Setting Of Pancreatic Ductal Adenocarcinoma Research Articles

Tumor-selective activity of RAS-GTP inhibition in pancreatic cancer.

Broad-spectrum RAS inhibition holds the potential to benefit roughly a quarter of human cancer patients whose tumors are driven by RAS mutations1,2. RMC-7977 is a highly selective inhibitor of the active GTP-bound forms of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RAS(ON) multi-selective)3. As >90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS4, we assessed the therapeutic potential of the RAS(ON) multi-selective inhibitor RMC-7977 in a comprehensive range of PDAC models. We observed broad and pronounced anti-tumor activity across models following direct RAS inhibition at exposures that were well-tolerated in vivo. Pharmacological analyses revealed divergent responses to RMC-7977 in tumor versus normal tissues. Treated tumors exhibited waves of apoptosis along with sustained proliferative arrest whereas normal tissues underwent only transient decreases in proliferation, with no evidence of apoptosis. In the autochthonous KPC model, RMC-7977 treatment resulted in a profound extension of survival followed by on-treatment relapse. Analysis of relapsed tumors identified Myc copy number gain as a prevalent candidate resistance mechanism, which could be overcome by combinatorial TEAD inhibition in vitro. Together, these data establish a strong preclinical rationale for the use of broad-spectrum RAS-GTP inhibition in the setting of PDAC and identify a promising candidate combination therapeutic regimen to overcome monotherapy resistance.

Abstract B101: Tumor-selective inhibition of active RAS in pancreatic ductal adenocarcinoma

Abstract RM-042 is a broad-spectrum inhibitor of the active (GTP-bound) form of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RASMULTI(ON)). Given that more than 90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RM-042 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and remarkable anti-tumor activity across these models following direct RAS inhibition by RM-042 at doses and concentrations that were tolerable in vivo. Analyses of tumor and normal tissues following RM-042 treatment revealed divergent cellular responses to RAS inhibition. While we observed anti-proliferative effects in both normal and tumor tissues, RAS-dependent tumors alone exhibited a susceptibility to cell death via apoptosis within hours of dosing. Finally, using single cell regulatory network analysis, we found that different subtypes of PDAC malignant epithelial cells responded in distinct ways to RAS inhibition by RM-042, resulting in an enrichment of the more differentiated gastro-intestinal lineage state (GLS) cellular subtype. Together, these data have significant implications for the clinical development of RAS inhibitors in the setting of PDAC. A related inhibitor, RMC-6236, is currently in early clinical evaluation (NCT05379985). Citation Format: Urszula N. Wasko, Jingjing Jiang, Lorenzo Tomassoni, Yingyun Wang, Bianca Lee, Margo Orlen, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Steven A. Sastra, Carmine F. Palermo, Stephanie Chang, Andrew J. Aguirre, Channing J. Der, Robert H. Vonderheide, Ben Z. Stanger, Andrea Califano, Mallika Singh, Kenneth P. Olive. Tumor-selective inhibition of active RAS 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 B101.

The divergent role of the GM-CSF/GM-CSFR signaling pathway in cholangiocarcinoma and pancreatic ductal adenocarcinoma.

736 Background: The granulocyte-macrophage colony-stimulating factor ligand and receptor (GM-CSF/GM-CSFR) pathway plays a multifaceted role in the setting of cancer, exerting an anti-tumorigenic or pro-tumorigenic effect depending on GM-CSF expression. In previous work, we and others have shown increased GM-CSF expression to correlate with poor prognosis in patients with cholangiocarcinoma (CCA) and pancreatic ductal adenocarcinoma (PDAC). We also demonstrated how GM-CSF neutralization leads to reduced tumor size in murine CCA models, in part due to inhibition of alternative macrophage polarization. Here, we explore the impact of blocking GM-CSFR signaling in CCA and PDAC, two immunologically cold tumors with poor prognoses. Methods: Immunohistochemistry (IHC) and digital quantification of staining was performed on tissue from a human PDAC and CCA databank. Murine F4/80+ bone marrow-derived macrophages were cultured in tumor-conditioned media (TCM) derived from PDAC (KP2) or CCA (URCCA4.3) cell lines, with and without anti-GM-CSFR antibody. Quantitative real time PCR (qRT-PCR) analysis was performed for gene expression. URCCA4.3 and a luciferase-labeled PDAC (KCKO) cell line were orthotopically implanted into Bc/BIL3 knockout (KO) mice which lack GM-CSFR and C57BL/6 mice. Mice implanted with URCCA4.3 were enrolled into vehicle or gemcitabine treatment groups. Mice implanted with KCKO were untreated. Tumor growth was monitored by ultrasonography or bioluminescence imaging. Results: Digital analysis of IHC staining for GM-CSFR in human PDAC tumors revealed low expression to be associated with improved overall survival (OS) and greater number of days to recurrence, while high levels were associated with worse OS and fewer days to recurrence (p<0.01). In addition, human CCA specimens had greater GM-CSFR expression compared to normal uninvolved liver (p<0.01). qRT-PCR analysis of RNA from bone marrow-derived macrophages exposed to either CCA or PDAC TCM demonstrated lower expression of genes associated with alternative macrophage polarization ( Arg1, Cd274, Pdcd1lg2) and chronic inflammation ( Ccl2, Ccl17, Irf4) (all p<0.01) in response to GM-CSFR blockade. GM-CSFR KO mice implanted with URCCA4.3 demonstrated no differences in tumor growth with or without chemotherapy, compared to wild-type controls. Similarly, KO mice implanted with an immunogenic PDAC cell line (KCKO) had no differences in tumor size compared to wild-type controls. Conclusions: GM-CSFR expression is prognostic in the setting of PDAC and elevated in human CCA compared to normal liver. In vitro, GM-CSFR blockade downregulated pro-tumor genes associated with immunosuppression and inflammation. However, complete disruption of GM-CSFR signaling reversed the efficacy generated with GM-CSF ligand neutralization, suggesting some signaling is required for inducing anti-tumor immune responses.

A Reduced Pancreatic Polypeptide Response is Associated With New-onset Pancreatogenic Diabetes Versus Type 2 Diabetes.

Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM). Subjects with new-onset DM (<3 years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of PP concentrations between groups were performed using Wilcoxon rank-sum test and analysis of covariance while adjusting for age, sex, and body mass index. The fasting PP concentration was lower in both the PDAC-DM and CP-DM groups than in the T2DM group (P = 0.03 and <0.01, respectively). The fold change in PP at 15 minutes following meal stimulation was significantly lower in the PDAC-DM (median, 1.869) and CP-DM (1.813) groups compared with T2DM (3.283; P < 0.01 for both comparisons). The area under the curve of PP concentration was significantly lower in both the PDAC-DM and CP-DM groups than in T2DM regardless of the interval used for calculation and remained significant after adjustments. Fasting PP concentrations and the response to meal stimulation are reduced in new-onset DM associated with PDAC or CP compared with T2DM. These findings support further investigations into the use of PP concentrations to characterize pancreatogenic DM and to understand the pathophysiological role in exocrine pancreatic diseases (NCT03460769).

Role of biliary stent and neoadjuvant chemotherapy in the pancreatic tumor microbiome

BackgroundIntra-tumor microbiota have been implicated in pancreatic ductal adenocarcinoma (PDAC) development, treatment response and post-treatment survivorship. Moreover, therapeutic interventions targeting microbiota may improve the response to chemotherapy and immunotherapy, further emphasizing the critical need to understand the origins of and growth of bacteria within the pancreatic tumor microenvironment. Here, we studied the role of several clinical factors on the bacterial colonization of PDAC.ResultsWe obtained matched tumor and normal pancreatic tissue specimens from 27 patients who had undergone surgical resection for PDAC between 2011 and 2015 from the University of Minnesota Biological Materials Procurement Network (BioNet). We found that 26 (48%) out of 54 pancreatic tissue samples harbored detectable bacterial communities using real-time PCR targeting the 16S rRNA gene. Bacterial colonization was detected significantly more frequently in samples from patients who had pancreatic head tumors, underwent Whipple procedure, or had preoperative biliary stent placement. There was also a significantly greater relative abundance of microbiota from the family Enterobacteriaceae among samples from patients who underwent biliary stent placement or neoadjuvant treatment with a combination of Gemcitabine and Paclitaxel.ConclusionsThese findings suggest that biliary stent placement and neoadjuvant chemotherapy are associated with specific alterations that promote the infiltration and growth of intra-tumor bacteria in the setting of PDAC. Further studies exploring whether specific bacterial communities could contribute to increased chemoresistance will be essential for optimizing medical therapies in the future.

Neoadjuvant therapy for pancreatic cancer.

Multimodal treatment including surgery and chemotherapy is considered the gold standard treatment of pancreatic cancer by most guidelines. Neoadjuvant therapy (NAT) has been seen as a possible treatment option for resectable, borderline resectable and locally advanced PaC. The aim of this paper is to offer a state-of-the-art review on neoadjuvant treatments in the setting of pancreatic ductal adenocarcinoma. A systematic literature search was performed using PubMed, Cochrane, Web of Science and Embase databases, in order to identify relevant studies published up to and including July 2021 that reported and analyzed the role of neoadjuvant therapy in the setting of pancreatic carcinoma. Most authors are concordant on the strong role of neoadjuvant therapy in the setting of borderline resectable pancreatic cancers. Recent randomized trials demonstrated improvement of R0 rate and survival after NAT in this setting. Patients with locally advanced cancers may become resectable after NAT, with better results than those obtained with palliative therapies. Even in the setting of resectable cancers, NAT is being evaluated by ongoing randomized trials. Chemotherapy regimens in the setting of NAT and response to NAT are discussed. NAT has an important role in the multimodal treatment of patients with borderline resectable pancreatic cancer. It has a role in patients with locally advanced tumors as it can allow surgical resection in a relevant proportion of patients. For resectable pancreatic cancers, the role of NAT is under evaluation by several randomized trials.

Postoperative outcomes and functional recovery after neoadjuvant chemotherapy for pancreatic cancer: A propensity score-matched study

Previous studies show encouraging oncologic outcomes for neoadjuvant chemotherapy (NACT) in the setting of pancreatic ductal adenocarcinoma (PDAC). However, recent literature reported an increased clinical burden in patients undergoing pancreaticoduodenectomy (PD) following NACT. Therefore, the aim of our study was to assess the impact of NACT on postoperative outcomes and recovery after PD.

Vascular Resection for Pancreatic Cancer: 2019 French Recommendations Based on a Literature Review From 2008 to 6-2019

Introduction: Vascular resection remains a subject of debate in the management of Pancreatic Ductal Adenocarcinoma (PDAC). These French recommendations were drafted on behalf of the French National Institute of Cancer (INCA-2019).Material and Methods: A systematic literature search, with PubMed, Medline® (OvidSP), EMBASE, the Cochrane Library, was performed for abstracts published in English from January 2008 to June 2019, and identified systematic reviews/metaanalyses, retrospective analyses and case series dedicated to vascular resections in the setting of PDAC. All selected articles were graded for level of evidence and strength of recommendation was given according to the GRADE system.Results: Neoadjuvant treatment should be performed rather than direct surgery in borderline and locally advanced non-metastatic PDAC with venous and/or arterial infiltration (T4 stage). Patients who respond or those with stable disease and good performance status should undergo surgical exploration to assess resectability because cross-sectional imaging often fails to identify the extent of the remaining viable tumor. Combining vascular resection with pancreatectomy in these cases increases the feasibility of curative resection which is still the only option to improve long-term survival. Venous resection (VR) is recommended if resection is possible in the presence of limited lateral or circumferential involvement but without venous occlusion and in the absence of arterial contact with the celiac axis (CA; cephalic tumors) or the superior mesenteric artery (SMA; all tumor locations) (Grade B). The patients should be in good general condition because mortality and morbidity are higher than following pancreatectomy without VR (Grade B). In case of planned VR, neoadjuvant treatment is recommended since it improves both rate of R0 resections and survival compared to upfront surgery (Grade B). Due to their complexity and specificities, arterial resection (AR; mainly the hepatic artery (HA) or the CA) must be discussed in selected patients, in multidisciplinary team meetings in tertiary referral centers, according to the tumor location and the type of arterial extension. In case of invasion of a short segment of the common HA, resection with arterial reconstruction may be proposed after neoadjuvant therapy. In case of SMA invasion, neoadjuvant therapy may be followed by laparotomy with dissection and biopsy of peri-arterial tissues. A pancreaticoduodenectomy (PD) with SMA-resection is not recommended if the frozen section examination is positive (Grade C). In case of distal PDAC with invasion of the CA, a distal pancreatectomy with CA-resection without arterial reconstruction may be proposed after neoadjuvant therapy and radiologic embolization of the CA branches (expert opinion).Conclusion: For PDAC with vascular involvement, neoadjuvant treatment followed by pancreatectomy with venous resection or even arterial resection can be proposed as a curative option in selected patients with selected vascular involvement.

Postoperative Outcomes and Functional Recovery After Preoperative Combination Chemotherapy for Pancreatic Cancer: A Propensity Score-Matched Study.

Introduction: Previous studies show encouraging oncologic outcomes for neoadjuvant chemotherapy (NACT) in the setting of pancreatic ductal adenocarcinoma (PDAC). However, recent literature reported an increased clinical burden in patients undergoing pancreaticoduodenectomy (PD) following NACT. Therefore, the aim of our study was to assess the impact of NACT on postoperative outcomes and recovery after PD.Methods: A retrospective propensity score-matched study was performed including all patients who underwent PD for PDAC in a single center between 2015 and 2018. Patients treated with NACT for resectable, borderline resectable or locally advanced PDAC were matched based on nearest neighbor propensity scores in a 1:1 ratio to patients who underwent upfront resection. Propensity scores were calculated using 7 perioperative variables, including gender, age, BMI, ASA score, Charlson-Deyo comorbidity score, fistula risk score (FRS), vascular resection. Primary outcome was the number and severity of complications at 90-days after surgery measured by the comprehensive complication index (CCI). Data are reported as median (IQR) or number of patients (%).Results: Of 283 resected patients, 95 (34%) were treated with NACT. Before matching, NACT patients were younger, had less comorbidities (Charlson-Deyo score 0 vs. 1, p = 0.04), similar FRS [2 (0–3) for both groups], and more vascular resections performed [n = 28 (30%) vs. n = 26 (14%), p < 0.01]. After propensity-score matching, preoperative and intraoperative characteristics were comparable. Postoperatively, CCI was similar between groups [8.7 (0–29.6) for both groups, p = 0.59]. NACT patients had a non-statistically significant increase in superficial incisional surgical site infections [n = 12 (13%) vs. 6 (6%), p = 0.14], while no difference was found for overall infectious complications and organ-space SSI. The occurrence of clinically-relevant pancreatic fistula was similar between groups [10 (11%) vs. 13 (14%), p = 0.51]. No difference was found between groups for length of hospital stay [8 (7–15) vs. 8 (7–14) days, p = 0.62], and functional recovery outcomes.Conclusion: After propensity score adjustment for perioperative risk factors, NACT did not worsen postoperative outcomes and functional recovery following PD for PDAC compared to upfront resection.

Effective Delivery of a Microtubule Polymerization Inhibitor Synergizes with Standard Regimens in Models of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDA) is a deadly cancer that is broadly chemoresistant, due in part to biophysical properties of tumor stroma, which serves as a barrier to drug delivery for most classical chemotherapeutic drugs. The goal of this work is to evaluate the preclinical efficacy and mechanisms of PTC596, a novel agent with potent anticancer properties in vitro and desirable pharmacologic properties in vivo.Experimental Design: We assessed the pharmacology, mechanism, and preclinical efficacy of PTC596 in combination with standards of care, using multiple preclinical models of PDA. We found that PTC596 has pharmacologic properties that overcome the barrier to drug delivery in PDA, including a long circulating half-life, lack of P-glycoprotein substrate activity, and high systemic tolerability. We also found that PTC596 combined synergistically with standard clinical regimens to improve efficacy in multiple model systems, including the chemoresistant genetically engineered "KPC" model of PDA. Through mechanistic studies, we learned that PTC596 functions as a direct microtubule polymerization inhibitor, yet a prior clinical trial found that it lacks peripheral neurotoxicity, in contrast to other such agents. Strikingly, we found that PTC596 synergized with the standard clinical backbone regimen gemcitabine/nab-paclitaxel, yielding potent, durable regressions in a PDX model. Moreover, similar efficacy was achieved in combination with nab-paclitaxel alone, highlighting a specific synergistic interaction between two different microtubule-targeted agents in the setting of pancreatic ductal adenocarcinoma. These data demonstrate clear rationale for the development of PTC596 in combination with standard-of-care chemotherapy for PDA.

Inhibition of HSP90 overcomes resistance to chemotherapy and radiotherapy in pancreatic cancer.

Resistance of pancreatic ductal adenocarcinoma (PDAC) to radiotherapy and chemotherapy represents a significant clinical issue. Although the mechanisms of resistance are multi-faceted, client proteins of heat shock protein 90 (HSP90) such as hypoxia induced factor-1α (HIF-1α) have a central role in this process. The purpose of this investigation was to evaluate inhibition of HSP90 as a therapeutic strategy for radiosensitization in pancreatic cancer. Ganetespib, a selective inhibitor of HSP90, was evaluated as a radio-sensitizer in setting of PDAC. Inhibition of HSP90 by ganetespib potentiated the ability of radiation therapy to limit cell proliferation and colony formation in vitro. HIF-1α expression was upregulated by irradiation and HIF-1α-overexpressing stable cell lines were resistant to radiation. Inhibition of HSP90 with ganetespib reversed the effects of HIF-1α overexpression, by reducing signaling via proliferative, angiogenic and anti-apoptotic pathways. The potentiation of the antitumor effects of chemoradiotherapy by ganetespib and modulation of key pathways (e.g. HIF-1α, STAT3, and AKT) was confirmed in vivo in nude mice bearing HPAC xenograft tumors. These novel data highlight HIF-1α-mediated mechanisms of HSP90 inhibition that sensitize PDAC cells to chemoradiotherapy. This pathway and its pleiotropic effects warrant further evaluation in concert with conventional therapy in pancreatic cancer clinical trials.

"Laparoscopic Para-Aortic Lymph Node Sampling" First Approach for Pancreatic Adenocarcinoma as an Oncological Practice.

Background: In the setting of pancreatic ductal adenocarcinoma (PDAC), para-aortic lymph node (PALN) involvement is considered as a metastasis disease. To date, no morphological examination can effectively identify lymph node metastasis, and a significant number of patients undergo futile invasive laparotomy for PALN involvement. From an oncological point of view, laparoscopy represents a better approach for PALN sampling. The main aim of the study is to propose a laparoscopic PALN sampling first approach. We describe the surgical technique and demonstrate its technical feasibility as a routine approach as the first surgical step before pancreaticoduodenectomy for localized PDAC. Materials and Methods: During a first step of staging laparoscopy, PALN sampling was done for 31 patients with localized PDAC between November 2015 and February 2017. Demographic data and intraoperative, postoperative, and pathological criteria were evaluated. The surgical technique is described in detail. Results: The median operative time was 35 (range 18-65) minutes. The median number of PALN analyzed per patient was 2 (range 1-5). Four (13%) of 31 patients had positive PALN in frozen section analysis. No severe complication was reported for patients with positive PALN, receiving laparoscopic exploration and PALN sampling. The median hospital stay for patients with positive PALN was 2 (range 1-7) days. Conclusion: To avoid futile laparotomy, a staging laparoscopy is usually carried out. We report the feasibility and safety of laparoscopic PALN sampling and suggest its systematic realization during staging laparoscopy as a first step in patients with localized PDAC before pancreaticoduodenectomy.

The receptor for advanced glycation end products (RAGE) enhances autophagy and neutrophil extracellular traps in pancreatic cancer.

Neutrophil extracellular traps (NETs) are formed when neutrophils expel their DNA, histones and intracellular proteins into the extracellular space or circulation. NET formation is dependent on autophagy and is mediated by citrullination of histones to allow for unwinding and subsequent expulsion of DNA. NETs play an important role in the pathogenesis of several sterile inflammatory diseases, including malignancy, therefore we investigated the role of NETs in the setting of pancreatic ductal adenocarcinoma (PDA). Neutrophils isolated from two distinct animal models of PDA had an increased propensity to form NETs following stimulation with platelet activating factor (PAF). Serum DNA, a marker of circulating NET formation, was elevated in tumor bearing animals as well as in patients with PDA. Citrullinated histone H3 expression, a marker of NET formation, was observed in pancreatic tumors obtained from murine models and patients with PDA. Inhibition of autophagy with chloroquine or genetic ablation of RAGE resulted in decreased propensity for NET formation, decreased serum DNA, and decreased citrullinated histone H3 expression in the pancreatic tumor microenvironment. We conclude that NETs are upregulated in pancreatic cancer through RAGE dependent/autophagy pathways.

Whipple Procedure for Carcinoma of the Pancreas - Part 1

Pancreatic ductal adenocarcinoma (PDAC) is the ninth most common cancer in the United States, but due to symptoms – such as back pain, jaundice and unexplained weight loss – usually only presenting when the disease has already moved beyond the pancreas, it is highly lethal, representing the fourth most common cause of cancer death.  As a result of widespread abdominal imaging, more early stage pancreatic cancers are being diagnosed, and these patients are candidates for a pancreaticoduodenectomy, more commonly known as the Whipple procedure.  The Whipple procedure is used to treat four types of cancer – periampullary, cholangiocarcinoma, duodenal, and pancreatic ductal adenocarcinoma – but is most well known in the setting of PDAC.  Although there are only a few basics steps to the procedure – removal of  the pancreatic head, distal bile duct, duodenum and either distal gastrectomy or plyloric preservation.  Next is the reconstruction with bringing up the stapled end of jejunum to the pancrease, then the hepatic duct, and lastly to the stomach.   The multiple crucial anatomic structures in the same region, as well as the unforgiving nature of the structures involved in the operation itself, lead to high morbidity and necessitate complex postoperative care.  Due to this, most Whipple procedures are performed at higher volume centers.

Whipple Procedure for Carcinoma of the Pancreas - Part 2

Pancreatic ductal adenocarcinoma (PDAC) is the ninth most common cancer in the United States, but due to symptoms – such as back pain, jaundice and unexplained weight loss – usually only presenting when the disease has already moved beyond the pancreas, it is highly lethal, representing the fourth most common cause of cancer death.  As a result of widespread abdominal imaging, more early stage pancreatic cancers are being diagnosed, and these patients are candidates for a pancreaticoduodenectomy, more commonly known as the Whipple procedure.  The Whipple procedure is used to treat four types of cancer – periampullary, cholangiocarcinoma, duodenal, and pancreatic ductal adenocarcinoma – but is most well known in the setting of PDAC.  Although there are only a few basics steps to the procedure – removal of  the pancreatic head, distal bile duct, duodenum and either distal gastrectomy or plyloric preservation.  Next is the reconstruction with bringing up the stapled end of jejunum to the pancrease, then the hepatic duct, and lastly to the stomach.   The multiple crucial anatomic structures in the same region, as well as the unforgiving nature of the structures involved in the operation itself, lead to high morbidity and necessitate complex postoperative care.  Due to this, most Whipple procedures are performed at higher volume centers.