bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B071: Preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal adenocarcinoma
Authors: Wasko Urszula N. , Sastra Stephen A. , Palermo Carmine F. , Wildes David , Singh Mallika , Olive Kenneth P. 
Published: November 2022

Abstract
Approximately 95% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, accounting for over 45,000 deaths per year in the United States. In KRAS-mutant cells, KRAS protein exists predominantly in an active, GTP-bound state, leading to excessive oncogenic signaling via RAF/MEK/ERK and other effector pathways. After decades of anticipation, the first therapeutic inhibitors of this oncoprotein target a specific mutant allele (KRASG12C) and have shown promising results in this rare subset of human PDAC patients (1-2% of cases). While these encouraging clinical results bolster support for targeting RAS in human PDAC, most patients harbor KRASG12D and KRASG12V mutations and remain unserved by targeted therapies. Here we report preclinical studies of RM-042, a first-in-class, potent, oral, small molecule inhibitor of GTP-bound RAS proteins, designed to treat cancers driven by a variety of RAS mutations. RMC-6236, a clinical candidate and RM-042, a tool compound, both act through non-covalent binding to an abundant intracellular chaperone protein, cyclophilin A (CypA), resulting in a binary complex that engages GTP-bound RAS to form a high-affinity, RAS-selective tri-complex that sterically inhibits RAS binding to effectors. We examined the anti-tumor activity of RM-042 in two complementary preclinical model systems of PDAC. Using primary human PDAC explant cultures (tissue slices cultured intact in optimized media for up to one week), we found that RM-042 potently inhibits phospho-ERK expression (a marker of KRAS/RAF/MEK pathway activity), in a concentration-dependent manner. Loss of pERK expression in tumors was also associated with reduced viability, and altered stromal content. Pilot studies in the K-rasLSL.G12D/+, p53LSL.R172H/+, Pdx1Cretg/+ (KPC) mouse model of PDAC found that RM-042 induced tumor stabilizations and regressions associated with loss of pERK expression, and alterations in apoptosis and proliferation, at tolerated doses. Ongoing studies will determine the duration of tumor responses and assess the mechanisms by which RM-042 may impact both epithelial and stromal cell populations. Together, these studies provide complementary evidence from in vivo murine and ex vivo human models for anti-tumor activity in response to GTP-Ras inhibition, supporting the inclusion of PDAC patients in future clinical trials of RMC-6236.
Citation Format: Urszula N. Wasko, Stephen A. Sastra, Carmine F. Palermo, David Wildes, Mallika Singh, Kenneth P. Olive. Preclinical evaluation of RM-042, an orally bioavailable inhibitor of GTP-RAS, in models of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B071.
Abstract B081: Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells
Authors: Choudhury Sangeeta , Chopra Neha , Jain Kriti , Yadav Poonam , Singh Surinder P. , Charla Yashika 
Published: November 2022

Abstract
The knowledge of immunomodulatory and reparative properties of Mesenchymal Stem cells (MSCs) are rapidly advancing and could be best suited as a therapeutic option for inflammatory or adverse immunological conditions such as cancer. In the last decade, Mesenchymal stem cells have attracted significant attention because of their accessibility, tumor-oriented homing capacity and the transplantation feasibility. Until date, MSC-based therapy for pancreatic cancer has not been demonstrated. As per the current understanding of the potentials of MSCs in regenerative medicine, we hypothesized their inhibitory influence on pancreatic cancer cells. For experimentation purposes, we have used human Wharton’s jelly derived MSCs (hWJ-MSCs) and pancreatic cell line models. Our findings show that secretion of soluble biologically active factors from hWJ-MSCs (secretome) had a greater impact on induction of anergy and apoptosis of pancreatic tumor cells. The mechanistic approach directed to influence the tumor microenvironment appear to be two pronged: one, via modulation of tumor glycoproteins (MUC-1 and EpCAM) and second, via GSK3β/Stat3/HIF1-α axis. Treatment with calcitriol, an analogue of Vitamin D known to regulate cell cycle, cell differentiation ca also reduce side effects of chemo-drugs, one of the mainstay of therapy in pancreatic cancer. Yet, the potential mechanism to exert anti-cancer effect remains underexplored. We attempted to elicit the involvement of VitD in one of the crucial stem-cell related embryonic pathway, the Sonic Hedgehog (SHH) pathway. Our data showed enhanced apoptosis of calcitirol treated-pCSCs cells when treated with salinomycin (SHH inhibitor). Further combinatorial treatment with secretome + VitD decreased copy numbers of transcription factors C-myc, SMO, PTCH1, PTCH2, and hypoxia-induced factor (HIF1-α) demonstrating the potential mechanism of action. In conclusion, our experimental evidence postulates a potential mechanism by which VitD-analogue regulate sHH-mTOR axis and in combination with mesenchymal stem cell secretome can affect the proliferation and migratory (oncogenic) capabilities of pancreatic cancer stem cells. So, what next? Do we have the evidence to suggest secretome as a novel cell-free therapeutic candidate!!
Citation Format: Sangeeta Choudhury, Neha Chopra, Kriti Jain, Poonam Yadav, Surinder P. Singh, Yashika Charla. Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B081.
Abstract C070: Investigation of the roles of BDKRB1 in pancreatic cancer progression and tumor microenvironment modulation
Authors: Li Ching-Fei , Fu Jie , Lee Heng-Huan , Wang Ying-Nai , Chu Yu-Yi , Chiao Paul J. , Hung Mien-Chie 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with features of early metastasis and extensive desmoplasia which is the growth of fibrous or connective tissue. The PDAC patient outcomes have not improved in decades, albeit a plenty of therapies that target PDAC have been tested but failed. It could be due to most research focused on tumor cells, whereas the effect of the stroma and immune cells during tumor progression has been largely ignored. Bradykinin receptor B1 (BDKRB1), one of the cell-surface G protein-coupled receptors plays a crucial role in the physiological process associated with coagulation, vasodilation and promotes fibrotic diseases and inflammation in pathological conditions. Based on the analyzed results of Cancer Genome Atlas (TCGA) database, BDKRB1 mRNA is upregulated in PDAC patients. Of note, BDKRB1 mRNA level positively associates with several activated human pancreatic stellate cells (HPSCs; the main fibroblastic cells of the pancreas)-related genes such as CTGF (connective tissue growth factor), IL6 (interleukin 6), and PDGFB (platelet derived growth factor subunit B) in PDAC patients. Interestingly, the conditioned medium from des-Arg9-bradykinin treated-HPSCs can induce M2-like macrophages polarization which dictate clinically relevant immunosuppression in metastatic tumors and express immunosuppressive cytokines such as IL-10, CCL17 and CCL18, implying that activation of BDKRB1 not only stimulates PDAC growth, but also causes HPSCs activation, desmoplasia and immune suppression, followed by exacerbating tumor progression. Moreover, a chemotherapy gemcitabine remains a cornerstone of PDAC treatment in all stages of PDAC despite of the low therapeutic efficacy, we demonstrated that treatment of gemcitabine increases the expression of BDKRB1 in HPSCs and PDAC, indicating that activation of BDKRB1 could be one of the mechanisms involved in gemcitabine resistance. Here, we hypothesize BDKRB1 activation may orchestrate the tumor microenvironment which promotes PDAC progression by inducing tumor cells survival, HPSCs activation, immune suppression, and may contribute to chemotherapy resistance. The outcomes of this proposal will provide not only a novel cellular and molecular mechanism involved in progression of PDAC, but also highlight a potential therapeutic approach to improve PDAC treatment.
Citation Format: Ching-Fei Li, Jie Fu, Heng-Huan Lee, Ying-Nai Wang, Yu-Yi Chu, Paul J. Chiao, Mien-Chie Hung. Investigation of the roles of BDKRB1 in pancreatic cancer progression and tumor microenvironment modulation [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C070.
Abstract C072: Cytokine modulation can suppress an EMT-like phenotype in pancreatic cancer
Authors: Bell Whitney , Kren Nancy , Wang Yan , Pylayeva-Gupta Yuliya 
Published: November 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate of only 11% and approximately half of patients present with distant metastasis at the time of diagnosis. PDAC is accompanied by pronounced alterations in stromal responses and immune surveillance programs, which are now recognized as some of the major drivers in PDAC tumor evolution. The role of immune modulators in driving metastatic potential in PDAC is poorly understood. We find that low expression levels of cytokine IL-23 in patients with PDAC correlate with poor differentiation status of these tumors, and thus predict poor outcomes. Consistent with this observation, we have found that a loss of host-derived IL-23 in a mouse model of pancreatic cancer promotes an EMT-like phenotype. The tumor morphology is altered and appears to be less differentiated. Additionally, we see a significant increase in the number of tumor cells expressing Zeb1 and a decrease in E-cadherin expression. We also find an increase in metastatic capacity in the absence of IL-23 in the tumor stroma. Single cell RNA sequencing of tumors injected orthotopically into IL-23 knockout mice reveals clusters of tumor cells with increases in EMT-associated genes such as Zeb1 and Vimentin and concurrent decreases in gastric identity genes. Overall, our findings indicate that IL-23 plays a role in suppressing an EMT-like phenotype in pancreatic cancer with one mechanism being through regulation of gastric lineage genes.
Citation Format: Whitney Bell, Nancy Kren, Yan Wang, Yuliya Pylayeva-Gupta. Cytokine modulation can suppress an EMT-like phenotype in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C072.
Abstract IA007: Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in cancer
Authors: Shalek Alex K. 
Published: November 2022

Abstract
Recent advances in high throughput genomic sequencing technologies have led to a detailed understanding of the genetic alterations that underlie human tumors. However, evidence increasingly indicates that using mutations alone to assign therapies has its limitations, even for cancers with actionable mutational heterogeneity. The advent of single-cell genomic technologies has confirmed extensive mutational heterogeneity in human tumors but also revealed that the complexity of cancer extends to variation in cell transcriptional state. Deciphering whether transcriptional variation informs treatment response heterogeneity represents a new but poorly understood frontier in cancer therapeutics. In pancreatic ductal adenocarcinoma (PDAC), clinically relevant RNA expression states exist but our understanding of their drivers, stability, and relationship to therapeutic response is limited. To examine these attributes systematically, we profiled metastatic biopsies and matched organoid models at single-cell resolution. We identify a new intermediate PDAC transcriptional cell state and uncover distinct site- and state-specific tumor microenvironments. Moreover, we reveal strong organoid culture-specific biases in cancer cell transcriptional state representation and nominate critical factors missing from the ex vivo microenvironment. By adding back specific factors, we restore in vivo expression state heterogeneity and show plasticity in culture models, demonstrating that microenvironmental signals are critical regulators of cell state. Importantly, we prove that non-genetic modulation of cell state can significantly influence drug responses and uncover state-specific vulnerabilities. Our work provides a broadly applicable framework for mapping cell states across in vivo and ex vivo settings, identifying drivers of transcriptional plasticity, and manipulating cell state to target its associated vulnerabilities.
Citation Format: Alex K. Shalek. Does cancer cell state matter? Moving from DNA genotype to RNA phenotype-directed therapies in cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA007.
Abstract IA010: Meeting the challenge of pancreatic cancer
Authors: Philip Philip A. 
Published: November 2022

Abstract
Approximately one third of patients (pts) with pancreatic adenocarcinoma (PDA) present with locally advanced unresectable disease (LAPC). Majority of pts with LAPC have micrometastatic disease at presentation. However, median survival times exceed those of pts with radiologically visible metastases and is currently around 14-16 months (versus less than 1 year). Initial treatment strategies in LAPC focused on radiation that did not improve survival. With improvements in systemic therapies, current treatments of LAPC are based on cytotoxic combinations similar to ones used in metastatic PDA. However, benefits of cytotoxic therapy remain very modest. Unfortunately, the development of systemic therapy for PDA was plagued by repeated failures of randomized clinical trials of a range of targeted and other agents. In recent years, we exponentially advanced knowledge of PDA’s molecular biology and are attempting to learn from our clinical failures. One thing that stood out, with very few exceptions, is lack of success in single target/pathway strategies, especially in the absence of predictive biomarkers and lack of targetable “driver” mutations. Immune checkpoint inhibitors were ineffective unlike successes in other cancers. Focus has therefore shifted to rational strategies based on biology that defines phenotype along with ongoing attempts to refine molecular characterizations of PDA. Major research strategies include targeting the stroma to enhance drug delivery (e.g., CEND-1), reversing the immune suppressive microenvironment (combinatorial immunotherapy), exploiting DNA repair defects (e.g., BRCA mutations), and most importantly tackling KRAS oncogene. KRASG12C, KRASwt, BRCAmutated, and microsatellite instability provide additional treatment opportunities in up to 10% of PDA patients. The goal of new therapy developments in LAPC must address the locoregional morbidity of the primary tumor with the ultimate goal of prolonging survival. Examples of ongoing research in locoregionally directed therapy include ablative radiation and tumor treating fields (TTF) that attempt to control its growth, reduce the tumor bulk, and improve possibilities of tumor resection. As our systemic therapies improve, locoregional therapy becomes more relevant. Improvements in molecular classifications of PDA, refinements in the use of organoids to predict drug and radiation effect, and use of liquid biopsies are examples of measures that will provide foundations for personalized treatment approaches. Collectively, we have endless opportunities for translational research based on advances in PDA’s basic science and our experiences from the many “negative” clinical trials.
Citation Format: Philip A. Philip. Meeting the challenge of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA010.
Abstract IA014: Collagen cleavage controls PDAC metabolism and malignancy via a DDR1-NRF2 cascade and mitochondrial biogenesis
Authors: Karin Michael , Su Hua 
Published: November 2022

Abstract
PDAC is distinct by being highly desmoplastic, due to the activation and eventual infiltration of cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) they produce, which is mainly composed of collagen type I (Col I). The role of fibroblasts and collagen in PDAC pathology is highly contentious, ranging from tumor stimulatory to tumor inhibitory. Using mouse models and human specimens we found that the way in which Col I affects PDAC progression, metabolism and its response to therapy is highly dependent on its cleavage by matrix metalloproteases (MMP). Whereas noncleaved Col I inhibits PDAC metabolism, inhibits human and mouse PDAC growth in mice and is correlated with improved survival after surgical resection, MMP generated Col I fragments stimulate tumor metabolism and growth and correlate with poor post-resection survival. These differential activities of cleaved and noncleaved Col I depend on its interactions with the receptor tyrosine kinase DDR1. Whereas MMP-generated Col I binds DDR1 and activates it, intact Col I induces DDR1 degradation. By activating DDR1, cleaved Col I triggers an NF-kB-p62-NRF2 signaling cascade, whose major efferent, NRF2, controls many aspects of PDAC metabolism, including macropinocytosis, aerobic glycolysis, respiration and mitochondrial biogenesis. Inhibitors of NRF2 and mitochondrial biogenesis induce regression of established PDAC in-vivo and compromise its growth and survival in-vitro.
Citation Format: Michael Karin, Hua Su. Collagen cleavage controls PDAC metabolism and malignancy via a DDR1-NRF2 cascade and mitochondrial biogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA014.
Abstract IA016: Determinants of B cell fate and function in cancer
Authors: Pylayeva-Gupta Yuliya 
Published: November 2022

Abstract
Effector B cell responses in solid malignancies are associated with anti-tumor immunity and favorable response to immunotherapy. B cells can amplify anti-tumor immune responses through antibody production, antigen presentation, and pro-inflammatory cytokine release; yet B cells in cancer patients and tumor-bearing mice often fail to support these effector cell functions. The determinants of B cell fate and function in cancer are still not clear. We find that systemic exposure to STING agonists potentiates expansion of immunosuppressive regulatory human and mouse IL-35+ B lymphocytes in an IRF3 dependent manner. Mechanistically, the loss of STING signaling in B cells or treatment with cGAMP combined with ablation of IL-35 facilitates increases NK cell proliferation and enhances NK cell dependent anti-tumor response. Further, we identify dysregulated transcriptional programs activated in pancreatic cancer-associated B cells that promote differentiation of naïve into immunosuppressive B cells and inhibit differentiation of anti-tumor plasma cells. The signaling network that contributes to this dysfunction is driven by IL35-mediated formation of STAT3-PAX5 complex that upregulates the transcriptional factor BCL6 in B cells. Transient inhibition of BCL6 in naïve B cells is sufficient to stimulate the intratumoral accumulation of plasma cells and effector T cells and renders pancreatic tumors sensitive to anti-PD-1 immune checkpoint blockade therapy. Our findings reveal that systemic STING signaling can expand immunosuppressive B cells and show that B cell differentiation can be re-routed towards anti-tumor plasma cell response, suggesting novel combinatorial strategies to facilitate anti-tumor immune activity.
Citation Format: Yuliya Pylayeva-Gupta. Determinants of B cell fate and function in cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA016.
Abstract PR003: Race plays a role on the rate of transdifferentiation in human pancreatic acinar ductal metaplasia and its' drug response
Authors: Perkins Corey , Jiang Jinmai , Hakimjavadi Hesam , Quashie David , Mao Yating , Ali Jamel , Schmittgen Thomas D. 
Published: November 2022

Abstract
Pancreatic diseases (acute/chronic pancreatitis, type 2 diabetes, pancreatic cancer) disproportionately affect the Black/African American community in comparison to non-White Hispanics and Whites. Acinar to ductal metaplasia (ADM), the process by which pancreatic acinar cells transdifferentiate into ductal epithelial cells, is believed to be an initiating event of pancreatic ductal adenocarcinoma. Our lab has developed a 3D organoid assay to display ADM using primary, human pancreatic acinar cells to study the rate of transdifferentiation among these three different races. Preliminary data shows that the rate of ADM is occurring significantly faster (p &lt; 0.05) in Blacks/African Americans (White=11, Hispanic=10, Black/African American=5), which may explain the disproportionately behind the incidence and mortality rates for this race in pancreatic diseases. We additionally use nanoparticles to study the biomechanical properties (I.e., viscoelasticity, storage modulus) of the ADM microenvironment which shows a stiffer microenvironment in Blacks/African Americans than for the other races (White=4, Hispanic=4, Black/African American=1). Furthermore, I study the use of histone deacetylase (HDAC) inhibitors in reversing the process of ADM, which has consequently shown race-related outcomes, with Blacks/African Americans displaying a significant chemoresistance (p &lt; 0.05) to HDAC treatment (White=6, Hispanic=6, Black/AA=3) by utilizing an ADM reversal index (ADMRI). Through further analysis, the plan is to continue procuring human samples from these three races to isolate an ADM-specific biomarker in relation race and drug reversal by studying the expression/activity of pancreatic associated genes by bulk-RNA and single-cell sequencing.
Citation Format: Corey Perkins, Jinmai Jiang, Hesam Hakimjavadi, David Quashie Jr, Yating Mao, Jamel Ali, Thomas D. Schmittgen. Race plays a role on the rate of transdifferentiation in human pancreatic acinar ductal metaplasia and its' drug response [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr PR003.