Pancreatic Cancer Therapy Research Articles

Modulating autophagy to boost the antitumor efficacy of TROP2-directed antibody-drug conjugate in pancreatic cancer

Pancreatic cancer, characterized by a dismal prognosis and limited treatment options, persists as a formidable challenge in oncology. Trophoblast cell surface antigen 2 (TROP2)-directed antibody-drug conjugates have achieved great success in solid tumors such as breast cancer and uroepithelial carcinoma. However, their efficacy against pancreatic cancer was insufficient in clinical trials, necessitating an imperative exploration of underlying mechanisms and new therapeutic strategies. In this study, we indicated that αTROP2-MMAE, an antibody-drug conjugate targeting TROP2, induced apoptosis through the caspase-9/PARP pathway and exerted potent antitumor effects against TROP2-positive pancreatic cancer. Simultaneously, RNA sequencing suggested significant changes in autophagy after αTROP2-MMAE treatment. The formation of autophagosomes and activation of autophagic flux were markedly induced through mechanisms associated with suppressing the activation of the Akt/mTOR pathway. The addition of pharmacological inhibitors of autophagy enhanced the cytotoxicity and apoptosis caused by αTROP2-MMAE, revealing the cytoprotective role of autophagy in TROP2-positive pancreatic cancer. In the subcutaneous xenograft model using BxPC3 cells, the combined administration of αTROP2-MMAE and an autophagy inhibitor elevated the tumor inhibition rate of αTROP2-MMAE from 71.6 % to 99.0 %, resulting in the eradication of tumors in half of the mice. Collectively, our research demonstrated for the first time the cytoprotective role of autophagy in TROP2-targeted antibody-drug conjugate therapy for pancreatic cancer, providing new perspectives for mechanistic exploration and therapeutic strategies in the treatment of pancreatic cancer.

Two‐Step Targeting‐Tunable Semiconducting Nanoswitches Amplify Mitochondrion Damage and PD‐L1 Blockade for Orthotopic Pancreatic Cancer Therapy

AbstractPancreatic cancer is a malignancy tumor with luxuriant extracellular matrix (ECM) and highly immunosuppressive microenvironment and its therapy remains an enormous challenge. A two‐step targeting‐tunable strategy is proposed for orthotopic pancreatic cancer therapy via designing semiconducting nanoswitches (C/SPNT/αP) to amplify the mitochondrion damage and programmed death ligand 1 (PD‐L1) blockade. A mitochondrion‐targeting small nanoparticle (SPNT) consisting of mitochondrial targeting moiety triphenylphosphine (TPP) and semiconducting polymer is embedded with PD‐L1 antibody (αPD‐L1) into sono‐responsive collagen binding peptide (CBP)‐conjugated nanoliposomes to form C/SPNT/αP. In the first targeting step, C/SPNT/αP achieve ECM targeting to observably increase their enrichment into orthotopic pancreatic tumor sites because CBP can effectively bind to collagen in ECM. Upon ultrasound (US) irradiation, C/SPNT/αP mediate a sono‐responsive structural failure via sonodynamic effect for on‐demand releases of SPNT and αPD‐L1. In the second targeting step, SPNT target to mitochondria to induce mitochondrial damage under US irradiation for triggering amplified cell apoptosis and immunogenic cell death (ICD). Moreover, the released αPD‐L1 blocks the immunosuppressive pathway to further boost immunological effect. Such a novel therapeutic regimen can almost completely eradicate orthotopic pancreatic Panc02 and KPC tumors in mouse models. This study presents the first two‐step targeting‐tunable nanomedicine for treatments of deep‐seated orthotopic tumors.

Investigation of interfractional range variation owing to anatomical changes with beam directions based on water equivalent thickness in proton therapy for pancreatic cancer.

To assess the interfractional anatomical range variations (ARVs) with beam directions and their impact on dose distribution in intensity modulated proton therapy, we analyzed water equivalent thickness (WET) from 10 patients with pancreatic cancer. The distributions of the interfractional WET difference ($\Delta{\mathrm{WET}}^{\theta }$) across 360° were visualized using polar histograms. Interfractional ARVs were evaluated using the mean absolute error and ΔWET pass rate, indicating the percentage of $\Delta \mathrm{WE}{\mathrm{T}}^{\theta }$ < thresholds. The impact on dose distribution in proton therapy was evaluated based on two treatment plans for 40Gy(RBE)/5 fractions: 'Plan A', using two beam angles, in which the target was closest to the body surface among four perpendicular directions; and 'Plan B', using two beam angles with small ARVs. Analysis revealed individual variations in angular trends of interfractional ARVs. Three distinct trends were identified: Group 1 exhibited small ARVs around posterior directions; Group 2 exhibited small ARVs except ~60°; Group 3 demonstrated minimal ARVs only ~90°. In dose evaluation, while 150° and 210° were selected in Plan B for 9 out of 10 patients, for the remaining patient, 60° and 90° were chosen. Comparing dose volume histogram parameters for all patients, Plan B significantly reduced target coverage loss while maintaining organ-at-risk sparing comparable to Plan A. These results demonstrated that selecting beam angles with small interfractional ARVs for each patient enhances the robustness of dose distribution, reducing target coverage loss.

The complement C3a/C3aR pathway is associated with treatment resistance to gemcitabine-based neoadjuvant therapy in pancreatic cancer

Gemcitabine is a standard first-line drug for pancreatic cancer chemotherapy. Nevertheless, gemcitabine resistance is common and significantly limits its therapeutic efficacy, impeding advancements in pancreatic cancer treatment. In this study, through a comprehensive analysis of gemcitabine-resistant cell lines and patient samples, 39 gemcitabine resistance-associated risk genes were identified, and two distinct gemcitabine response-related phenotypes were delineated. Through a combination of bioinformatics analysis and in vivo and in vitro experiments, we identified the C3a/C3aR signaling pathway as a pivotal player in the development of gemcitabine resistance in pancreatic cancer. We found that activation of the C3a/C3aR signaling pathway promoted the proliferation, migration and gemcitabine resistance of pancreatic cancer cells, while the C3aR antagonist SB290157 effectively counteracted these effects by impeding the activation of the C3a/C3aR pathway. Our study reveals the fundamental role of complement C3a in the progression of pancreatic cancer, suggesting that complement C3a may serve as a promising biomarker in pancreatic cancer.

C-Myc inhibition and p21 modulation contribute to unsymmetrical bisacridines-induced apoptosis and senescence in pancreatic cancer cells.

Pancreatic cancer (PC) is one of the most aggressive cancers and is the seventh leading cause of cancer-related death worldwide. PC is characterized by rapid progression and resistance to conventional treatments. Mutations in KRAS, CDKN2A, TP53, SMAD4/DPC4, and MYC are major genetic alterations associated with poor treatment outcomes in patients with PC. Therefore, optimizing PC therapy is a tremendous challenge. Unsymmetrical bisacridines (UAs), synthesized by our group, are new promising compounds that have exhibited high cytotoxicity and antitumor activity against several solid tumors, including pancreatic cancer. The cellular effects induced by UAs in PC cells were evaluated by MTT assay (cell growth inhibition), flow cytometry, and fluorescence and light microscopy (cell cycle distribution, apoptosis, and senescence detection). Analysis of the effects of UAs on the levels of proteins (c-Myc, p53, SMAD4, p21, and p16) was performed by Western blotting. Apoptosis was the main triggered mechanism of death after UAs treatment, and induction of the SMAD4 protein can facilitate this process. c-Myc, which is one of the molecular targets of UAs, can participate in the induction of cell death in a p53-independent manner. Moreover, UAs can also induce accelerated senescence through the upregulation of p21. Notably, senescent cells can die via apoptosis after prolonged exposure to UAs. UAs have emerged as potent anticancer agents that induce apoptosis by inhibiting c-Myc protein and triggering cellular senescence in a dose-dependent manner by increasing p21 levels. Thus, UAs exhibit desirable features as promising candidates for future pancreatic anticancer therapies.

Targeting the CSF1/CSF1R signaling pathway: an innovative strategy for ultrasound combined with macrophage exhaustion in pancreatic cancer therapy.

Pancreatic cancer (PC) is a highly aggressive and lethal malignancy characterized by a complex tumor microenvironment (TME) and immunosuppressive features that limit the efficacy of existing treatments. This paper reviews the potential of combining ultrasound with macrophage exhaustion in the treatment of pancreatic cancer. Macrophages, particularly tumor-associated macrophages (TAMs), are crucial in pancreatic cancer progression and immune escape. Prolonged exposure to the immunosuppressive TME leads to macrophage exhaustion, reducing their anti-tumor ability and instead promoting tumor growth. The CSF1/CSF1R signaling pathway is key in macrophage recruitment and functional regulation, making it an effective target for combating macrophage exhaustion. Ultrasound technology not only plays a significant role in diagnosis and staging but also enhances therapeutic efficacy by guiding radiofrequency ablation (RFA) and percutaneous alcohol injection (PEI) in combination with immunomodulators. Additionally, ultrasound imaging can monitor the number and functional status of TAMs in real-time, providing a basis for optimizing treatment strategies. Future studies should further investigate the combined use of ultrasound and immunomodulators to refine treatment regimens, address challenges such as individual variability and long-term effects, and offer new hope for pancreatic cancer patients.

A meta-analysis and systematic review of randomized controlled trials in combination gemcitabine with erlotinib in the pancreatic cancer.

Previous studies have demonstrated the efficacy and safety of combining gemcitabine and erlotinib (Gem-Erlo) for the treatment of pancreatic cancer (PaC). However, there is a limited number of clinical studies and multiple prospective randomized controlled trials (RCTs) have yielded inconsistent conclusions. The question of whether Gem-Erlo has significant advantages over conventional chemotherapy in the treatment of PaC has been controversial. In order to provide valuable insights for PaC treatment, this study conducted a meta-analysis based on the current evidence from RCTs. We searched several databases including PubMed/Medline, Web of Science, Cochrane Library, and Embase, as well as relevant conference abstracts from the beginning of their inception to July 2023. We used the patient/population, intervention, comparison, outcomes and study design (PICOS) principle to screen the literature. After title, abstract and full text filtering, we extract the data from each study to assess the risk of bias by examining the quality of the literature. We used a meta-analysis with random effects model to synthesize and summarize the results regarding objective response rate (ORR), disease control rate (DCR), median progression-free survival (median PFS), median overall survival (median OS) and 1-year survival rate. Seven RCTs were included, involving 2,152 PaC patients treated with either Gem-Erlo or gemcitabine alone. The results showed that Gem-Erlo significantly improved DCR [odds ratio (OR) =1.74; 95% confidence interval (CI): 1.03 to 2.92; P=0.04]; but did not significantly improve median OS [standardized mean difference (SMD) =-0.20; 95% CI: -1.46 to 1.06; P=0.75], median PFS (SMD =-0.97; 95% CI: -4.01 to 2.07; P=0.53), ORR (OR =1.29; 95% CI: 0.84 to 1.97), or 1-year survival rate (OR =1.18; 95% CI: 0.88 to 1.57). In addition, sensitivity analysis of the median OS showed the Gem-Erlo group significantly prolonged the median OS compared to the gemcitabine alone group [weighted mean difference (WMD) =-1.74; 95% CI: -1.87 to -1.62; P<0.001]. The most common adverse events (AEs) were rash, diarrhea, fatigue, neutropenia and thrombocytopenia in both groups, but the Gem-Erlo group is more often than the gemcitabine alone (OR =1.40, 95% CI: 1.19 to 1.65; P<0.001), and all AEs were within the acceptable range for patients. Gem-Erlo can improve DCR when compared to gemcitabine. There was no statistically significant improvement in median PFS, median OS, ORR and 1-year survival rate. However, sensitivity analysis showed a statistical difference in the median OS. Our study indicated that Gem-Erlo had better efficacy than gemcitabine alone in PaC therapy. The occurrence of AEs is under the acceptable range for patients.

Feasibility and safety of endoscopic ultrasound-guided diffusing alpha emitter radiation therapy for advanced pancreatic cancer: Preliminary data

Abstract Background and study aims Pancreatic cancer is a devastating disease with limited locoregional treatment options. Diffusing alpha-emitter radiation therapy (Alpha DaRT), a novel cancer treatment using alpha-particle interstitial radiotherapy, may help address this challenge. The aim of this study was to evaluate the feasibility and safety of endoscopic ultrasound (EUS)-guided Alpha DaRT for advanced pancreatic cancer. Patients and methods Patients with inoperable locally advanced or metastatic pancreatic adenocarcinoma were treated with EUS-guided Alpha DaRT insertion. The Alpha DaRT sources were delivered into pancreatic tumors using a standard EUS needle with a novel proprietary applicator. Adverse events (AEs) were assessed based on the Common Terminology Criteria for Adverse Events version 5.0. Tumor response was evaluated by imaging 4 to 6 weeks post treatment. Results The first five patients were treated between March and September 2023. The procedure was technically successful in all cases, with Alpha DaRT sources inserted into the target tumor. Estimated gross tumor volume coverage ranged from 8% to 44%. Fourteen AEs were reported among three patients. Four were serious AEs, none of which was associated with the treatment, but rather, with disease progression or medical assistance in dying. Only two AEs (mild) were deemed possibly related to the study device. At the 35-day visit, two patients had progressive disease and three had stable disease, with one of the latter showing partial response 2 months post procedure. Conclusions Preliminary results from this first-in-human trial indicate that EUS-guided Alpha DaRT treatment for unresectable pancreatic cancer is feasible and safe, with no device-associated serious AEs. Further investigation of this promising novel modality is underway.

Current evidence for neoadjuvant therapy in resectable pancreatic cancer

Current evidence for neoadjuvant therapy in resectable pancreatic cancer

Prescribing of pancreatic enzyme therapy for malabsorption in unresectable pancreatic cancer: Cross-sectional survey across New Zealand and Australia

ObjectiveTo investigate the practices of clinicians prescribing pancreatic enzyme replacement therapy (PERT) for unresectable pancreatic cancer in Aotearoa New Zealand and Australia. MethodsA mixed media advertising campaign was used to recruit appropriate clinicians to complete a questionnaire that collected demographic data, information regarding prescribed medication, and awareness of PERT guidelines. ResultsThe study recruited 161 clinicians, with 93 and 68 respondents from Aotearoa New Zealand and Australia respectively. Most respondents from both countries were experienced gastrointestinal surgeons and dietitians. Aotearoa New Zealand clinicians and dietitians used faecal elastase more frequently to diagnose PEI than other groups. Clinicians had a tendency to under-prescribe PERT, and to advise incorrectly on the timing of the medication. The majority of clinicians from Aotearoa New Zealand and Australia were not aware of any best practice clinical guidelines for PERT (70 % and 77 %, respectively). ConclusionThis study suggests clinicians are over-reliant on faecal elastase to diagnose PEI and are uncertain about the correct dose and timing of PERT for optimal patient benefit in those with unresectable pancreatic cancer. Most clinicians were not aware of best practice guidelines.

Folate-Functionalized Chitosan-PLGA Nanoparticles: A Novel approach for targeted osthole delivery in pancreatic cancer

Efficient drug delivery systems targeting cancer cells are crucial for enhancing cancer therapy. In this study, we developed PLGA nanoparticles coated with folate-conjugated chitosan (osthole-PLGA-NPs/CS-FA) to deliver osthole to cancer cells and investigated its inhibitory and molecular signaling mechanisms in the PANC-1 pancreatic cancer cell line. Field emission scanning electron microscopy (FESEM) revealed that osthole-PLGA-NPs/CS-FA had a spherical structure with a uniform size distribution. Dynamic light scattering (DLS) analysis showed an average size of 171.76 nm, a dispersion index 0.26, and a surface charge of + 33.08 mV, indicating stability and uniform dispersion. Fourier-transform infrared (FTIR) spectrum analysis confirmed the successful incorporation of osthole into the PLGA nanoparticles, with an encapsulation efficiency of 93.12 %. These physicochemical properties suggest efficient cellular uptake and targeted delivery. The antioxidant potential of osthole-PLGA-NPs/CS-FA was evaluated using the ABTS assay, showing concentration-dependent inhibition of free radicals with an IC50 value of 172.95 μg/mL. The anticancer properties were assessed using the MTT assay, demonstrating a significant and concentration-dependent cytotoxic effect on PANC-1 cells (IC50 = 31.2 μg/mL) with minimal impact on normal human foreskin fibroblast (HFF) cells. DAPI staining and flow cytometry analyses confirmed a concentration-dependent increase in apoptosis in PANC-1 cells. The nanoparticles induced upregulation of Bax and downregulation of Bcl2, indicating activation of the intrinsic mitochondrial apoptotic pathway. The anti-angiogenic activity of osthole-PLGA-NPs/CS-FA was evaluated using the chick chorioallantoic membrane (CAM) assay. The results showed significant inhibition of angiogenesis in a concentration-dependent manner, starting at 40 μg/mL and increasing up to 120 μg/mL. In conclusion, osthole-PLGA-NPs/CS-FA nanoparticles exhibit promising potential for targeted pancreatic cancer therapy by enhancing cellular uptake, inducing apoptosis, and inhibiting angiogenesis.

Radiopharmaceuticals for Pancreatic Cancer: A Review of Current Approaches and Future Directions

The poor prognosis of pancreatic cancer requires novel treatment options. This review examines the evolution of radiopharmaceuticals in the treatment of pancreatic cancer. Established strategies such as peptide receptor radionuclide therapy (PRRT) offer targeted and effective treatment, compared to conventional treatments. However, there are currently no radiopharmaceuticals approved for the treatment of pancreatic cancer in Europe, which requires further research and novel approaches. New radiopharmaceuticals including radiolabeled antibodies, peptides, and nanotechnological approaches are promising in addressing the challenges of pancreatic cancer therapy. These new agents may offer more specific targeting and potentially improve efficacy compared to traditional therapies. Further research is needed to optimize efficacy, address limitations, and explore the overall potential of these new strategies in the treatment of this aggressive and harmful pathology.

Targeting Hypoxia-Inducible Factor-1α in Pancreatic Cancer: siRNA Delivery Using Hyaluronic Acid-Displaying Nanoparticles

Background/Objectives: Conventional anticancer therapies often lack specificity, targeting both cancerous and normal cells, which reduces efficacy and leads to undesired off-target effects. An additional challenge is the presence of hypoxic regions in tumors, where the Hypoxia Inducible Factor (HIF) transcriptional system drives the expression of pro-survival and drug resistance genes, leading to radio- and chemo-resistance. This study aims to explore the efficacy of targeted nanoparticle (NP)-based small interfering RNA (siRNA) therapies in downregulating these genes to enhance treatment outcomes in pancreatic cancer, a tumor type characterized by high CD44 expression and hypoxia. Methods: We utilized hyaluronic acid (HA)-displaying nanoparticles composed of positively charged chitosan (CS) complexed with siRNA to target and knock down HIF-1α in pancreatic cancer cells. Two NP formulations were prepared using either low molecular weight (LMW) or high molecular weight (HMW) CS. These formulations were evaluated for their internalization by cells and their effectiveness in gene silencing, both in vitro and in vivo. Results: The study found that the molecular weight (MW) of CS influenced the interaction between HA and CD44, as well as the release of siRNA upon internalization. The LMW CS formulation shows faster uptake kinetics, while HMW CS is more effective in gene knockdown across different cell lines in vitro. In vivo, both were able to significantly knockdown HIF-1α and some of its downstream genes. Conclusions: The results suggest that HMW and LMW CS-based NPs exhibit distinct characteristics, showing that both MWs have potential for targeted pancreatic cancer therapy by influencing different aspects of delivery and gene silencing, particularly in the hypoxic tumor microenvironment.

Targeted Therapies in Pancreatic Cancer: A New Era of Precision Medicine.

Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality in the United States, presents significant treatment challenges due to its late diagnosis and poor prognosis. Despite advances, the five-year survival rates remain dismally low, with only a fraction of patients eligible for potentially curative surgical interventions. This review aims to comprehensively examine the current landscape of targeted therapies in PDAC, focusing on recent developments in precision medicine approaches. We explore various molecular targets, including KRAS mutations, DNA damage repair deficiencies, mismatch repair pathway alterations, and rare genetic fusions. The review discusses emerging therapies, such as PARP inhibitors, immune checkpoint inhibitors, and novel targeted agents, like RET and NTRK inhibitors. We analyze the results of key clinical trials and highlight the potential of these targeted approaches in specific patient subgroups. Recent developments in PDAC research have emphasized precision oncology, facilitated by next-generation sequencing and the identification of genetic and epigenetic alterations. This approach tailors treatments to individual genetic profiles, improving outcomes and reducing side effects. Significant strides have been made in classifying PDAC into various subtypes, enhancing therapeutic precision. The identification of specific mutations in genes like KRAS, along with advancements in targeted therapies, including small molecule inhibitors, offers new hope. Furthermore, emerging therapies targeting DNA repair pathways and immunotherapeutic strategies also show promising results. As research evolves, integrating these targeted therapies with conventional treatments might improve survival rates and quality of life for PDAC patients, underscoring the shift towards a more personalized treatment paradigm.

Gelatin-coated glutathione depletion and oxygen generators in potentiated chemotherapy for pancreatic cancer

Chemotherapy is generally acknowledged as an effective method for pancreatic cancer (PC). However, its treatment efficacy is often compromised due to inefficient drug delivery and drug resistance propensity of tumor tissues. The purpose of this study is to design and develop a novel drug delivery system (Manganese-doped mesoporous silica nanoparticles, Mn-MSN) in which paclitaxel (PTX), a conventional chemotherapeutic agent used to effectively treat pancreatic cancer clinically. Through cross-linking with glutaraldehyde, gelatin (Ge) was encapsulated on the carrier surface, endowing the nanoparticles (Ge-Mn-MSN@PTX) with excellent biocompatibility, low hemolytic activity, and enzyme-responsive degradation. Mn was added for the following purposes: (1) catalyzing hydrogen peroxide (H2O2) to generate oxygen (O2), thereby alleviating tumor hypoxia and drug resistance; (2) depleting glutathione (GSH), inducing intracellular lipid peroxidation and ferroptosis; (3) enabling real-time monitoring of the therapeutic efficacy of the nanoparticles via magnetic resonance imaging (MRI). The experimental results demonstrated that Ge-Mn-MSN@PTX has satisfactory biosafety, antitumor activity, controlled drug release as well as imaging tracking capabilities. In the SW1990 nude mice model, the Ge-Mn-MSN@PTX effectively inhibited tumor growth by suppressing the expression of the resistance protein P-glycoprotein (P-gp) and inducing ferroptosis. In conclusion, the designed gelatin-coated Mn-MSN shows potential for application in future pancreatic cancer therapy.

Comparative Efficacy of 21 Treatment Strategies for Resectable Pancreatic Cancer: A Network Meta-Analysis.

The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches for resectable PC. A thorough search was carried out on January 31, 2023, encompassing PubMed/MEDLINE, Cochrane Library, and Embase databases. We incorporated randomized clinical trials (RCTs) that compared surgical interventions with or without (neo)adjuvant or perioperative therapies for operable PC. We conducted a fixed-effects Bayesian NMA. We presented the effect sizes in terms of hazard ratios (HRs) for overall survival (OS) along with 95% credible intervals (95% CrIs). The treatment was deemed statistically superior when the 95% credible interval (CrI) did not encompass a null value (hazard ratio < 1). Treatment rankings were established based on the surface under the cumulative ranking curve (SUCRA). A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone, with HRs ranging from 0.38 for perioperative treatments to 0.73 for adjuvant 5-fluorouracil. After the exclusion of studies conducted in Asia, it was found that the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen (SUCRA, p = 0.99). The findings endorse the utilization of perioperative CT, especially multi-agent CT, as the favored intervention for operable PC in Western nations.

Cutting-Edge Approach to Targeted Therapy: Repositioning of Old Drugs in Combination with Standard Clinical Chemotherapeutics Potentiates a Propitious Novel Targeted Therapy for Human Pancreatic Cancer

Metastatic pancreatic cancer leads to a fatal outcome, with a median progression-free survival of approximately six months when utilizing the most successful combination of chemotherapeutic regimens. When drug resistance develops, it facilitates an increase in primary tumor growth and new and growing metastases. Patients inevitably and quickly succumb to their disease and die. Notably, chemotherapy has an unintended impact on the development of drug resistance through the enhancement of EMT development and the enrichment of cancer stem cells (CSC). Recent report discovered that neuraminidase-1 (Neu-1) regulates EMT induction, angiogenesis, and cellular proliferation by the activation of several receptor tyrosine kinases. Here, the continual therapeutic inhibition of Neu-1 through intravenous administration of oseltamivir phosphate (OP) and aspirin (ASA) alongside GEM treatment significantly inhibits tumor progression, crucial compensatory signaling pathways, EMT program, CSC, and metastasis progression in a preclinical RAG2xCy double mutant BALB/c mouse model of human PANC-1 pancreatic cancer. The tumorigenic and metastatic potential of the xenotumors from the animals treated with the experimental protocols were significantly ablated when transferred into the mammary fat pads of NSG (NOD SCID gamma) branded mice. Keywords: pancreatic cancer; chemoresistance; drug repurposing; EMT.

Abstract B060: Unveiling resistance mechanisms to CAR T-cell therapy in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening

Abstract Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer death by 2030. PDAC lacks effective treatment options and innovative strategies for therapeutic intervention are urgently needed. Chimeric Antigen Receptor (CAR)-T cell therapy has shown remarkable success in treating hematologic malignancies, yet achieving efficacy in solid tumors remains a significant challenge. Early results from clinical trials show limited efficacy of CAR T-cell therapy in PDAC. To uncover tumor-intrinsic mechanisms of resistance to CAR T-cell therapy in vivo, we performed iterative CRISPR/Cas9-based pooled screens in a fully immunocompetent, orthotopic model of PDAC. We identified a variety of genes influencing CAR T-cell treatment efficacy. In particular, loss of genes involved in redox biology and oxidative stress sensitized PDAC tumors to CAR T-cell therapy in vivo. Additionally, single-cell RNA sequencing of PDAC tumors subjected to CAR T-cell therapy unveiled a distinct subset of tumor cells resilient to the treatment, characterized by changes in oxidative stress. Our findings indicate a potential avenue for therapeutic synergy by targeting pathways involved in oxidative stress to increase the efficacy of CAR T cell therapy in PDAC. Citation Format: Julia Fröse, Charlie Whittaker, Paul Leclerc, Adam Langenbucher, Riley Hellinger, Daniel R. Goulet, Michael T. Hemann. Unveiling resistance mechanisms to CAR T-cell therapy in pancreatic cancer through in vivo CRISPR/Cas9 knockout screening [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 B060.

Abstract B078: A comprehensive spatial atlas of neoadjuvant chemoradiation therapy in resected pancreatic cancer identifies cellular &amp; microenvironmental determinants of persister populations

Abstract Background The molecular pathways involved in the response to radiation therapy (RT) in pancreatic ductal adenocarcinoma (PDAC) remain poorly understood. Despite extensive molecular stratification efforts, improvements in molecularly informed RT-based therapeutic strategies in the neoadjuvant setting have been limited. This study aims to elucidate the adaptive mechanisms and interactions within PDAC to identify new combinatorial therapeutic targets with RT. MethodsWe constructed a high-resolution molecular landscape of the cellular subtypes and spatial communities that constitute PDAC. Single-cell RNA sequencing (scRNA- seq) was performed on 16 PDAC biopsies of matched pre- and post-treatment samples from a Phase I/II dose-escalation clinical trial of pancreatic stereotactic body radiation therapy (SBRT). Additionally, Visium spatial transcriptomics (ST) was conducted on biopsies from primary PDAC patients collected at the time of surgery. These patients received either no neoadjuvant therapy (n = 8) or neoadjuvant chemoradiation (chemoRT) (n = 20). Cell type profiles were determined from scRNA-seq to compare changes in cell type proportions and signatures before and after RT. From these profiles, we employed robust cell type decomposition to analyze cell type signatures in our ST dataset. ResultsChemoRT induced several significant effects compared to controls within the tumor microenvironment, including an increase in the proportion of myofibroblasts, specifically senescent cancer-associated fibroblasts (CAFs), with signatures consistent with immune cell dysfunction. We observed an increase in CD8 and CD4 effector memory cells with RT; however, this occurred alongside a rise in immunosuppressive alternatively activated tumor-associated macrophages. Additionally, RT upregulated pathways related to HIF, cytokine production, B cell proliferation, and negative regulation of lymphocytes. Patients with increased infiltration of NK, memory B, and CD8 effector memory cells demonstrated improved overall survival outcomes. Inference of copy number variations enabled us to identify cancer subclones as either responsive or resistant in matched pre and post RT biopsies. Resistance was characterized by augmented hypoxia, KRAS activation, epithelial- mesenchymal transition, and interferon-gamma response signaling. Conversely, responders exhibited increased oxidative phosphorylation signaling and pathway enrichment associated with cell proliferation and cell cycle progression. Interestingly, RT induced a decrease in cancer cells characterized as harboring a chemoresistant basal-like molecular subtype. ConclusionThrough both longitudinal and therapy stratified tumor biopsies, we were able to observe significant selection pressures on stromal and cancer cells following RT. This includes upregulation of innate and adaptive immune pathways with a compensatory immunosuppressive response driven by myeloid cells and CAFs. This may provide opportunities for development of clinical trials to therapeutically target specific cellular phenotypes and their interactions. Citation Format: Vincent Bernard, Galia Jacobson, Kimal Rajapakshe, Jimin Min, Guangsheng Pei, Daniel Lin, Ayush Suresh, Dadi Jiang, Ching-Wei Tzeng, Manoop S Bhutani, Linghua Wang, Paola A Guerrero, Ethan B Ludmir, Albert C Koong, Anirban Maitra, Cullen M Taniguchi, Eugene J Koay. A comprehensive spatial atlas of neoadjuvant chemoradiation therapy in resected pancreatic cancer identifies cellular &amp; microenvironmental determinants of persister populations [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 B078.

Abstract C054: Clinicogenomic determinants of response to FOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line systemic therapy for pancreatic cancer

Abstract Background: FOLFIRINOX (FFX) and gemcitabine plus nab-paclitaxel (GA) are two recommended first-line systemic options for pancreatic cancer; however, there is limited evidence to support a particular regimen or provide guidance for treatment selection. We sought to compare outcomes for FFX versus GA across disease stages, and test whether there was an association between clinicogenomic features, treatment response, and survival. Methods: For this retrospective analysis, we utilized AACR’s GENIE PANC v1.2 database, the first large-scale pancreatic cancer dataset that combines genomic data with clinical annotations. The clinicogenomic profiles of patients were stratified and compared by stage: resectable/borderline resectable (R/BR), locally advanced (LA), or metastatic (MET). Patients who received FFX or GA as first-line therapy were compared across stages, with a focus on MET patients. We evaluated OS and PFS as survival outcomes and performed an adjusted analysis using Cox proportional hazards modeling. Treatment responses were further evaluated by change in serum CA 19-9. To test for features associated with treatment response, the genomic profiles of best and worst responders were compared. Results: Of 987 patients with complete genomic data, there were 452 R/BR, 82 LA, and 453 MET. While there was no difference in KRAS status, patients with later-stage disease accumulated greater common co-alterations: CDKN2A (19%, 23%, 35%), SMAD4 (26%, 29%, 30%), TP53 (72%, 73%, 77%), and ARID1A (6%, 6%, 11). Within MET patients, there was no significant difference in PFS between those treated with FFX (n=239) and GA (n=82), but patients treated with FFX had significantly longer OS, even after multivariable adjustment (median 1.14 vs. 0.854 years, p &amp;lt; 0.01; HR: 0.66, 95% CI: 0.49- 0.89, p &amp;lt; 0.01). Despite improved OS in FFX patients, GA patients had a greater reduction in CA 19-9 (median 50.0 vs. 69.0 U/mL). In addition, when comparing the genomic profiles of best/worst responders for MET patients treated with FFX and GA, there was no clear signal that one regimen should be favored over another in a specific context. Exploratory analyses in the R/BR and LA groups indicated no significant survival differences between first-line FFX vs. GA patients, nor in first-line treatment among patients who developed metastases post- diagnosis. Conclusion: Common co-alterations appear to accumulate in later-stage disease, and outcomes in patients undergoing systemic therapy is worse generally in patients with more complex genomic profiles. However, we did not observe any specific genomic features suggestive of a particular response to FFX vs. GA. Of note, we found that Met GA patients had a larger magnitude in CA 19-9 response, even though Met FFX was associated with improved OS. This provokes important questions regarding how biochemical response should be gauged in patients treated with these regimens. Citation Format: Kunling Tong, Elishama Kanu, Ethan Agritelley, Jiayin Bao, Peter J Allen, Daniel P Nussbaum. Clinicogenomic determinants of response to FOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line systemic 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 C054.