tbuckley/cabot-search huggingface dataset:
Abstract IA15: What the surgeon has learned from pancreas cancer genomics, and vice versa
Authors: Steven Gallinger
Journal: Cancer Research (2024)

Abstract Recent advances in molecular profiling and fundamental science discoveries are impacting care of PDAC patients, including surgical decision making. Our multidisciplinary group at the Ontario Institute for Cancer Research and the Princess Margaret in Toronto has focused on elucidating both germline and somatic genomic changes in PDAC, with aims to understand genetic predisposition to the disease, foster early detection and conduct trials for improved selection of standard and novel therapies. Using laser capture microdissection overseen by expert pathologists, seamless tumor banking and aggressive biopsy of chemo-naïve and progressive metastases, we have generated high epithelial tumor cell content whole genomes and transcriptomes (WGTS) on over 600 PDAC patients with all stages of the disease. Germline sequencing of all PDAC patients should be considered standard of care to detect patients with uniquely actionable genomic changes due to less common mutational pathways. The genetic basis of familial pancreas cancer remains elusive and we continue to collaborate with the PACGENE Network spearheaded by colleagues at Mayo, Hopkins and McGill to discover novel genes in high risk cases. Our genomic work and others explains the clinical conundrum of late presentation of PDAC due to rapid punctuated evolution which challenges the ‘holy grail’ of early detection. Thus, screening high risk groups is still within the realm of investigational studies such as the PRECEDE consortium, of which we are an active member. Focused clinical trials (eg COMPASS and PASS-01) using WGTS has revealed both large scale changes in genomes (eg. HRD, tandem duplicators, etc) and transcriptomes (the Moffit ‘continuum’) and discreet mutations (eg BRAF mutations in Kras wild type tumors) that are important to identify as early as possible in the patient’s clinical course. Subspecialty PDAC surgeons need to keep abreast of recent developments of both prognostic and predictive transcriptomic biomarkers that will soon be important in selecting appropriate patients for appropriate neoadjuvant therapies. A few clinical vignettes will be shown to provide evidence for the importance of WGTS and other profiling approaches for almost all PDAC patients. Citation Format: Steven Gallinger. What the surgeon has learned from pancreas cancer genomics, and vice versa [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 IA15.
Abstract PR10: Uridine-to-ribose axis supports glucose-restricted pancreatic cancer
Authors: 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
Journal: Cancer Research (2024)

Abstract 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 &amp;gt;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.
Abstract B084: Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling
Authors: Qingxiang (Nick) Lin
Journal: Cancer Research (2024)

Abstract Background: RAS mutations occur in ~20% of all cancers that drive tumor progression, and therapy targeting most predominant RAS mutations remains unavailable. Mutant-selective RAS inhibitors (RASi), such as FDA-approved KRAS G12C inhibitors, have demonstrated initial clinical responses but drug resistance frequently emerges that minimize the drug efficacy, mechanistically mediated by RAS signaling reactivation. Methods and Results: To address this challenge, we characterized a class of novel pan-RASi that universally inhibit all RAS mutations, which forms a ‘tri-complex’ with the chaperone protein (cyclophilin A) that specifically binds to RAS, including wild-type RAS (KRAS, NRAS, HRAS). Mutant-selective RASi induced RAS signaling rebound intensively, whereas pan-RASi enabling to inhibit wild-type RAS minimized this rebound, which was surmountable in a concentration-dependent manner. Importantly, pan-RASi abrogated cell viability in patient-derived KRAS-mutant cancer organoids rather than in normal patient-derived wild-type RAS organoids, implicating drug selectivity and manageable toxicity. Interestingly, intrinsic resistance to pan-RASi was rare in RAS-mutant cancer cell screening but was observed only in a handful of pancreatic and lung cancer cell lines. Our time-resolved signaling analyses of pan-RASi treatment showed the re-activation of mTOR signaling and a contrast correlation that mTOR signaling decreased in sensitive lines but remained in resistant lines, underscoring the critical contribution of mTOR pathways to RASi resistance. Mechanistically, we further identified mTOR signaling that drives intrinsic resistance to pan-RASi, and combined pan-RASi with mTOR inhibitors (mTORi) suppressed mTOR signaling in resistant lines, thereby improving efficacy. Conclusion: Pan-RASi hold promise in treating RAS-mutant cancer clinically and a combination of pan-RASi with mTORi can improve drug efficacy. Citation Format: Qingxiang (Nick) Lin. Overcoming drug resistance of ‘tri-complex’ pan-RAS inhibitors: Inhibition of mTOR signaling [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 B084.
Abstract C079: Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new approach to treat pancreatic cancer
Authors: Bruno Jr Sainz, Sonia Alcalá, Lara Villarino, Laura Ruíz-Cañas, José Couceiro, Miguel Martínez-Calvo, Adrián Palencia-Campos, Diego Navarro, Pablo Cabezas-Sainz, Alfonso Cordero-Barreal, Juan A. Rubiolo, Cristina González-Páramos, Alfredo Carrato, Patrick C. Hermann, Laura Sánchez, Susana Torrente, Miguel Ángel Fernández-Moreno, José L. Mascareñas
Journal: Cancer Research (2024)

Abstract Background and aims: Annual world-wide cancer-related fatalities remain high for pancreatic ductal adenocarcinoma (PDAC), largely due to the presence of “stem-like” tumor cells known as cancer stem cells (CSCs). Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic CSCs meet their energetic requirements; therefore, OXPHOS represents an Achille’s heel of these highly tumorigenic cells. Methods: The anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) was evaluated across primary PDAC cultures and 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. Results: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for PaCSCs that heavily depend on mitochondrial respiration. Conclusion Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover an unprecedented approach to fight PDAC based on targeting CSC OXPHOS. Citation Format: Bruno Jr Sainz, Sonia Alcalá, Lara Villarino, Laura Ruíz-Cañas, José Couceiro, Miguel Martínez-Calvo, Adrián Palencia-Campos, Diego Navarro, Pablo Cabezas-Sainz, Alfonso Cordero-Barreal, Juan A. Rubiolo, Cristina González-Páramos, Alfredo Carrato, Patrick C. Hermann, Laura Sánchez, Susana Torrente, Miguel Ángel Fernández-Moreno, José L. Mascareñas. Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new approach to treat 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 C079.
Abstract C072: Andrographolide exhibits anti-cancer activity via restoring DNMT3B-suppressed ZNF382 expression in pancreatic cancer
Authors: Kai-Ru Zhuang, Hsin-Yu Chan, Chian-Feng Chen, Shu-Ling Fu
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive and lethal malignancy. Due to the lack of early diagnosis and the limited response to current clinical treatments, PDAC has a high recurrence rate and a poor 5-year survival rate. Andrographolide, a labdane diterpenoid compound and the main active ingredient found in the medicinal plant Andrographis paniculata, is known for its anti-cancer effects against a variety of cancer types. Nevertheless, there are few studies on the anti-cancer activity and underlying mechanism of andrographolide against PDAC. We recently found that andrographolide suppressed cell viability, proliferation and migration abilities of PDAC cells, as well as impaired tumor growth in vivo. Notably, andrographolide induced the mRNA and protein expression of Zinc finger protein 382 (ZNF382) in PDAC cells. ZNF382 functions as a transcription repressor but its biological function in pancreatic cancer remains unclear. Through analysis of pancreatic adenocarcinoma (PAAD) patient data from TCGA, the expression of ZNF382 is lower in tumor samples than in normal tissues, and patients with higher ZNF382 expression showed better overall survival rates. Recently, we confirmed that ZNF382 expression was significantly decreased in clinical tumor tissues compared with matched normal tissues in 9 out of 10 pancreatic cancer patients. In addition, we demonstrated that overexpression of ZNF382 inhibited malignant phenotypes of PDAC cells and suppressed tumor growth in mice. Based on TCGA database analysis, the ZNF382 promoter is hypermethylated in primary pancreatic tumors, and this hypermethylation pattern correlates with its low expression. We further showed that andrographolide treatment inhibited the expression of DNA methyltransferase 3 beta (DNMT3B) and promoted the demethylation of ZNF382 promoter in PDAC cells. Notably, overexpression of DNMT3B attenuated both the andrographolide-induced expression of ZNF382 and its associated anti-cancer effects. In summary, our findings indicate that ZNF382 serves as a tumor suppressor in pancreatic cancer and suggest that andrographolide exerts its anticancer effects in pancreatic cancer through the suppression of DNMT3B-dependent DNA methylation, leading to the reactivation of ZNF382 expression. Citation Format: Kai-Ru Zhuang, Hsin-Yu Chan, Chian-Feng Chen, Shu-Ling Fu. Andrographolide exhibits anti-cancer activity via restoring DNMT3B-suppressed ZNF382 expression 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 C072.
Abstract A105: Wild-type IDH1 inhibition enhances chemotherapy response in pancreatic cancer
Authors: Mehrdad Zarei, Omid Hajihassani, Jonathan J. Hue, Hallie J. Graor, Alexander W. Loftus, Luke D. Rothermel, Jordan M. Winter
Journal: Cancer Research (2024)

Abstract Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer, with a five-year overall survival rate of 12% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with the rapid development of drug resistance. We examined mechanistic and therapeutic implications of combining anti-wild-type IDH1 therapy with conventional chemotherapeutics to treat PDAC. Methods: Therapeutic responses were tested in vivo and in vitro through survival studies, testing for the effects of ivosidenib (an allosteric IDH1 inhibitor) and PDAC chemotherapeutics. Usage of ivosidenib is based on pre-clinical work showing anti-wild-type IDH1 activity under tumor associated conditions. Results: Chemotherapy treatment of PDAC cells induced the production of reactive oxygen species and increased TCA cycle activity. Treatment also resulted in the rapid induction of wild-type IDH1 expression, which served as a key resistance factor. The enzyme is protective under chemotherapy-associated stress by supporting antioxidant defense and mitochondrial function, through the generation of NADPH and alpha-ketoglutarate, respectively. Pharmacologic suppression of wild-type IDH1 was synergistic with conventional chemotherapeutics in vitro, and potentiated sub-therapeutic doses of these drugs in murine PDAC models. Conclusions: Pharmacologic wild-type IDH1 inhibition with ivosidenib proved to be cooperative with conventional PDAC chemotherapeutics in diverse models. This promising new treatment approach is easily translatable, and provides the basis of an ongoing clinical trial (NCT05209074). Citation Format: Mehrdad Zarei, Omid Hajihassani, Jonathan J. Hue, Hallie J. Graor, Alexander W. Loftus, Luke D. Rothermel, Jordan M. Winter. Wild-type IDH1 inhibition enhances chemotherapy response 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 A105.
Abstract B034: Antigen-presenting cancer-associated fibroblasts are found in immunotherapy-sensitive murine models of pancreatic ductal adenocarcinoma
Authors: Saumya Maru, Kathryn Howe, Lalitya Andaloori, James Leatherman, Joseph Tandurella, Edward J. Pearce, Elizabeth M. Jaffee
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths. Despite the advent of immune checkpoint inhibition (ICI) that has markedly changed the treatment landscape for select tumors with respect to both outcomes and tolerability, PDAC remains unresponsive to such an approach. One feature of the PDAC tumor microenvironment (TME) that remains poorly understood is the interaction between cancer-associated fibroblasts (CAFs) and immune and tumor cells. Unique subsets of CAFs have been identified, including antigen-presenting CAFs (apCAFs) which are defined by expression of MHC-II and can activate CD4 T cells in genetically engineered mouse models of PDAC. apCAFs are rarely found in human PDAC; in a human PDAC atlas consisting of six published human single cell RNA-sequencing (scRNA-seq) datasets, we identified 370 apCAFs out of 8736 total CAFs, the majority of which were found in one dataset. Here, we have orthotopically implanted cell lines derived from the autochthonous KPC murine model of PDAC which mimics the stromal components of human disease to further study the influence of apCAFs on the anti-tumor response. We have found that although the overall CAF population is equivalent between tumors, apCAFs are present primarily in tumors derived from KPC cell lines that display ICI sensitivity. apCAFs sorted from these tumors and pulsed with OVA peptides upregulated CD25 and CD69 expression on naïve OT-II CD4 T cells, confirming that apCAFs in our system can present via MHC-II. Furthermore, these apCAFs increased CD4 activation markers upon ex-vivo coculture with dissociated KPC tumors. We therefore hypothesize that apCAFs are required for the ICI-mediated anti-tumor effect and do so via modulation of CD4 T cell responses. Although a small proportion of the total compartment, the apCAF subset may be enhanced in number and function by CAF-targeted modulators to synergize with ICI to affect the antitumor response, which could provide a solution to the currently unmet need for new and more effective treatments for PDAC patients. Citation Format: Saumya Maru, Kathryn Howe, Lalitya Andaloori, James Leatherman, Joseph Tandurella, Edward J. Pearce, Elizabeth M. Jaffee. Antigen-presenting cancer-associated fibroblasts are found in immunotherapy-sensitive murine models of 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 B034.
Abstract A106: Single cell RNA sequencing of EPCAM+ cells reveals unique malignant biology
Authors: Edward H. Arbe-Barnes, Ashwin Jainarayanan, Enas Abu-Shah, Rachael J.M. Bashford-Rogers, Shivan Sivakumar
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is notable due to its complex and dense stroma which comprises a high proportion of non-malignant cells. Studying PDAC epithelial cells at the single cell level may yield insights which have not been appreciated through bulk tissue analysis. We analysed a novel single cell RNA sequencing (scRNA seq) dataset of 11000 epithelial (EPCAM+) cells from 7 resected PDAC samples and used a validation cohort of 43 samples from two published scRNA seq datasets. Malignant epithelial cells were identified by: gene expression, changes in copy number, and by the presence of known PDAC single nucleotide variants. This confirmed that sorting for EPCAM+ cells prior to scRNA seq resulted in an enriched proportion of malignant vs non-malignant tumor epithelial cells. This dataset of enriched single cell dataset was therefore useful for studying the influence of intrinsic malignant cell factors on PDAC biology. We observed that malignant cells do not segregate into classical or basal-like signatures, despite these being clinically validated bulk transcriptomic tumor subtypes. Indeed, classical and basal-like signatures module scores in PDAC in individual malignant cells were positively correlated, suggesting they are not divergent programs in malignant cells. Bulk transcriptomic signature subtypes are therefore most likely to reflect differences in PDAC tissue stroma, rather than in intrinsic malignant cell factors. Moreover, we sort to investigate intra- and inter- sample heterogeneity to understand the intrinsic malignant cell factors which may influence the biology of PDAC. We analysed single cell velocity to understand the dynamics of malignant cell states. This showed heterogeneity in expression of known pan-cancer malignant cell meta-programs which identified a population of cells with high expression of cell cycle genes, suggesting greater proliferation. We then explored expression of immune modulating genes to determine how malignant cells influence the immunosuppressive microenvironment. For example, we identified heterogeneity in HLA class 1 and antigen presentation gene expression which may be a mechanism of immune suppression in PDAC. Together these data demonstrate how studying scRNA seq of EPCAM+ cells reveals intrinsic malignant cell factors which cannot be appreciated through bulk RNA seq. Citation Format: Edward H. Arbe-Barnes, Ashwin Jainarayanan, Enas Abu-Shah, Rachael J.M. Bashford-Rogers, Shivan Sivakumar. Single cell RNA sequencing of EPCAM+ cells reveals unique malignant biology [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 A106.