tbuckley/cabot-search huggingface dataset:
Abstract A026: Studying the synergistic potential of a p53 reactivator with ROS-mediated therapies for the treatment of pancreatic cancer
Authors: Daniel Parra Sánchez, Andrés García-Sampedro, Isabela Laughland, Sylvain Peuget, Galina Selivanova, Stephen P Pereira, Pilar Acedo
Journal: Cancer Research (2024)

Abstract Introduction: Pancreatic cancer, with a dismal five-year survival rate of just 12%, demands innovative approaches due to its resistance to current therapies. TP53 mutations, present in 75% of patients, make mutant p53 an appealing target. Thus, p53 reactivation, restoring its tumour suppressor functions, represents a promising strategy to address this challenge. While the proposed reactivator has shown efficacy in other malignancies, its potential in pancreatic cancer therapy requires further exploration. Methods: In this project, we have assessed the potential of repurposing a reactivator of mutant p53 protein, to inactivate pancreatic cancer cells. We have performed RNA-sequencing analysis in patient-derived models available in the lab, to study the signalling pathways regulated by the p53 reactivator anticancer activity. We have also studied the possibility to synergistically combine this repurposing strategy with reactive oxygen species (ROS)-mediated therapeutic approaches, as we previously observed p53 reactivation inhibits the glutathione antioxidant pathway. Results: The combination treatment induced synergistic cell death (3-fold increase) compared to monotherapy as evaluated by different molecular assays (e.g. MTT and Live/Death Assay). It also increased ROS levels (Flow cytometry) and induced paraptosis and apoptosis (Western Blot, Tomography Electron Microscopy). The RNA-seq data revealed differential expression of more than 200 genes, confirming the activation of oxidative stress and a cellular response to unfolded proteins. Moreover, Sanger sequencing results demonstrated that the sensibility of each pancreatic model to treatment was dependent on the mutational status of TP53. Conclusion/discussion: The combination therapy of a TP53 reactivator and a ROS mediated therapeutic strategy works synergistically in patient derived models, inducing cell death and changes in the expression of certain RNAs directly involved in unfolded protein response. This pilot study shows that this combination is a feasible strategy to treat pancreatic cancer, setting the path for its testing on in vivo models. Citation Format: Daniel Parra Sánchez, Andrés García-Sampedro, Isabela Laughland, Sylvain Peuget, Galina Selivanova, Stephen P Pereira, Pilar Acedo. Studying the synergistic potential of a p53 reactivator with ROS-mediated therapies for the treatment of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A026.
Abstract C037: Characterization of cysteine dependency implicates glutathione metabolism as a critical adaptation axis in pancreatic cancer
Authors: Chiamaka J Ezeh, Matthew H Ward, Chesta Jain, Verodia Charlestin, Daeho D Kim, Andrew Yang, Maya Nassif, Nneka Mbah, Peter Sajjakulnukit, Anthony Andren, Li Zhang, Marina Pasca di Magliano, Costas A Lyssiotis, Zeribe C Nwosu
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer that is highly malignant and lethal. The treatment options are limited, contributing to its high mortality rate. PDAC is known to have profound metabolic alterations that enable its growth and survival. Here, we screened for amino acid dependency in PDAC cell lines and found that the cells cluster into cysteine highly dependent, moderately dependent, and independent cells. In the highly dependent cells, cysteine deprivation reduces viability by ∼90%, which could be rescued by glutathione (GSH) supplementation. Metabolomics revealed that cysteine deprivation led to GSH depletion, suggesting an impairment in the GSH pathway machinery in these cells. Consistently, most metabolite intermediates in the GSH pathway are downregulated in the cysteine-reliant PDAC cell lines compared to cell lines that resist cysteine deprivation, and those cells showed higher sensitivity to oxidative stress induction. Bioinformatics analysis of multiple PDAC tumor gene expression datasets indicated that the GSH pathway is strongly upregulated in PDAC and correlates with proliferation, metastasis, and oncogenic KRAS upregulation. Using CRISPR/Cas9, we found that the knockout of GSH genes enhanced sensitivity to oxidative stress. Our data implicate the GSH pathway as a critical nexus to be targeted to overcome metabolic adaptation in PDAC. Citation Format: Chiamaka J Ezeh, Matthew H Ward, Chesta Jain, Verodia Charlestin, Daeho D Kim, Andrew Yang, Maya Nassif, Nneka Mbah, Peter Sajjakulnukit, Anthony Andren, Li Zhang, Marina Pasca di Magliano, Costas A Lyssiotis, Zeribe C Nwosu. Characterization of cysteine dependency implicates glutathione metabolism as a critical adaptation axis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C037.
Abstract A078: Functional screen for mediators of onco-mRNA translation specificity in pancreatic cancer
Authors: Joanna R Kovalski, Goksu Sarioglu, Vishvak Subramanyam, Grace Hernandez, Gilles Rademaker, Juan A Oses-Prieto, Macey Slota, Kwun Wah Wen, Grace E Kim, Alma L Burlingame, Hani Goodarzi, Rushika M Perera, Davide Ruggero
Journal: Cancer Research (2024)

Abstract Oncogenic protein dosage is tightly regulated to enable cancer cells to adapt and survive. In healthy cells, translation initiation of onco-mRNA transcripts encoding oncogenes and growth factors is tightly regulated to maintain accurate protein expression levels. However, this process is broken in cancer cells, which rely on the maintenance of high dosage of oncogenic proteins for their survival and to drive cancer development. Whether this is regulated at the level of translational control and the key factors in cis and trans remain unknown. The Myc oncogene is a central paradigm of an exquisitely regulated oncogene and a major driver of pancreatic ductal adenocarcinoma (PDAC). While there has been a tremendous effort to target Myc in cancer, clinically relevant Myc inhibition remains a challenge. Therefore, identifying selective promoters of MYC translation may present a novel therapeutic opportunity. Employing a genome-wide CRISPRi screen for modulators of MYC mRNA translation initiation in PDAC cells, we identified regulators of selective MYC translation and validated four RNA binding proteins (RBPs), including epitranscriptome modifiers. We focused on a top hit, a little studied RBP, RBM42, which is highly expressed in PDAC and predicts poor patient survival. We found that RBM42 binds and selectively regulates the translation of MYC and a precise, yet vital suite of pro-oncogenic transcripts, including JUN and EGFR. Mechanistically, employing immunoprecipitation-mass spectrometry analysis, we found that RMB42 is a novel ribosome-associated protein (RAP). Through RNA structure determination and mutagenesis analysis, we showed that RBM42 directly binds and remodels the MYC 5’UTR RNA structure, facilitating the formation of the translation pre-initiation complex and increasing MYC translation. Importantly, we demonstrated that RBM42 is necessary for human PDAC cell growth and fitness and PDAC tumorigenesis in xenograft mouse models in a Myc-dependent manner in vivo. In PDAC patient samples, RBM42 expression is correlated with Myc protein levels and transcriptional activity. This work transforms our understanding of the translational code in cancer and offers a new therapeutic opening to target the expression of oncogenes. Citation Format: Joanna R Kovalski, Goksu Sarioglu, Vishvak Subramanyam, Grace Hernandez, Gilles Rademaker, Juan A Oses-Prieto, Macey Slota, Kwun Wah Wen, Grace E Kim, Alma L Burlingame, Hani Goodarzi, Rushika M Perera, Davide Ruggero. Functional screen for mediators of onco-mRNA translation specificity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A078.
Abstract A010: A patient first approach using CRISPR-directed gene editing as an augmentative therapy for the treatment of pancreatic ductile adenocarcinoma
Authors: London P McGill, Kelly H Banas, Gregory Tiesi, Eric B Kmiec
Journal: Cancer Research (2024)

Abstract At the Gene Editing Institute, we are advancing a novel strategy for the treatment of pancreatic ductile adenocarcinoma by employing CRISPR-directed gene editing to disable the functions of key genes that block effective drug application including chemotherapy, radiation and immunotherapy. No matter how careful one is at designing a specific drug against a specific protein, ultimately, the tumor cell develops a workaround. A paradigm shift is required to truly overcome this formidable barrier. We’ve accomplished this by leveraging the effectiveness of standard care and augmenting it, thereby reducing patient suffering, increasing treatment tolerance and, most importantly, improving outcomes. With an enthusiastic response for this concept from the FDA- INTERFACT meeting, we have demonstrated that a carefully selected CRISPR/Cas complex disables the NRF2 gene in the tumor cell and significantly reduces the dose of chemotherapy required to halt pancreatic tumor cell growth, and consequently promoting cell death. The efficiency of gene editing approaches 70 % routinely, which destroys the function of NRF2 and enables additional killing of residual tumor cells by chemotherapeutic agents. As a consequence of CRISPR/Cas activity, we effectively reduce the amount of chemotherapy needed to kill tumor cells by over 20-fold. This level of reduction should enable patients to complete their treatment regimens more successfully, at lower dosages and with far fewer adverse side effects. In addition to reduced suffering, this will invariably prolong survival as we are augmenting already proven treatments. This approach is agnostic to the haplotype of the tumor cell and does not rely on specific biomarker composition; radically expanding the patient population that would be suitable for this type of treatment. We will discuss the impact of CRISPR/Cas-gene editing to disable specific genes, including NRF2 and mutant KRAS, to enable current therapies to work at greater efficacy and at lower dosages. Citation Format: London P McGill, Kelly H Banas, Gregory Tiesi, Eric B Kmiec. A patient first approach using CRISPR-directed gene editing as an augmentative therapy for the treatment of pancreatic ductile adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A010.
Abstract C044: PI5P4Kα regulates cell fitness through iron homeostasis in pancreatic cancer
Authors: Gurpreet Kaur Arora, Ryan Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R Anderson, Chantal Pauli, David A Scott, Yoav Altman, Cosimo Commisso, Brooke M Emerling
Journal: Cancer Research (2024)

Abstract PI5P4Ks (Phosphatidylinositol 5-phosphate 4-kinases) are a family of lipid kinases that phosphorylate phosphatidylinositol 5-monophosphate (PI-5-P) at the 4-position to generate distinct pools of phosphatidylinositol 4,5-bisphosphate (PI-4,5-P2) largely on intracellular membranes. These lipid species are involved in cellular and metabolic stress responses, signaling and organelle communication. PI5P4Ks have been implicated in multiple cancers, with compelling evidence showing synthetic lethality when PI5P4Ks are inhibited in TP53-mutant cancer cells. Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive metabolic rewiring but despite the critical roles of PI5P4Ks in cellular metabolism, their role in PDAC remains completely unexplored. We have found that depletion of PI5P4Kα selectively induces apoptotic cell death in PDAC cells. To gain insights into the metabolic mechanisms underlying this apoptotic cell death, we quantified polar metabolites using gas chromatography- mass spectrometry (GC/MS) and found significant reductions in the ratio of monounsaturated to saturated fatty acids, lactate and TCA metabolites. Orthogonal rescue assays demonstrated that exogenous supplementation with fatty acids, pyruvate or lactate fail to rescue the observed apoptosis in PI5P4Kα-knockdown cells; however, TCA cycle metabolites did reverse the extent of apoptosis. Interestingly, we identify that these altered metabolic read-outs and the effects on cell fitness are dependent on iron. Consistent with these findings, intracellular iron levels are reduced upon PI5P4Kα inhibition, and this is directly linked to PI5P4Kα depletion disturbing the intracellular labile iron pools via iron import. Using a heterotopic xenograft mouse model, we demonstrate that PI5P4Kα knockdown leads to the abrogation of PDAC tumor growth due to increased intratumoral cell death. Validating the physiological relevance of PI5P4Kα in human PDAC, we find that PIP4K2A, the gene that encodes PI5P4Kα, is upregulated in human PDAC specimens relative to normal pancreas, and that PIP4K2A gene expression is strongly correlated with iron uptake related gene signatures. This study highlights the critical role of PI5P4Kα in PDAC and suggests that PI5P4Kα inhibition has therapeutic potential in pancreatic cancer. Citation Format: Gurpreet Kaur Arora, Ryan Loughran, Kyanh Ly, Cheska Marie Galapate, Alicia Llorente, Taylor R Anderson, Chantal Pauli, David A Scott, Yoav Altman, Cosimo Commisso, Brooke M Emerling. PI5P4Kα regulates cell fitness through iron homeostasis in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C044.
Abstract B079: Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases
Authors: Deanne E Yugawa, Ryan Kawalerski, Mariana Torrente Gonçalves, Chun-Hao Pan, Robert Tseng, Lucia Roa-Pena, Cindy V Leiton, Luke A Torre-Healy, Taryn Boyle, Sumedha Chowdhury, Natasha T Snider, Kenneth R Shroyer, Luisa F Escobar-Hoyos
Journal: Cancer Research (2024)

Abstract Keratin 17 (K17), an intermediate filament protein typically expressed during embryonic development, is a hallmark of one of the most aggressive pancreatic ductal adenocarcinoma (PDAC) subtypes. Its expression is also associated with poor patient survival and resistance to first-line therapies. However, the mechanistic roles of K17 in malignancy remain largely unexplored. Here, we demonstrate that K17 expression and disassembly enhance tumor growth, increase metastatic potential, and shorten overall survival. Using the Clinical Proteomic Tumor Analysis Consortium (CPTAC) stratified by K17 phosphorylation status, we found that increased K17 phosphorylation correlated with worse survival. Mass spectrometry of untreated PDAC patient samples identified a phosphorylation hotspot at serines 10-13, which is conserved across species and type I keratin proteins. We found that K17 phosphorylation, mediated by the PKC/MEK/RSK pathway, led to increased disassembly and nuclear translocation in pancreatic cancer cells. Mice with phosphomimetic mutations at the serine hotspot showed increased metastases and decreased survival compared to wild-type and phosphorylation-resistant K17. Lastly, detergent-soluble nuclear K17 promoted metastasis- related genes in both patient and murine tumors. These findings suggest that disassembly of K17 mediated by phosphorylation at serines 10-13 is sufficient to promote metastases and decrease overall survival in PDAC. This opens the door for further investigation into K17 phosphorylation as a novel therapeutic target to enhance PDAC patient survival, especially in those with more aggressive, chemoresistant subtypes. Citation Format: Deanne E Yugawa, Ryan Kawalerski, Mariana Torrente Gonçalves, Chun-Hao Pan, Robert Tseng, Lucia Roa-Pena, Cindy V Leiton, Luke A Torre-Healy, Taryn Boyle, Sumedha Chowdhury, Natasha T Snider, Kenneth R Shroyer, Luisa F Escobar-Hoyos. Disassembly of embryonic keratin filaments promotes pancreatic cancer metastases [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B079.
Abstract B047: Antigenic properties determine the outcome of B cell driven anti-tumor immunity
Authors: Colleen Sturdevant, Nancy Kren, Harrison Silva, Ismael Gomez, Austin Hepperla, Yuliya Pylayeva-Gupta
Journal: Cancer Research (2024)

Abstract B cells have the capacity to elicit both anti- and pro-tumorigenic effects; yet the determinants of productive B cell responses in cancer remain elusive. Using a system where a B cell neoantigen is either soluble or tethered to the surface of pancreatic cancer cells, we demonstrate that membrane-tethered antigen is sufficient to elicit activation of anti-tumor immunity and reduce tumor growth in an NK cell-dependent manner. We also show that decreased antigen affinity to the BCR promotes regulatory B cell function which can be overcome by increased avidity of membrane-tethered antigen. Furthermore, soluble and membrane-tethered antigens drive qualitatively distinct germinal center, plasma cell, memory B cell, and Treg responses. Finally, we describe two classes of membrane-associated antigens that correlate with GC B cell signature and improved survival in pancreatic cancer patients. Thus, antigen localization impacts basic mechanisms governing B cell differentiation and the resulting immune response to solid malignancy with implications for vaccine engineering. Citation Format: Colleen Sturdevant, Nancy Kren, Harrison Silva, Ismael Gomez, Austin Hepperla, Yuliya Pylayeva-Gupta. Antigenic properties determine the outcome of B cell driven anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B047.
Abstract B035: Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer
Authors: Kelly D DeMarco, Loretah Chibaya, Christina F Lusi, Griffin I Kane, Meghan L Brassil, Chaitanya N Parikh, Katherine C Murphy, Shreya R Chowdury, Junhui Li, Boyang Ma, Tiana E Taylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R Pitarresi, Lihua Julie Zhu, Katherine A Fitzgerald, Prabhani U Atukorale, Marcus Ruscetti
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma has quickly risen to become the 3rd leading cause of cancer- related death. This is in part due to its fibrotic tumor microenvironment (TME) that contributes to poor vascularization and immune infiltration and subsequent chemo- and immunotherapy failure. Here we investigated an innovative immunotherapy approach combining delivery of STING and TLR4 innate immune agonists via lipid-based nanoparticles (NPs) co-encapsulation with senescence-inducing RAS-targeted therapies that can remodel the immune suppressive PDAC TME through the senescence-associated secretory phenotype. Treatment of transplanted and autochthonous PDAC mouse models with these regimens led to enhanced uptake of NPs by multiple cell types in the PDAC TME, induction of type I interferon and other pro-inflammatory signaling, increased antigen presentation by tumor cells and antigen presenting cells, and subsequent activation of both innate and adaptive immune responses. This two-pronged approach produced potent T cell-driven and Type I interferon-mediated tumor regressions and long-term survival in preclinical PDAC models dependent on both tumor and host STING activation. STING and TLR4-mediated Type I interferon signaling were also associated with enhanced NK and CD8+ T cell immunity in human PDAC. Thus, combining localized immune agonist delivery with systemic tumor-targeted therapy can synergize to orchestrate a coordinated Type I interferon-driven innate and adaptive immune assault to overcome immune suppression and activate durable anti-tumor T cell responses against PDAC. Citation Format: Kelly D DeMarco, Loretah Chibaya, Christina F Lusi, Griffin I Kane, Meghan L Brassil, Chaitanya N Parikh, Katherine C Murphy, Shreya R Chowdury, Junhui Li, Boyang Ma, Tiana E Taylor, Julia Cerrutti, Haruka Mori, Miranda Diaz-Infante, Jessica Peura, Jason R Pitarresi, Lihua Julie Zhu, Katherine A Fitzgerald, Prabhani U Atukorale, Marcus Ruscetti. Nanoparticle delivery of innate immune agonists combines with senescence- inducing agents to mediate T cell control of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B035.
Abstract A020: Exocytosed amino acids as a selective and side effect-free therapy for pancreatic cancer
Authors: Alfred Akinlalu, Zachariah Flaten, Komila Rasuleva, Ang Guo, Sijo Mathew, Dali Sun
Journal: Cancer Research (2024)

Abstract Pancreatic adenocarcinoma (PDAC) remains one of the fatal cancers due to its poor prognosis and the lack of effective treatments, often diagnosed at advanced stages. There is an urgent need for innovative and selective therapies as current treatments show limited efficacy and significant side effects. Our proteomics analysis of extracellular vesicles from PDAC tumor cells revealed a distinctive imbalance in secreted amino acids. Specifically, we found that PDAC cells preferentially excrete proteins enriched with amino acids such as isoleucine and histidine, which are linked to disease progression. By targeting these exocytosed amino acids, we observed selective toxicity against PDAC cells in both in vitro and in vivo experiments. Additionally, we identified XRN1 as a potential target influenced by these amino acids. This approach demonstrated high selectivity, targeting tumor metabolism with minimal toxicity to normal tissues, and showed to be easy to administer with sustained tumor-killing effects. Our findings suggest that targeting exocytosed amino acids offers a promising therapeutic strategy for PDAC and potentially other cancers. Citation Format: Alfred Akinlalu, Zachariah Flaten, Komila Rasuleva, Ang Guo, Sijo Mathew, Dali Sun. Exocytosed amino acids as a selective and side effect-free therapy for pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A020.