Chemotherapy In Pancreatic Ductal Adenocarcinoma Research Articles

Abstract 6433: Anti-CD36 monoclonal antibody can sensitize the neoadjuvant chemotherapy response in PDAC by eliminating the senescent tertiary lymphatic structure

Abstract Objective: Pancreatic ductal adenocarcinoma (PDAC) is deadly and aggressive. Neoadjuvant chemotherapy (NAC) may reduce tumor volume and alter the resectability of the tumor. The efficacy of neoadjuvant chemotherapy in patients is still limited. Tertiary lymphoid structures (TLSs) develop in peripheral non-lymphoid tissues and are essential for the immune response and correlate with chemotherapy in various tumor types. However, more research is needed to determine how TLSs affect neoadjuvant chemotherapy in PDAC. We aim to determine how neoadjuvant chemotherapy affects tumor-infiltrating lymphocytes (TLSs) in PDAC patients. We also want to find a biomarker to boost PDAC neoadjuvant chemotherapy response. Methods: We retrospectively collected formalin-fixed paraffin embedded (FFPE) tissues from 115 PDAC patients without preoperative treatment and 72 patients pretreated with neoadjuvant chemotherapy. Multispectral images were processed using AI-powered image analysis software (Tissue Gnostics; Zeiss, Germany). The 10X Genomics platform was used to sequence single cells in tissue samples from five patients who received neoadjuvant chemotherapy (NAC) and five patients who had not received any treatment before analysis (pretreatment naïve, PN). TLS was separated using Laser Microdissection. The mouse model was created by orthotopically injecting tumor cells into the pancreas. Results: Patients who received NAC have a senescent microenvironment. High-throughput single-cell sequencing showed that the senescent gene signature score was enriched in the NAC group, especially in immune cells. The percentage of p16+ CD20+ B cells and P16+ CD3+ T cells in TLSs also increased in the NAC group. Spatial transcriptomics analysis exhibited that CD36 is highly expressed in senescent TLSs, which suggested that CD36 may be a marker for senescent TLSs. Moreover, CD36+ TLSs induced the infiltration of MDSCs and regulatory T cells. CD36+ TLSs were an independent prognostic factor for poor overall survival (OS) (HR=0.67, p=0.002) and progression-free survival (PFS) (HR=0.71, p=0.003). A mice orthotopic xenograft model showed that an anti-CD36 monoclonal antibody eliminated senescent TLSs in pancreatic tissue. MDSCs and Tregs in the surrounding tissue also decreased. Additionally, in vivo KPC mice model showed that the combination of an anti-CD36 and chemotherapy reduced tumor volume and increased survival compared to chemotherapy alone. Conclusion: NAC has the potential to induce the senescence of tumor-associated TLSs, a phenomenon that has been linked to unfavorable prognosis in PDAC. CD36 serves as a viable marker for senescent TLSs that can be targeted. The administration of an anti-CD36 monoclonal antibody can potentially enhance the efficacy of chemotherapy in PDAC by selectively eliminating CD36+ senescent TLSs in mouse models. Citation Format: Jingrui Yan, Tianxing Zhou, Chao Yang, Yongjie Xie, Jun Yu, Jihui Hao. Anti-CD36 monoclonal antibody can sensitize the neoadjuvant chemotherapy response in PDAC by eliminating the senescent tertiary lymphatic structure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6433.

Single dual-specific anti-PD-L1/TGF-β antibody synergizes with chemotherapy as neoadjuvant treatment for pancreatic ductal adenocarcinoma: a preclinical experimental study.

Chemotherapy resistance is an important cause of neoadjuvant therapy failure in pancreatic ductal adenocarcinoma (PDAC). BiTP (anti-PD-L1/TGF-β bispecific antibody) is a single antibody that can simultaneously and dually target transforming growth factor-beta (TGF-β) and programmed cell death ligand 1 (PD-L1). We attempted in this study to investigate the efficacy of BiTP in combination with first-line chemotherapy in PDAC. Preclinical assessments of BiTP plus gemcitabine and nab-paclitaxel were completed through a resectable KPC mouse model (C57BL/6J). Spectral flow cytometry, tissue section staining, enzyme-linked immunosorbent assays, Counting Kit-8, transwell, and Western blot assays were used to investigate the synergistic effects. BiTP combinatorial chemotherapy in neoadjuvant settings significantly downstaged PDAC tumors, enhanced survival, and had a higher resectability for mice with PDAC. BiTP was high affinity binding to targets and reverse chemotherapy resistance of PDAC cells. The combination overcame immune evasion through reprogramming tumor microenvironment via increasing penetration and function of T cells, natural killer cells, and dendritic cells and decreasing the function of immunosuppression-related cells as regulatory T cells, M2 macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts. Our results suggest that the BiTP combinatorial chemotherapy is a promising neoadjuvant therapy for PDAC.

Poor clinical outcomes and immunoevasive contexture in CD161+CD8+ T cells barren human pancreatic cancer

BackgroundThe role of CD161 expression on CD8+ T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161+CD8+ T cells in pancreatic ductal...

Abstract B090: Targeting the unfolded protein response enhances sensitivity to chemotherapy

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is currently the 3rd leading cause of cancer-related deaths in North American with ~10% survival 5 years after diagnosis. A contributing factor to this low survival rate is chemotherapy resistance. Major risk factors for PDAC, including smoking and chronic pancreatitis, promote activation of the unfolded protein response (UPR). The UPR reduces protein load to alleviate stress, and cancer cells can utilize the UPR to promote cell survival. We previously showed loss of Activating Transcription Factor 3 (ATF3), a mediator of the UPR, restricted early events in PDAC progression. The goal of this study was to determine if ATF3 and the UPR promote resistance to chemotherapy in PDAC. We hypothesized that cancer cells activate the UPR and ATF3 to reduce cell stress and promote chemotherapeutic resistance. Methods: Murine-derived organoids (MDOs) were developed from pancreatic tissue expressing KRASG12D with (Ptf1acreERT/+KRASG12D/+) or without Atf3 (Atf3-/-Ptf1acreERT/+KRASG12D; referred to as APK) expression, and patient-derived organoids (PDOs) were examined for mediators of the UPR. Transcriptomic changes related to ATF3 loss was determined by RNA-sequencing of Ptf1acreERT/+KRASG12D/+ and APK organoids. UPR activation was examined by qRT-PRC in MDOs and PDOs with and without gemcitabine treatment, and related to organoid viability and phenotype. PDOs viability was examined following treatment with gemcitabine +/- UPR inhibitors. Results: RNA-seq analysis of Ptf1acreERT/+KRASG12D/+ and APK MDOs identified drug metabolism cytochrome P450, metabolism of xenobiotics by cytochrome P450, and platinum drug resistance as key pathways affected by the loss of ATF3 suggesting reduced UPR activation impacts drug metabolism in KRASG12D expressing cells. Ptf1acreERT/+KRASG12D/+ and APK MDOs showed a differential response in cell viability and UPR activation to gemcitabine treatment suggesting an importance of ATF3 in gemcitabine resistance. Consistent with this role, treatment of PDOs with gemcitabine resulted in UPR activation in a patient-specific fashion, particularly regarding increased expression of ATF3 and spliced XBP1. In lines showing enhanced UPR activation to gemcitabine, combinatorial treatment with UPR inhibitors showed increased cell death compared to gemcitabine alone. Conclusions: This study shows the UPR and ATF3 are rapidly activated in response to gemcitabine, but in a patient-specific fashion. These results suggest cancer cells activate the UPR to increase resistance to chemotherapies, and a subset of patients may benefit from combined gemcitabine treatment with UPR inhibitors. Since the tumor microenvironment is believed to be a major contributing factor to chemotherapy resistance, future experiments will include the tumor microenvironment interactions and UPR inhibition. Citation Format: Mickenzie B. Martin, Teresa Borello, Fatemeh Mousavi, Nelson Dusetti, Christopher L. Pin. Targeting the unfolded protein response enhances sensitivity to chemotherapy [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 B090.

Predicting Pathological Response to Preoperative Chemotherapy in Pancreatic Ductal Adenocarcinoma Using Post-Chemotherapy Computed Tomography Radiomics.

Assessing the response to preoperative treatment in pancreatic cancer provides valuable information for guiding subsequent treatment strategies. The present study aims to develop and validate a computed tomography (CT) radiomics-based machine learning (ML) model for predicting pathological response (PR) to preoperative chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Retrospective data were analyzed from 86 PDAC patients undergoing neoadjuvant or conversion chemotherapy followed by surgical resection from January 2018 to May 2023. The cohort was randomly divided into training (70%, n = 60) and testing (30%, n = 26) sets. Favorable PR was defined as Evans grade IIb or greater. Radiomic features were extracted from post-chemotherapy CT images, and dimensionality reduction was performed using the least absolute shrinkage and selection operator (LASSO) logistic regression. Four ML classifiers (Light Gradient Boosting Machine (LGBM), Random Forest, AdaBoost, and Quadratic Discriminant Analysis) were evaluated for predicting a favorable PR. Model performance was primarily assessed using the area under the receiver operating characteristic curve (AUC), Brier score, and decision curve analysis. Forty-one (47.7%) patients had a favorable PR. LASSO analysis on the training set identified five radiomic features. The LGBM model demonstrated the best performance, with a training AUC of 0.902 and a testing AUC of 0.923. It also exhibited the lowest Brier scores, both in training (0.136) and testing (0.135). Decision curve analysis further confirmed its clinical potential. The CT radiomics-based ML model exhibited promising performance in predicting PR in PDAC after neoadjuvant/conversion chemotherapy. This suggests clinical utility in optimizing surgical candidates and timing of surgery, leading to personalized treatment strategies.

REV7 is involved in outcomes of platinum-based chemotherapy in pancreatic cancer by controlling the DNA damage response.

REV7 is a multifunctional protein implicated in various biological processes, including DNA damage response. REV7 expression in human cancer cells affects their sensitivity to DNA-damaging agents. In the present study, we investigated the significance of REV7 in pancreatic ductal adenocarcinoma (PDAC). REV7 expression was immunohistochemically examined in 92 resected PDAC specimens and 60 endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) specimens of unresectable PDAC treated with platinum-based chemotherapy, and its association with clinicopathologic features was analyzed. Although REV7 expression was not significantly associated with the progression of primary tumors (T-factor and Stage) in either resected or unresectable PDAC, decreased levels of REV7 expression in EUS-FNAB specimens of unresectable PDAC were significantly associated with better outcomes of platinum-based chemotherapy and a favorable prognosis. REV7-deficient PDAC cell lines showed suppressed cell growth and enhanced sensitivity to cisplatin invitro. Tumor-bearing mice generated using REV7-deficient PDAC cell lines also showed enhanced sensitivity to cisplatin invivo. RNA sequencing analysis using WT and REV7-deficient PDAC cell lines revealed that REV7 inactivation promoted the downregulation of genes involved in the DNA repair and the upregulation of genes involved in apoptosis. Our results indicate that decreased expression of REV7 is associated with better outcomes of platinum-based chemotherapy in PDAC by suppressing the DNA damage response. It is also suggested that REV7 is a useful biomarker for predicting the outcome of platinum-based chemotherapy and the prognosis of unresectable PDAC and is a potential target for PDAC treatment.

Noninvasive Computed Tomography-Based Deep Learning Model Predicts In Vitro Chemosensitivity Assay Results in Pancreatic Cancer.

We aimed to predict in vitro chemosensitivity assay results from computed tomography (CT) images by applying deep learning (DL) to optimize chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Preoperative enhanced abdominal CT images and the histoculture drug response assay (HDRA) results were collected from 33 PDAC patients undergoing surgery. Deep learning was performed using CT images of both the HDRA-positive and HDRA-negative groups. We trimmed small patches from the entire tumor area. We established various prediction labels for HDRA results with 5-fluorouracil (FU), gemcitabine (GEM), and paclitaxel (PTX). We built a predictive model using a residual convolutional neural network and used 3-fold cross-validation. Of the 33 patients, effective response to FU, GEM, and PTX by HDRA was observed in 19 (57.6%), 11 (33.3%), and 23 (88.5%) patients, respectively. The average accuracy and the area under the receiver operating characteristic curve (AUC) of the model for predicting the effective response to FU were 93.4% and 0.979, respectively. In the prediction of GEM, the models demonstrated high accuracy (92.8%) and AUC (0.969). Likewise, the model for predicting response to PTX had a high performance (accuracy, 95.9%; AUC, 0.979). Our CT patch-based DL model exhibited high predictive performance in projecting HDRA results. Our study suggests that the DL approach could possibly provide a noninvasive means for the optimization of chemotherapy.

In Neoadjuvant FOLFIRINOX Chemotherapy for Pancreatic Ductal Adenocarcinoma, Which Response is the More Reliable Indicator for Prognosis, Radiologic or Biochemical?

In this era of increasing neoadjuvant chemotherapy, methods for evaluating responses to neoadjuvant chemotherapy are still diverse among institutions. Additionally, the efficacy of adjuvant chemotherapy for patients undergoing neoadjuvant chemotherapy remains unclear. Therefore, this retrospective study was performed to evaluate the effectiveness of methods for assessing response to neoadjuvant chemotherapy and the need for adjuvant chemotherapy in treating patients with non-metastatic pancreatic ductal adenocarcinoma. The study identified 150 patients who underwent neoadjuvant FOLFIRINOX chemotherapy followed by curative-intent pancreatectomy. The patients were stratified by biochemical response based on the normalization of carbohydrate antigen 19-9 and by radiologic response based on size change at imaging. The patients were classified into the following three groups based on their response to neoadjuvant chemotherapy and prognosis: biochemical responders (BR+), radiology-only responders (BR-/RR+), and non-responders (BR-/RR-). The 3-year overall survival rate was higher for BR+ (71.0%) than for BR-/RR+ (53.6%) or BR-/RR- (33.1%) (P < 0.001). Response to neoadjuvant chemotherapy also was identified as a significant risk factor for recurrence in a comparison between BR-/RR+ and BR+ (hazard ratio [HR], 2.15; 95% confidence interval [CI] 1.19-3.88; P = 0.011) and BR-/RR- (HR, 3.82; 95% CI 2.41-6.08; P < 0.001). Additionally, regardless of the response to neoadjuvant chemotherapy, patients who completed adjuvant chemotherapy had a significantly higher 3-year overall survival rate than those who did not. This response evaluation criterion for neoadjuvant chemotherapy is feasible and can significantly predict prognosis. Additionally, completion of adjuvant chemotherapy could be helpful to patients who undergo neoadjuvant chemotherapy regardless of their response to neoadjuvant chemotherapy.

Postoperative Carbohydrate Antigen 19-9 Level as a Good Indicator of Ineffective Response to the Currently Recommended S-1 Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma: A Single-Center, Retrospective Study.

The intensity of adjuvant treatment for pancreatic ductal adenocarcinomas (PDACs) has not been stratified according to the risk after resection. This study was designed to identify patients with PDACs in whom the current S-1 adjuvant treatment is ineffective. This single-center, retrospective study included patients who underwent pancreatectomy for PDACs from 2009 to 2020 at Sendai Open Hospital and were receiving S-1 adjuvant treatment. The independent risk factors for recurrence and survival were determined by using a Cox proportional hazards regression model. The effects of S-1 adjuvant treatment and detailed patterns of recurrence were evaluated in patients with high-risk factors. Overall, 118 patients with PDAC received S-1 adjuvant treatment. Postoperative nonnormalized carbohydrate antigen (CA19-9) was a predictive risk factor for recurrence (p < 0.010; hazard ratio [HR], 3.87; 95% confidence interval [CI], 2.26-6.62) and survival (p = 0.008; HR, 2.25; 95% CI, 1.24-4.11) after S-1 adjuvant treatment. In 24 patients with nonnormalized postoperative CA19-9, S-1 monotherapy was ineffective in preventing recurrence, even during the treatment period, compared with that noted in patients who did not receive adjuvant treatment. The recurrence rate during adjuvant treatment was 41.7%; in all cases, recurrence was caused by distant metastasis. The total recurrence rate was up to 95.8%, and distant recurrence was especially frequent. The current S-1 adjuvant treatment regimen is ineffective for patients with postoperative nonnormalized CA19-9. The postoperative CA19-9 level may be a good indicator for further aggressive treatment. This study may lead to further discussions on intensity stratification of adjuvant treatments for PDAC.

Geriatric Nutritional Risk Index Predicts Tolerability of S-1 as Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma.

Surgery plus adjuvant chemotherapy (AC) for resectable pancreatic ductal adenocarcinoma (PDAC) has been shown to prolong survival compared with surgery alone. Thus, it is of clinical importance that these patients receive a continuous dose of S-1. The aim of this study was to examine whether the geriatric nutritional risk index (GNRI) is a predictor for the completion of S-1 as AC for PDAC. Seventy-seven patients who were administered S-1 as AC after pancreatectomy for PDAC between January 2010 and October 2021 were retrospectively enrolled. Predictive markers were statistically analyzed for S-1 completion, which was defined as continued oral administration with relative dose intensity of >80%. Patients were divided into the S-1 complete group (n = 55; 71.4%) and S-1 incomplete group (n = 22; 28.6%). There was a significant association of higher GNRI (P = 0.013) at the onset of AC with the completion of S-1. Receiver operating characteristic curve analysis revealed 94.4 as the optimal cutoff value of GNRI for predicting the completion of S-1. Univariate and multivariate analyses confirmed that GNRI >94.4 was independently associated with the completion of S-1 (P = 0.007). High GNRI value is a predictive marker for the completion of S-1 as AC for PDAC.

Inflammatory landscape after neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma

Inflammatory landscape after neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma

Intravoxel Incoherent Motion (IVIM) Magnetic Resonance Imaging (MRI) for Assessment of Treatment Response in Pancreatic Cancer

Intravoxel Incoherent Motion (IVIM) Magnetic Resonance Imaging (MRI) is an emergent technique used to quantify diffusion and perfusion without the use of contrast agent. Our objective was to evaluate changes in IVIM parameters pre- and post-Radiation Therapy (RT) / chemotherapy in Pancreatic Ductal Adenocarcinoma (PDAC) patients to correlate these parameters and their changes with tumor radiation response. Pre- and post-treatment IVIM scans were acquired from 12 patients (median age: 70 [41-83]) with PDAC treated with RT (median: 98 [39-116] Gy BED) and chemotherapy. CA19-9 was used as a surrogate of radiation response and its validity was confirmed using the Kaplan-Meier method and the log-rank test. The Diffusion Weighted Images (DWI) were acquired on a 3T MRI scanner using a free-breathing, spin echo-based echo-planar imaging (SE-EPI) sequence with six b-values (0, 30, 60, 100, 600, 1000 s/mm2). Tumors were segmented using Dynamic Contrast Enhanced (DCE) MRI and registered to the DWI images. A voxel-wise, bi-exponential, IVIM model was fitted to the DWI images to derive the perfusion fraction (f), diffusion coefficient (D), and pseudo-diffusion coefficient (D*) distributions inside the tumor. IVIM parameter distributions were described using histogram analysis by extracting the median, standard deviation, skew, kurtosis, and percentiles (5, 10, 25, 75, 90, 95). Statistical comparisons between pre- and post-RT images were performed using the nonparametric permutation test for small sample sizes. Kaplan-Meier analysis of pre- and post-RT showed significantly reduced survival (p = 0.04) in patients who had a CA19-9 increase (n = 6) compared to those who decreased or stayed the same (n = 6). The median f showed a significant increase (p = 0.03) in patients who experienced a decrease in CA19-9 while D showed a significant decrease (p = 0.03). Among the calculated histogram percentiles, both the 5th and 10th percentile in the f distribution showed a near-significant increase (p = 0.06) when CA19-9 decreased while the 95th of the D distribution showed a near-significant decrease (p = 0.06). In patients who experienced an increase in CA19-9, a near-significant change (p = 0.06) in the skew (decrease) and kurtosis (increase) of the f distribution was observed. D* showed no significant correlations across all testing. Both f and D exhibited significant changes in PDAC patients undergoing RT and chemotherapy, reflecting changes in tumor response to treatment. The findings warrant further investigation to utilize IVIM in characterizing treatment response in PDAC patients.

Feasibility of delivering supervised exercise training following surgical resection and during adjuvant chemotherapy for pancreatic ductal adenocarcinoma (PRECISE): a case series

IntroductionPancreatic ductal adenocarcinoma (PDAC) is an aggressive neoplasm, with surgical resection and adjuvant chemotherapy the only curative treatment. Treatment-related toxicities place a considerable burden on patients although exercise training has shown promise is helping to manage such adversities and facilitate rehabilitation. The feasibility and safety of exercise training as a supportive therapy during adjuvant chemotherapy remains unknown.MethodsPatients with PDAC were screened post-surgical resection and enrolled in a 16-week, progressive, concurrent exercise programme alongside their chemotherapy regimen. Feasibility was the primary objective detailing recruitment, retention and adherence rates throughout as well as the safety and fidelity of the intervention. Secondarily, the impact on functional fitness and patient-reported outcomes was captured at baseline, post-intervention and 3-month follow up.ResultsEight patients consented to participate in this trial, with five proceeding to enrol in exercise training. Concurrent exercise training is feasible and safe during adjuvant chemotherapy and prevented an expected decline in functional fitness and patient-reported outcomes during this time.DiscussionThis case series provides preliminary evidence that concurrent exercise training during adjuvant therapy is safe, feasible and well tolerated, preventing an expected decline in functional fitness, muscular strength and health-related quality of life (HRQoL). Given the adverse effects of treatment, these findings are promising and provide further evidence for the inclusion of exercise training as a standard of care for surgical rehabilitation and managing treatment-related toxicities. Future research should explore the impact of exercise training during neoadjuvant chemotherapy, with prehabilitation now standard practice for borderline resectable disease.Trial registrationClinicalTrials.gov Identifier: NCT04305067, prospectively registered 12/03/2020, https://classic.clinicaltrials.gov/ct2/show/NCT04305067.

Pancreatic Ductal Adenocarcinoma: Current and Emerging Treatments

Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease with increasing incidence and mortality rates. The most effective treatment for Pancreatic Ductal Adenocarcinoma is surgery, but because of the late-stage diagnosis which is typical among PDAC patients, as well as poor imaging technology, surgery is not a viable option for 80-85% of patients. Therefore, the most common treatments for PDAC currently are Chemotherapy, Immunotherapy, and Radiotherapy. Chemotherapy for PDAC is performed with a combination of drugs. The current standards of chemotherapy drug combinations are being challenged and new chemotherapy combinations are under clinical trial. Immunotherapy for PDAC consists of immunomodulators, oncolytic viruses, adoptive cell therapies, and cancer vaccines. Recently, a shift of focus within PDAC immunotherapy research has yielded an emphasis on protein inhibition. A new protein inhibition strategy is under clinical trial. Radiotherapy is rarely used to treat PDAC in recent years, but there is an emerging hypothesis implying that radiotherapy may be used on tumors to kill tissue that may not be removed via surgery. The future of PDAC treatment is unpredictable - because of the high mortality rate and low survival rate relative to other cancers, researchers are forced to think creatively and pursue treatments different than those of other cancers. The likelihood of improvement in PDAC treatment is great because of the current poor standard and the vast amount of emerging research.

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer.

The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

Development and evaluation of 5FUCore, OxaliCore, and IrinoCore transcriptomic signatures for predicting response to individual drugs in the FOLFIRINOX regimen: Towards toxicity reduction and personalized chemotherapy in PDAC.

4141 Background: Recently, we have successfully developed a transcriptomic signature that predicts the response to gemcitabine treatment in patients with localized pancreatic ductal adenocarcinoma (PDAC) (PMID: 36178036) and also in those with metastatic PDAC (PMID: 36496056). This was achieved by using an approach that combined several preclinical PDAC models. The FOLFIRINOX regimen (FFX) consisting of 5-Fluorouracil (5FU), Oxaliplatin, and Irinotecan is the more effective treatment option, but the high toxicity limits its use. In this study, we developed and analyzed three different transcriptomic signatures for the drugs composing FFX separately and evaluated their clinical utility. Methods: We combined the transcriptomic profile of 14 patients derived xenograft (PDX) and 31 patients derived cell cultures (PDC) with their corresponding chemotherapy response profiles. We developed predictive signatures for 5FU ( 5FUCore), Oxaliplatin ( OxaliCore), and Irinotecan ( IrinoCore), as previously reported for the GemCore signature (PMID: 36178036). They were then validated in three independent cohorts of patients: COMPASS (n = 94), Linehan (n = 28), and a new cohort of 87 advanced PDAC patients. Results: Three ICA components that reflect the chemotherapy response profiles for 5FU, oxaliplatin, and irinotecan were evaluated in the COMPASS cohort to determine their ability to identify sensitive patients in the FFX arm. Patients predicted as sensitive to each drug separately had a median overall survival (OS) of 77.6 (95% CI, 67.9-NR, P =0.02), 78.7 (95% CI, 57.6-NR, P= 0.002), and 70.4 (95% CI, 57.6-NR, P= 0.02) months for 5FU, oxaliplatin, and irinotecan, respectively. Notably, the model that integrated the group of sensitive patients to two or three drugs had the highest median OS in the COMPASS and Linehan cohorts with a HR of 0.25 (95% CI, 0.11-0.57; P &lt; 0.001) and 0.11 (95% CI, 0.02-0.70; P= 0.019), respectively. Importantly, they also show a better objective response than the other groups ( P= 0.009). In the advanced PDAC group, the signatures showed a strong ability to discriminate sensitive patients in the FFX arm with a median OS of 20.1 (95% CI, 2.3-NR, P= 0.006), 13.64 (95% CI, 9.57-NR, P= 0.003), and 15.87 (95% CI, 2.9-NR, P= 0.002) months for 5FU, oxaliplatin, and irinotecan, respectively. Finally, we evaluated the best combination of two drugs in the pooled group. Patients sensitive to both 5FU and oxaliplatin showed the best response with 60% of patients achieving partial response. Conclusions: The signatures developed provide a tool for predicting responsiveness to the individual therapeutic drugs of the FFX regimen. They may ultimately lead to the development of a personalized strategy for combined chemotherapy regimens, increasing efficacy and reducing toxicity in PDAC.

TPX2 expression as a negative predictor of gemcitabine efficacy in pancreatic cancer

BackgroundTargeting protein for Xenopus kinesin-like protein 2 (TPX2) overexpression in human tumours is associated with increased malignancy. Its effect on gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC) has not been studied yet.MethodsThe prognostic impact of TPX2 expression was examined in the tumour tissue of 139 patients with advanced PDAC (aPDAC) treated within the AIO-PK0104 trial or translational trials and of 400 resected PDAC (rPDAC) patients. The findings were validated using RNAseq data of 149 resected PDAC patients.ResultsIn the aPDAC cohorts, 13.7% of all samples showed high TPX2 expression, conferring significantly shorter progression-free survival (PFS, HR 5.25, P < 0.001) and overall survival times (OS, HR 4.36, P < 0.001) restricted to gemcitabine-based treated patients (n = 99). In the rPDAC cohort, 14.5% of all samples showed high TPX2 expression, conferring significantly shorter disease-free survival times (DFS, HR 2.56, P < 0.001) and OS times (HR 1.56, P = 0.04) restricted to patients treated with adjuvant gemcitabine. RNAseq data from the validation cohort confirmed the findings.ConclusionsHigh TPX2 expression may serve as a negative predictor of gemcitabine-based palliative and adjuvant chemotherapy in PDAC and could be used to inform clinical therapy decisions.Clinical trial registryThe clinical trial registry identifier is NCT00440167.

Lauric Acid Overcomes Hypoxia-Induced Gemcitabine Chemoresistance in Pancreatic Ductal Adenocarcinoma.

Although gemcitabine (GEM) is widely used in chemotherapy for pancreatic ductal adenocarcinoma (PDA), drug resistance restricts its clinical effectiveness. To examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl2-induced chemical hypoxia. One resistant cell line possessed reduced energy production and decreased mitochondrial reactive oxygen species levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. Inhibition of hypoxia-inducible factor-1α in both cell lines did not restore the GEM sensitivity. In contrast, treatment of both cell types with lauric acid (LAA), a medium-chain fatty acid, restored GEM sensitivity. These results suggest that decreased energy production, decreased mitochondrial reactive oxygen species levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of oxidative phosphorylation by LAA could be a tool to overcome GEM resistance. Clinical verification of the effectiveness of LAA in GEM resistance is necessary in the future.

Abstract 4801: Laurine acid enhances GEM-chemosensitivity targeting hypoxia-induced mitochondrial disfunction and stemness in pancreatic ductal adenocarcinoma

Abstract Hypoxia is a feature of the pancreatic ductal adenocarcinoma (PDA). Although gemcitabine (GEM) is widely used in chemotherapy for PDA, drug resistance restricts its clinical effectiveness. We have found that hypoxia contributes to chemoresistance, however the mechanism is still unclear. The aim of this study is to clarify the mechanism and to develop a new therapeutic strategy. First, we examined the effect of hypoxia to GEM sensitivity, stemness and energy metabolism in three human pancreatic ductal carcinoma cell lines. The inhibition rate by GEM was lower under CoCl2-induced chemical hypoxia than normoxia. Reactive oxygen species (ROS) after GEM was increased under normoxia but not under hypoxia. Flux analysis showed that both oxidative phosphorylation (OXPHOS) and glycolysis were suppressed under hypoxia, indicating a quiescent state. Next, we investigated the relationship between hypoxia and stemness. Hypoxia increased stem cell markers mRNA (C-Myc, Oct-3/4, CD24, CD44, CD133) expression and tumorsphere formation efficiency (TFE). In addition, hypoxia and GEM administration reduced sphere size but increased the number of spheres and TFE. This indicated that hypoxia and GEM suppressed proliferation, however promoted stemness. Second, to examine the mechanism of GEM resistance, we established two GEM-resistant cell lines from human PDA cells by continuous treatment with GEM and CoCl2-induced chemical hypoxia. One resistant cell line possessed reduced OXPHOS and decreased mitochondrial ROS levels, while the other resistant cell line possessed increased stemness. In both cell lines, ethidium bromide-stained mitochondrial DNA levels decreased, suggesting mitochondrial DNA damage. In addition, tetramethylrhodamine-stained mitochondrial membrane potential levels decreased, suggesting mitochondrial impairment. This indicated that long hypoxia and treatment with GEM induced mitochondrial impairment and acquisition of stemness, causing chemoresistance. We further investigated the effect of lauric acid (LAA), a medium-chain fatty acid, on GEM resistance. We have previously reported that LAA causes reprogramming of energy metabolism and induces cell death in cancer cells. Treatment with LAA restored GEM sensitivity in both GEM-resistant cell lines. Flux analysis showed that both OXPHOS and glycolysis were promoted, indicating displacement from quiescent state by LAA. These results suggest that decreased energy production, decreased mitochondrial ROS levels, and increased stemness associated with mitochondrial damage caused by GEM lead to GEM resistance, and that hypoxia may promote this process. Furthermore, forced activation of OXPHOS by LAA could be a tool to overcome GEM resistance. Citation Format: Tadataka Takagi, Hiroki Kuniyasu, Masayuki Sho, Rina Tani, Shiori Mori, Shingo Kishi, Yukiko Nishiguchi, Yudai Hojo. Laurine acid enhances GEM-chemosensitivity targeting hypoxia-induced mitochondrial disfunction and stemness in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4801.

Extracellular volume fraction determined by dual-layer spectral detector CT: Possible role in predicting the efficacy of preoperative neoadjuvant chemotherapy in pancreatic ductal adenocarcinoma

PurposeTo clarify the relationship between extracellular volume (ECV) measured by dual-energy CT (DECT) and efficacy of preoperative neoadjuvant chemotherapy (NAC) in patients with pancreatic ductal adenocarcinoma (PDAC), as compared with single-energy CT (SECT). MethodsWe enrolled 67 patients with PDAC who underwent dynamic contrast-enhanced CT with a dual-energy CT system prior to NAC. Attenuation values were measured on unenhanced and the equilibrium-phase 120-kVp equivalent CT images for PDAC and the aorta. ΔHU-tumor, ΔHU-tumor/ΔHU-aorta, and SECT-ECV were calculated. Iodine densities of the tumor and aorta were measured in the equilibrium phase, and DECT-ECV of the tumor was calculated. Response to NAC was evaluated and the correlation between imaging parameters and response to NAC was statistically assessed. ResultsTumor DECT-ECVs were significantly lower in the response group (n = 7) than in the non-response group (n = 60), with most significant difference (p = 0.0104). DECT-ECV showed highest diagnostic value with an Az value of 0.798. When using the optimal cut off value of DECT-ECV (<26.0 %), sensitivity, specificity, accuracy, positive predictive value, and negative value for predicting response group were 71.4 %, 85.0 %, 83.6 %, 35.7 % and 96.2 %, respectively. ConclusionPDAC with lower DECT-ECV can potentially show better response to NAC. DECT-ECV might be a useful biomarker for predicting response to NAC in patients with PDAC.