic cancer.

Citation Format: Suyakarn Archasappawat, EunJung Lee, Keely Ji, Jocelyn Pena, Virneliz Fernandez-Vega, Ritika Gangaraju, Nitin Sai Beesabathuni, Martin Jean Kim, Qi Tian, Priya Shah, Louis Scampavia, Timothy Spicer, Chang-Il Hwang. A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2-deficient pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A079.
Abstract A101: Codon-specific KRAS mutations predict survival in advanced pancreatic cancer
Authors: Boilève Alice , Rousseau Adrien , Hilmi Marc , Tarabay Anthony , Mathieu Jacques R.R. , Goudarzi Negaar , Cartry Jérôme , Bedja Sabrina , Nicotra Claudio , NgoCamus Maud , Boige Valérie , Valéry Marine , Bani Mohamed Amine , Tselikas Lambros , Italiano Antoine , Jaulin Fanny , Smolenschi Cristina , Hollebecque Antoine , Ducreux Michel
Published: January 2024

Background: How distinct KRAS alterations in pancreatic adenocarcinoma (PDAC) influence tumor initiation and outcomes remains unclear. Moreover, KRAS is now partly targetable with novel specific inhibitors targeting KRASG12 (G12C or G12D) but specific outcomes of these subgroups of patients is poorly described. We analyzed clinical/genomic characteristics, and outcomes of PDAC depending on codon-specific KRAS (G12 vs others), as well as gene expression profiles and in vitro drug sensibility using organoids (PDO). Methods: All metastatic patients with PDAC and available molecular profile from 2015-2022 were eligible and patients with KRAS mutation were included (NCT0493252) in a monocentric retrospective cohort. A cohort of PDO was used to assess the efficacy of 25 antitumor therapies (chemogram) and transcriptomic data from 69 KRAS-mutated tumors was also analyzed. Results: Overall, 263 patients were included, 238 KRASG12 (91%) and 24 (9%) KRASother. There was no difference between KRASG12 and KRASother regarding clinicopathological characteristics and potentially actionable alterations, except for BRAF that was found in 13% of KRASother (p=0.01). GNAS was found more altered in KRASother tumors (p=0.002) suggesting potential TIPMP precursors. Median overall survival from metastatic diagnosis was 16.7 months (95%CI:14.3-18.3) in KRASG12 and 24.9 months (95% CI:17.4-43.4) in KRASother (HR (ref:KRASG12)=0.56 (0.34-0.94), p=0.03 adjusted). First-line treatment-response was not different between groups (ORR and PFS), as confirmed with a similar PDO in vitro sensibility. Transcriptomic analyses showed a significant and exclusive upregulation of immune pathways in KRASG12 tumors. Conclusion: Codon-specific KRAS mutations are not equal and we report for the first time that KRASG12 patients have a worst prognosis than KRASother patients in PDAC. KRASG12 appears as a prognostic factor, as confirmed by transcriptomic analyses. These results warrant to be confirmed in larger scale studies.

Citation Format: Alice Boilève, Adrien Rousseau, Marc Hilmi, Anthony Tarabay, Jacques R.R. Mathieu, Negaar Goudarzi, Jérôme Cartry, Sabrina Bedja, Claudio Nicotra, Maud NgoCamus, Valérie Boige, Marine Valéry, Mohamed Amine Bani, Lambros Tselikas, Antoine Italiano, Fanny Jaulin, Cristina Smolenschi, Antoine Hollebecque, Michel Ducreux. Codon-specific KRAS mutations predict survival in advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A101.
Abstract A114: Low-dose carbon monoxide halts pancreatic cancer metastasis
Authors: Zhang Tiantian , Zhang George , Chen Xiang , Chen Zhengming , Tan Adrian Y. , Lin Anthony , Zhang Cheryl , Zhang Guoan , Xiang Jenny , Hissong Erika , Chen Yao-Tseng , Du Nancy
Published: January 2024

Pancreatic cancer is projected to become the second leading cause of cancer-related death by 2030. Pancreatic ductal adenocarcinoma (PDAC) accounts for about 90% of pancreatic cancer cases. Over the last 30 years, standard care of chemotherapy only extends the survival of metastatic pancreatic cancer patients for a few months. Despite years of remarkable innovations in cancer treatment, the 5-year survival rate of PDAC has remained dismal. The recalcitrant nature of PDAC to available treatments highlights an urgent need for novel therapeutics in order to substantially increase survival. Carbon monoxide (CO) is produced endogenously in humans and has been established as an important, biologically active signaling molecule. Accumulating evidence suggests the therapeutic applications of safe, low-dose CO for various diseases. We evaluate the therapeutic effect of CO on pancreatic cancer progression. We show that 250 ppm CO inhibits migration of pancreatic cancer. We demonstrate that low-dose CO suppresses metastasis of PDAC in an orthotopic mouse model of liver metastasis and a spontaneous PDAC metastasis mouse model after the removal of primary tumor xenograft tumors. Mechanistically, low-dose CO blocks transcription of heme importers, leading to diminished intracellular heme levels and a heme-regulated enzyme, cytochrome P4501B1 (CYP1B1). Either supplementing heme or overexpressing CYP1B1 reverses the anti-migration effect of low-dose CO. Altogether, low-dose CO therapy inhibits pancreatic cancer cell migration, prevents disseminated cancer cells from expanding into gross metastases, and improves survival in pre-clinical mouse models of metastasis.

Citation Format: Tiantian Zhang, George Zhang, Xiang Chen, Zhengming Chen, Adrian Y. Tan, Anthony Lin, Cheryl Zhang, Guoan Zhang, Jenny Xiang, Erika Hissong, Yao-Tseng Chen, Nancy Du. Low-dose carbon monoxide halts pancreatic cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A114.
Abstract B059: A novel pancreatic cancer mouse model with human immunity
Authors: Miyamura Norio , Suzuki Kodai , Friedman Richard A. , Floratos Aristidis , Kunisada Yuki , Masuda Kazuya , Lowy Andrew M. , Tsuji Moriya , Sugahara Kazuki N.
Published: January 2024

The iRGD tumor-penetrating peptide delivers chemically linked drugs and even co-injected free drugs selectively to extravascular tumor tissue by targeting the αvβ5 integrin and neuropilin-1 (NRP1). A phase 1b clinical trial showed that iRGD appears to safely double the response rate of standard chemotherapy in patients with stage 4 pancreatic ductal adenocarcinoma (PDAC). We recently found that long-term iRGD treatment, even as a monotherapy, reduced regulatory T cells (Tregs) selectively in the PDAC tissue, which led to the expansion of CD8+ T cells and improved efficacy of immunotherapy in syngeneic PDAC mice. This finding led to the discovery of αvβ5 integrin being a novel targetable marker for tumor-resident Tregs in PDAC mice. Our recent data show that αvβ5 integrin+ Tregs are also present in human PDAC tissue. To study the significance of αvβ5 integrin+ human Tregs as a therapeutic target for iRGD, we developed a humanized PDAC (huPDAC) mouse model by transplanting human PDAC cells into human immune system (HIS) mice, which harbor fully matured human CD8+ and CD4+ T cells, natural killer T cells, B cells, and dendritic cells. The CD8+ T cells are human leukocyte antigen (HLA)-restricted and show a tumor antigen-specific response. We orthotopically implanted HLA-matched human PDAC cells into HLA-A2-positive HIS mice. Both an established human PDAC cell line (PANC-1) and patient-derived PDAC cells (0779E) successfully formed orthotopic tumors and liver metastases. The tumors were infiltrated by various human immune cells at a ratio similar to that found in patient-derived PDAC tissues. Of note, αvβ5 integrin+ human Tregs were also noted in the tumors but not in the spleen. iRGD monotherapy increased the ratio of CD8+ T cells per Tregs in the tumors, suggesting that iRGD will likely function as an immunomodulator in humans. The first patient was recently dosed in a new phase 1b/2a clinical trial (iLSTA Trial: ACTRN12623000223639), which assesses the safety and preliminary efficacy of iRGD in combination with standard-of-care chemotherapy and immunotherapy in locally advanced PDAC patients.

Citation Format: Norio Miyamura, Kodai Suzuki, Richard A. Friedman, Aristidis Floratos, Yuki Kunisada, Kazuya Masuda, Andrew M. Lowy, Moriya Tsuji, Kazuki N. Sugahara. A novel pancreatic cancer mouse model with human immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B059.
Abstract B115: Single-cell transcriptomic analysis reveals both shared and separate functions for GATA6 and KRT17 in pancreatic cancer
Authors: Nelson Brian J. , Marchenko Natalie , Escobar-Hoyos Luisa F. , Shroyer Kenneth , Powers Scott , MacCarthy Thomas
Published: January 2024

Human pancreatic ductal carcinomas (PDACs) are transcriptionally heterogeneous and can be grouped into two classes, the classical subtype associated with GATA6 expression and the basal subtype associated with KRT17 expression. Accordingly, GATA6 and KRT17 are generally thought to have opposing functions in PDAC. However, through our analysis of single cell RNA sequencing data, we have found that many of the genes that are the highly correlated with KRT17 expression are also highly correlated with GATA6 expression, including KLF5, which encodes a transcription factor that promotes PDAC development, and several genes that encode components of intercellular junctions (e.g. CDH1, CLDN4, CLDN18, JUP, and SHROOM3). These results suggest that KRT17 and GATA6 share certain biological functions including the maintenance or modulation of intercellular junctions. We also found evidence for separate functions. Genes with expression that correlated specifically with GATA6 included transcription factor genes involved in normal pancreatic differentiation along with genes encoding components of the Hippo signaling pathway. On the other hand, genes with expression that correlated specifically with KRT17 included several components of PIK3-Akt signaling. Further analysis of scRNA-seq data should reveal more about the mechanisms by which these genes are involved in influencing PDAC progression and maintenance.

Citation Format: Brian J. Nelson, Natalie Marchenko, Luisa F. Escobar-Hoyos, Kenneth Shroyer, Scott Powers, Thomas MacCarthy. Single-cell transcriptomic analysis reveals both shared and separate functions for GATA6 and KRT17 in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B115.
Abstract C016: Pre-existing T cell inflammation is a determinant of response to mesothelin chimeric antigen receptor T cell therapy in pancreatic ductal adenocarcinoma
Authors: Plesset Jacqueline B. , Coho Heather , Markowitz Kelly , Patel Dhruv , Wattenberg Max M. , Stone Meredith L. , Delman Devora , Beatty Gregory L.
Published: January 2024

Background: Pancreatic ductal adenocarcinoma (PDAC) has a 12.5% 5-year survival rate and is predicted to become the 2nd leading cause of cancer-related death by 2030. PDAC is known to be resistant to immunotherapy. Thus, while chimeric antigen receptor (CAR) T cell therapy shows the potential to mediate durable responses against some hematologic and solid tumors, in PDAC, the efficacy of CAR T therapy has remained limited. PDAC tumors show heterogenous T cell infiltration with some tumors containing a high number of T cells. As T cell infiltration associates with prolonged survival, we hypothesized that the density of pre-existing T cell infiltration would predict response to CAR T therapy. Methods: Previously established clonal mouse PDAC cell lines, which show a T cell inflamed or non-inflamed tumor microenvironment upon in vivo implantation, were used. Mouse CAR T cells specific to mesothelin, a tumor antigen expressed by PDAC, were generated using retroviral transduction. Mice were implanted subcutaneously with T cell inflamed or non-inflamed tumor cell lines. Ten days later mesothelin CAR T cells were administered intravenously. Flow cytometry and multiplex immunohistochemistry was used to define the density and spatial location of CAR T cell infiltration. The impact of CAR T cells on tumor growth and survival was also measured. Results: CAR T cells were found to traffic to T cell inflamed tumors, which led to delayed tumor outgrowth. However, such results were not seen in T cell non-inflamed tumors. Rather in mice with T cell non-inflamed tumors, CAR T cells accumulated in the liver. Further, CAR T cells effectively eliminated T cell inflamed and non-inflamed tumor cells in vitro, demonstrating that tumor intrinsic mechanisms of resistance to T cell killing were not a major determinant of treatment efficacy. Conclusions: Our findings suggest the therapeutic potential of CAR T cells in PDAC but highlight mechanisms of T cell exclusion as a therapeutic barrier wherein CAR T cells accumulate in host organs.

Citation Format: Jacqueline B. Plesset, Heather Coho, Kelly Markowitz, Dhruv Patel, Max M. Wattenberg, Meredith L. Stone, Devora Delman, Gregory L. Beatty. Pre-existing T cell inflammation is a determinant of response to mesothelin chimeric antigen receptor T cell therapy in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C016.
Abstract C026: Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups
Authors: Sivakumar Shivan , Jainarayanan Ashwin , Arbe-Barnes Edward , Abu-Shah Enas , Bashford-Rogers Rachael
Published: January 2024

Pancreatic cancer has the worst survival of any human cancer with a 5 year survival of less than 10% with minimal treatment options. We have previously made the observation that patients with a T cell infiltrate in their primary tumor have a better prognosis then those that do not. To understand the nature of the immune infiltrate, we have in 12 patients performed 10X sequencing on CD45 cells from the tumor as well as single cell TCR-seq, BCR-seq and cite-seq and have performed the same experiment on the matching PBMCs. We have generated a dataset of approximately 185000 cells with half coming from the tumor. This unravels a complex immune infiltrate with the predominant immune cell types consisting of T cells. Our data shows that within the tumor infiltrate, patients either have high or low myeloid infiltration. We see a highly active Treg population that has multiple checkpoints activated. Using TCR data, we saw the biggest clonal expansions in CD8 EM, CD8 senescent cells and Tregs. Circulating TIL CD4 T cells are dominated by activated Tregs, Tfh, and Th2 and circulating TIL CD8 T cells are dominated by CD8 EM T cells. Our work identifies multiple novel therapeutic targets that should form the basis for rational design of a new generation of clinical trials in pancreatic ductal adenocarcinoma.

Citation Format: Shivan Sivakumar, Ashwin Jainarayanan, Edward Arbe-Barnes, Enas Abu-Shah, Rachael Bashford-Rogers. Single-cell multi-omics in pancreatic cancer reveals differential immune evasion mechanisms between prognostic groups [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C026.
Abstract C027: Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model
Authors: Sorrentino Anthony , Alcantara-Hirsch Carolina , Shapiro Beny , Ma Erica , Javed Ammar , Wolfgang Christopher , Bar-Sagi Dafna
Published: January 2024

Surgical resection is currently the mainstay of treatment for pancreatic ductal adenocarcinoma (PDAC). After “curative intent” resection, distant metastasis occurs in majority of patients, indicating that PDAC is a systemic disease and should be considered as such at the time of surgical resection. Despite this, the effects of tumor resection on the systemic disease are not fully elucidated. Surgical trauma induces systemic immunosuppression, that can result in a “window of opportunity”, affecting metastatic seeding and outgrowth, as well as responsiveness to therapy. We used an orthotopic resection model in immunocompetent mice by performing a distal pancreatectomy and splenectomy. Using this model system, we identified outcomes similar to human disease, such as a survival benefit upon resection, systemic disease at the time of resection, and metastatic dissemination predominantly in the liver, lung, and peritoneum. Since the liver is the most common site of recurrence in human PDAC and portends a poorer prognosis than other metastases, we investigated the effect of tumor resection on the hepatic microenvironment. In surgically stressed mice undergoing sham resection and splenectomy, we identified an increase in eosinophils and a decrease in neutrophils, and these immune perturbations were augmented upon tumor resection. Time-course analysis identified transient changes in tissue resident and conventional NK cells, as well as macrophage and monocyte populations. Taken together, we have utilized a preclinical model that simulates human disease progression and response to surgery, and identified tumor resection specific alterations in the liver metastatic microenvironment. An improved understanding of the immune perturbations during this perioperative window may identify new immunotherapy strategies benefiting PDAC patients to help treat this systemic disease.

Citation Format: Anthony Sorrentino, Carolina Alcantara-Hirsch, Beny Shapiro, Erica Ma, Ammar Javed, Christopher Wolfgang, Dafna Bar-Sagi. Perioperative immune perturbations of the metastatic microenvironment in a murine PDAC orthotopic resection model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C027.
Abstract C029: Multiple non-redundant immune checkpoints direct therapeutic resistance to chemotherapy and anti-CSF1R in pancreatic ductal adenocarcinoma
Authors: Stone Meredith L. , Herrera Veronica M. , Li Yan , Coho Heather , Yue Yuqing , Graham Kathleen , Delman Devora , O'Brien Shaun , Beatty Gregory L.
Published: January 2024

A hallmark of pancreatic ductal adenocarcinoma (PDA) is the formation of a myeloid rich immunosuppressive microenvironment which acts as a barrier to treatment. Therapeutic blockade/depletion of immunosuppressive myeloid cells in combination with chemotherapy or anti-PD-1 checkpoint blockade is under investigation in PDA but has yet to demonstrate broad clinical success. Here, we studied mechanisms of resistance to myeloid-targeted therapy to inform rational combination strategies. Spatial and molecular profiling of the tumor microenvironment in mouse and human PDA revealed vast intra-tumoral myeloid heterogeneity. Depletion of distinct myeloid cell populations triggered T cell infiltration into tumors but also provoked compensatory remodeling of the myeloid compartment. However, concurrent depletion of multiple myeloid subsets using drugs targeting CSF1R, CCR2/5, and CXCR2 was unexpectedly insufficient to overcome treatment resistance and failed to restore productive T cell surveillance in murine models of PDA. Therefore, we next investigated the role of the lymphoid compartment. High-dimensional single cell analyses of T cell infiltrates in PDA revealed an upregulation of multiple checkpoint molecules, including PD-1, LAG3 and CTLA-4, in both mice and humans, suggesting potential resistance mechanisms. In contrast to combinatory myeloid cell depletion, combined blockade of PD-1, LAG3, and CTLA-4 with gemcitabine and anti-CSF1R triggered peripheral CD4+ and CD8+ T cell activation and produced deep and durable tumor responses with a nearly 3-fold increase in median survival and in some cases, tumor cures. Taken together, these studies highlight the contribution of multiple immune checkpoints to cancer immune evasion and reveal a novel role for LAG3 in treatment resistance in PDA. Together, these findings suggest that a multipronged approach to disrupting negative regulatory signals controlling T cell function may be needed to realize the potential of immunotherapy in PDA.

Citation Format: Meredith L. Stone, Veronica M. Herrera, Yan Li, Heather Coho, Yuqing Yue, Kathleen Graham, Devora Delman, Shaun O'Brien, Gregory L. Beatty. Multiple non-redundant immune checkpoints direct therapeutic resistance to chemotherapy and anti-CSF1R in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C029.
Abstract C050: The unique metabolic signatures of keratin-17 expressing pancreatic ductal adenocarcinomas
Authors: Salem Mahmoud M. , Horowitz Michael , Oblein Lyanne , Pan Chun-Hao , Marchenko Natalia , Escobar-Hoyos Luisa , Chen Bo , Shroyer Kenneth
Published: January 2024

Background: Overexpression of Keratin 17 (K17) is associated with upregulation of de novo pyrimidine synthesis, which is linked to resistance to gemcitabine (dC analog) and 5-fluorouracil (dT analog) in pancreatic ductal adenocarcinomas (PDAC). The metabolic rewiring associated with K17 in upstream pathways has not been defined, and the spatial relationships between K17 overexpression and the metabolome are unknown. Understanding these relationships may elucidate the roles of K17 in drug resistance and metabolic phenotypes of PDACs. We test the hypothesis that K17 is spatially linked to alterations of various metabolites, and that there exists an association with the upregulation of upstream pathways to de novo pyrimidine synthesis. Methods: KPC cells transduced to express wtK17 versus an empty vector were orthotopically implanted into the head of the pancreas of mice. Mice were administered 5-FU at 50 mg/kg twice a week. To evaluate the metabolic profile in situ, MALDI-MSI (Matrix-assisted laser desorption/ionization mass spectrometry imaging) was performed on snap-frozen tumor specimens. Following removal of the MALDI matrix, immunohistochemistry (IHC) was performed on the same sections for K17 to define elevated or low expressing regions. ROIs were selected within the MALDI-MSI for High K17, Low K17, and empty vector viable tissue. Principal component analysis was then performed on the mass spectra of these regions to provide unbiased pattern recognition. Results: The principal component analysis segregated K17-positive ROIs from empty vector (EV) ROIs, revealing that K17-positive tissue has a unique metabolic signature compared to EV tissue. Metabolites with loadings outside the 95th percentiles in the 5-component PCA included UMP, UDP, orotate, sedoheptulose 7-phosphate, glucose 6-phosphate, glutamate, malate, phosphoglycerate, and lactate. Conclusion: These metabolites, therefore, distinguish between the EV and K17-positive clusters. Further hierarchical clustering will be performed to provide a more comprehensive evaluation of the rewired pathways in pancreatic cancer.

Citation Format: Mahmoud M. Salem, Michael Horowitz, Lyanne Oblein, Chun-Hao Pan, Natalia Marchenko, Luisa Escobar-Hoyos, Bo Chen, Kenneth Shroyer. The unique metabolic signatures of keratin-17 expressing pancreatic ductal adenocarcinomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C050.
Abstract C099: Mutant-selective, covalent inhibitors of K-Ras(G12D)
Authors: Zheng Qinheng , Zhang Ziyang , Guiley Keelan , Shokat Kevan
Published: January 2024

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer. A high percentage (>90%) of PDAC patients harbor KRAS mutations, with the majority expressing the K-Ras(G12D) missense mutation protein. Despite extensive drug discovery efforts across academia and industry, there are no approved drugs directly targeting oncogenic K-Ras(G12D) in a mutant-selective manner. We have developed a series of small molecules that form covalent bonds with the mutant protein at its missense site. The lead molecule inhibits the interaction of K-Ras with effector proteins, and therefore inhibits growth of KRASG12D-driven cancer cell lines but not non-G12D cells.

Citation Format: Qinheng Zheng, Ziyang Zhang, Keelan Guiley, Kevan Shokat. Mutant-selective, covalent inhibitors of K-Ras(G12D) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C099.
Abstract PR10: Uridine-to-ribose axis supports glucose-restricted pancreatic cancer
Authors: Nwosu Zeribe C. , Ward Matthew H. , Sajjakulnukit Peter , Poudel Pawan , Ragulan Chanthirika , Kasperek Steven , Radyk Megan , Sutton Damien , Menjivar Rosa E. , Andren Anthony , Apiz-Saab Juan J. , Tolstyka Zachary , Brown Kristee , Lee Ho-Joon , Dzierozynski Lindsey , He Xi , Ps Hari , Ugras Julia , Nyamundanda Gift , Zhang Li , Halbrook Christopher J. , Carpenter Eileen , Shi Jiaqi , Shriver Leah P. , Patti Gary J. , Muir Alexander , di Magliano Marina Pasca , Sadanandam Anguraj , Lyssiotis Costas A.
Published: January 2024

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate of 12% in the USA. PDA highly rely on glucose but is surrounded by a nutrient-limited microenvironment. How PDA survive such condition, and the metabolites enabling that process, is unclear. To determine how PDA adapt to starvation, we profiled the utility of >175 metabolites by 21 pancreatic cell lines cultured in glucose limited condition. This nutrient profiling assay revealed that PDA use uridine when glucose is depleted. Uridine utilization strongly correlated with uridine phosphorylase 1 (UPP1) – the enzyme that breaks down uridine to uracil and ribose-1-phosphate. Metabolomics, including stable isotope tracing, revealed that when glucose is limited, PDA cells use the ribose from uridine to sustain central carbon metabolism and that this process is blocked upon the knockout of UPP1. We found that UPP1 is regulated by KRAS, is high in PDA, and correlates with poor survival in patients. Moreover, deletion of UPP1 blunted tumor growth in mice. Our data identify the uridine-ribose axis as a crucial compensatory pathway in nutrient-deprived PDA, suggesting a potential therapeutic target.

Citation Format: Zeribe C. Nwosu, Matthew H. Ward, Peter Sajjakulnukit, Pawan Poudel, Chanthirika Ragulan, Steven Kasperek, Megan Radyk, Damien Sutton, Rosa E. Menjivar, Anthony Andren, Juan J. Apiz-Saab, Zachary Tolstyka, Kristee Brown, Ho-Joon Lee, Lindsey Dzierozynski, Xi He, Hari Ps, Julia Ugras, Gift Nyamundanda, Li Zhang, Christopher J. Halbrook, Eileen Carpenter, Jiaqi Shi, Leah P. Shriver, Gary J. Patti, Alexander Muir, Marina Pasca di Magliano, Anguraj Sadanandam, Costas A. Lyssiotis. Uridine-to-ribose axis supports glucose-restricted pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR10.
TREX1 Inactivation Unleashes Cancer Cell STING–Interferon Signaling and Promotes Antitumor Immunity
Authors: Tani Tetsuo , Mathsyaraja Haritha , Campisi Marco , Li Ze-Hua , Haratani Koji , Fahey Caroline G. , Ota Keiichi , Mahadevan Navin R. , Shi Yingxiao , Saito Shin , Mizuno Kei , Thai Tran C. , Sasaki Nobunari , Homme Mizuki , Yusuf Choudhury Fabliha B. , Kashishian Adam , Panchal Jipsa , Wang Min , Wolf Benjamin J. , Barbie Thanh U. , Paweletz Cloud P. , Gokhale Prafulla C. , Liu David , Uppaluri Ravindra , Kitajima Shunsuke , Cain Jennifer , Barbie David A.
Published: January 2024

A substantial fraction of cancers evade immune detection by silencing Stimulator of Interferon Genes (STING)-Interferon (IFN) signaling. Therapeutic reactivation of this program via STING agonists, epigenetic, or DNA-damaging therapies can restore antitumor immunity in multiple preclinical models. Here we show that adaptive induction of three prime exonuclease 1 (TREX1) restrains STING-dependent nucleic acid sensing in cancer cells via its catalytic function in degrading cytosolic DNA. Cancer cell TREX1 expression is coordinately induced with STING by autocrine IFN and downstream STAT1, preventing signal amplification. TREX1 inactivation in cancer cells thus unleashes STING–IFN signaling, recruiting T and natural killer (NK) cells, sensitizing to NK cell–derived IFNγ, and cooperating with programmed cell death protein 1 blockade in multiple mouse tumor models to enhance immunogenicity. Targeting TREX1 may represent a complementary strategy to induce cytosolic DNA and amplify cancer cell STING–IFN signaling as a means to sensitize tumors to immune checkpoint blockade (ICB) and/or cell therapies.

Significance:

STING–IFN signaling in cancer cells promotes tumor cell immunogenicity. Inactivation of the DNA exonuclease TREX1, which is adaptively upregulated to limit pathway activation in cancer cells, recruits immune effector cells and primes NK cell–mediated killing. Targeting TREX1 has substantial therapeutic potential to amplify cancer cell immunogenicity and overcome ICB resistance.

This article is featured in Selected Articles from This Issue, p. 695
Network Analysis of Borderline Personality Features in Adolescence Using a Screening Tool in a Chinese Community Sample
Authors: Wang Qian , Li Zirong , Zhong Jie
Published: January 2024

Introduction: This study investigated the structure of the borderline personality features (BPFs) network and the most central BPF in adolescence. Methods: Cross-sectional self-report data from 4,866 Chinese adolescents (M = 13.96, SD = 1.64; 61.3% girls) were included in the network analysis models. BPFs were assessed with the McLean Screening Instrument for Borderline Personality Disorder. Results: Identity disturbance and affective instability emerged as the most central BPF in the current adolescent sample. In addition, chronic emptiness was also found with high centrality. The general networks of BPF were very similar between adolescent boys and girls, although some differences were detected. Discussion: This study further supports the necessity of BPD assessment and diagnosis in adolescence and identifies the distinctive importance of identity and affective dysregulation in the early development of BPD. The findings provide empirical insights into the interconnections of BPF, which resonate with therapeutic mechanisms of evidence-based treatments for BPD. However, the research was limited in its use of a screening measurement rather than a diagnostic tool. Future studies can further explore BPD psychopathology in adolescence with longitudinal data and clinical interviews.
Primary Pleural Epithelioid Angiosarcoma with Lung and Bone Metastases: A Case Report
Authors: Zhu Chenghua , Yang Ning , Yao Jing , Du Xingran
Published: January 2024

Introduction: Primary pleural epithelial angiosarcoma (EAS) is an extremely rare tumor with no specific clinical symptoms. Clinical data on primary pleural EAS are limited, and misdiagnosis often occurs. Case Presentation: The present study reports the case of a 31-year-old patient diagnosed with primary pleural EAS with lung and bone metastases. The patient presented with persistent right chest pain for 5 months and dyspnea for 2 months. Chest computed tomography (CT) scan revealed right hydropneumothorax, diffuse thickening of the right pleura, passive atelectasis, and scattered nodules in the left lung. A medical thoracoscopic pleural biopsy revealed a vasogenic tumor. To further confirm the diagnosis, positron emission tomography/CT (PET/CT) examination was recommended to determine the biopsy site after multidisciplinary discussion. Increased 18F-FDG uptake in the right pleura and hypermetabolic nodules in the right chest wall, first lumbar vertebrae, second sacral vertebrae, and bilateral iliac crest was detected via PET/CT. CT-guided chest wall and lung biopsies were performed. Immunohistochemistry of specific markers was performed according to remote consultation with a pathologist, and tumor cells with strong positive expression of CD31, CD34, and ETS-related genes led to the final diagnosis of primary pleural EAS. Conclusion: Primary pleural EAS should be considered for hydropneumothorax of an unknown cause. PET/CT can accurately locate the lesion. The pathological examination is the basis for primary pleural EAS diagnosis. Moreover, multidisciplinary discussion and remote expert consultation can improve the diagnosis rate of primary pleural EAS.
Hemangioma of the Urinary Bladder: A Brief Narrative Review of Their Diagnosis, Histology, and Treatment Options
Authors: Garaz Radion , Stühler Viktoria , Stenzl Arnulf , Rottscholl Robert , Amend Bastian
Published: January 2024

Background: Hemangioma of the urinary bladder is a rare benign tumor. Although benign, their presenting symptoms are alarming for both patients and doctors, and their rarity makes them challenging to correctly diagnosis and treat. This review paper summarizes current knowledge about hemangioma of the urinary bladder, treatment options, and follow-up modalities. Summary: After the kidney, the bladder is the second most common location of hemangiomas in the urinary tract. There is painless gross hematuria on clinical presentation once the lesion has eroded the urothelium. Magnetic resonance imaging (MRI) has been reported to be valuable in diagnosing soft-tissue hemangiomas. Cystoscopic findings of a sessile, blue, multilocular mass suggest hemangioma. Most tumors are solitary, smaller than 3 cm, and have smooth or irregular surfaces. Histologically, lesions comprise numerous proliferative capillaries with thin-walled, dilated, blood-filled vessels lined with flattened endothelium. The treatment of patients with hemangioma has been controversial. It depends on the tumor size and the degree of penetration. The prognosis of these tumors is excellent. Key Messages: Despite the widespread use of MRI, CT, and endoscopy in evaluating hematuria, hemangioma remains one of the rarest bladder tumors. Moreover, only a histological examination can confirm the diagnosis. Transurethral resection, fulguration, and YAG laser ablation are standard treatments for small tumors. In terms of follow-up, cystoscopy after 6 months of treatment helps assess recurrence. In addition, MRI is a practical, noninvasive technique for follow-up of small hemangiomas.
Effects of Extracorporeal Blood Flow Rates on Patient Tolerance for LIXELLE® Treatment during Outpatient Hemodialysis
Authors: Dhande Onkar S. , Teichert Arnaud , Broumand Varshasb , Kakita Haruki , Kitamura Ayaka , Fukunishi Masaaki , Argyropoulos Christos P. , Czirr Eva , Nelson Peter J.
Published: January 2024

Introduction: Accumulation of β2-microglobulin (B2M) in dialysis patients contributes to several comorbidities of end-stage kidney disease (ESKD). The LIXELLE® device adsorbs B2M from blood using sorbent bead technology. Studies in Japan showed that LIXELLE treatment during hemodialysis (HD) at blood flow rates up to 250 mL/min removes B2M above HD alone and is well tolerated. We investigated tolerance for LIXELLE treatment during HD at higher HD blood flow rates standard in the USA. Methods: A prospective, open-label, non-randomized, single-arm, early-feasibility study (EFS) assessed tolerance and safety of LIXELLE treatment during HD at blood flow rates up to 450 mL/min. ESKD patients (40–75 years old) on thrice weekly outpatient HD were eligible. After a 1-week HD run-in, patients received LIXELLE plus HD at a blood flow rate of 250 mL/min (1 week), followed by LIXELLE plus HD at a blood flow rate up to 450 mL/min (1 week). These blood flow rates were tested with three LIXELLE column sizes in sequence (treatment = 6 weeks). B2M removal was assessed for each combination. Results: Ten patients with a historic intradialytic hypotension (IDH) rate of 0.42 events/HD session/patient were enrolled. Nine patients completed all combinations without IDH events (treatment IDH rate: 0.56 events/HD session/patient). No treatment-emergent serious adverse events or significant changes in red blood cell, platelet, or complement indices except haptoglobin were reported. B2M reduction ratios and removal of select proteins (<40 kDa) increased with escalating column size and blood flow rate. Conclusion: LIXELLE plus HD across all column sizes was safe and well tolerated at blood flow rates up to 450 mL/min. Extent of B2M removal corresponded to column size-blood flow rate combinations. This EFS provides a risk profile to guide further studies of LIXELLE in ESKD patients at US-standard blood flow rates.
Shared Neuroanatomical Substrates for Co-Occurring Swallowing and Communication Impairments after Acute Stroke
Authors: Flowers Heather , Mikulis David , Silver Frank , Hour Kannika , Steffener Jason , Poublanc Julien , Rochon Elizabeth , Martino Rosemary
Published: January 2024

Introduction: Post-stroke dysphagia and communication impairments occur in two-thirds of acute stroke survivors. Identifying the shared neuroanatomical substrate for related impairments could facilitate the development of cross-system therapies. Our purpose was to elucidate discrete brain regions predictive of the combined presence of dysphagia alongside dysarthria and/or aphasia post-stroke. Methods: We included 40 right hemisphere stroke (RHS) and 67 left hemisphere stroke (LHS) patients from an acute ischemic stroke cohort with lesions demarcated on diffusion-weighted imaging. We undertook binary non-parametric voxel-lesion symptom mapping with a false discovery rate of p < 0.05 for co-occurring dysphagia, dysarthria, and aphasia (LHS only). If no voxels survived the threshold, a cluster analysis of >20 voxels involving an uncorrected p < 0.01 was applied to identify brain regions associated with the co-occurring impairments. Results: Cluster analyses revealed that dysphagia and dysarthria were associated with insular and superior temporal gyrus (STG) involvement after RHS and with basal ganglia (BG), internal capsule, and thalamic involvement after LHS. Co-occurring dysphagia, dysarthria, and aphasia were associated with BG, STG, and insular cortex involvement. Discussion: Our findings highlight the role of the insula and structures of the BG in co-occurrence patterns involving dysphagia, dysarthria, and aphasia. These newly identified biomarkers may inform new rehabilitation therapeutic targets for treating cross-system functions.
Intensive Blood Pressure Lowering and Renal Function in Ischemic Stroke Patients: Secondary Analysis of the ENCHANTED Trial
Authors: Chen Chen , Ren Xinwen , Zhao Yang , Ouyang Menglu , Li Mbiostat Qiang , Wang Xia , Li Yunke , You Shoujiang , Wang Yanan , Robinson Thompson G. , Lindley Richard , Arima Hisatomi , Chalmers John , Li Gang , Chen Xiaoying , Anderson Craig S. , Song Lili ,   ENCHANTED Investigators
Published: January 2024

Introduction: Renal failure is a major safety concern of intensive systolic blood pressure (SBP) lowering. We aimed to determine the effect of this treatment on early change in renal function in participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). Methods: Post hoc analysis of the ENCHANTED BP-arm in which thrombolyzed patients with acute ischemic stroke (AIS) were randomized to intensive (target 130–140 mm Hg within 1 h) or guideline-recommended (target <180 mm Hg) management within 6 h of symptom onset. Primary outcome is the early change in renal function, defined by a difference in estimated glomerular filtration rate (∆eGFR = 24 h – baseline eGFR), analyzed using linear regression with adjustment for clinical variables. Key SBP parameters were attained (mean), variability (standard deviation), and magnitude of reduction within 24 h. Results: Of 2,151 participants (mean age 66.9 years; 38% female) included with the available baseline eGFR, there were significant differences in attained 144.3 ± 10.2 versus 149.8 ± 12.0 [Δ5.5 mm Hg]; p < 0.0001), variation (15.1 ± 5.4 vs. 14.0 ± 5.6 mm Hg; p < 0.0001), and magnitude of reduction (44.6 ± 16.2 vs. 38.7 ± 17.6 mm Hg; p < 0.0001) in SBP within 24 h. 1,718 (79.9%) participants with complete follow-up eGFR were included in the primary analysis, and there was no significant difference in ∆eGFR (adjusted mean difference −1.10, 95% confidence interval [CI] −3.14 to −0.94; p = 0.29) between the intensive and guideline groups, respectively. The neutral effect on ∆eGFR was consistent in patients with different baseline eGFR stages and in sensitivity analysis after multiple imputations for missing follow-up eGFR. SBP variability was significantly associated with decreasing ∆eGFR (per 5 mm Hg increase by category: adjusted mean difference −1.35, 95% CI: −2.43 to −0.28; p for trend = 0.01). Conclusion: Intensive SBP lowering with a target of 130–140 mm Hg had no impact on early renal function in thrombolyzed AIS patients. Wide SBP variability was associated with a larger decline in eGFR.
Tierra de imbunches y ch’uqtas: la dis-capacidad como dispositivo colonial en América Latina y el Caribe
Authors: Vallejo Ortega Diana Carolina
Published: January 2024

Este ensayo analiza la dis-capacidad como un dispositivo colonial en América Latina, destacando las implicaciones ontológicas y ético-políticas que esto tiene especialmente para los cuerpos que han sido etiquetados como discapacitados. Asimismo, en este ensayo se propone una respuesta alternativa a esta ontología colonial, reconociendo la existencia de cuerpos no normativos, imbunches y ch'uqtas —términos estos que hacen referencia a las identidades y experiencias de las personas que desafían la normatividad impostada/importada, como formas singulares de resistencia desde la diáspora al discurso y las prácticas hegemónicas. La noción de dis-capacidad se examina, entonces, desde una mirada crítica y en una perspectiva decolonial del pensamiento latinoamericano, que la entiende como un constructo sociocultural que se utiliza en calidad de herramienta de dominación y opresión. Se sostiene, así, que la dis-capacidad es impuesta sobre los cuerpos para mantener y reproducir las estructuras de poder y control. Mientras que la diáspora se plantea como un espacio de apertura y posibilidad para la resistencia contra la ontología colonial de la dis-capacidad. Desde este lugar, se invita a repensar y cuestionar las categorías impuestas, promoviendo una concepción más inclusiva y respetuosa de la diversidad de los cuerpos.
 
[1] Palabra que en mapuzugun, la lengua del pueblo mapuche que habita el territorio sur de Chile y Argentina, quiere decir ‘persona deforme o desproporcionada’.
[2] Palabra que en Quechua, lengua que se habla en territorio peruano y boliviano, propia de nacionalidad Quechua, quiere decir ‘torcido o feo’.