Efficacy In Pancreatic Cancer Research Articles

Targeted intervention in nerve-cancer crosstalk enhances pancreatic cancer chemotherapy.

Nerve-cancer crosstalk has gained substantial attention owing to its impact on tumour growth, metastasis and therapy resistance. Effective therapeutic strategies targeting tumour-associated nerves within the intricate tumour microenvironment remain a major challenge in pancreatic cancer. Here we develop Escherichia coli Nissle 1917-derived outer membrane vesicles conjugated with nerve-binding peptide NP41, loaded with the tropomyosin receptor kinase (Trk) inhibitor larotrectinib (Lar@NP-OMVs) for tumour-associated nerve targeting. Lar@NP-OMVs achieve efficient nerve intervention to diminish neurite growth by disrupting the neurotrophin/Trk signalling pathway. Moreover, OMV-mediated repolarization of M2-like tumour-associated macrophages to an M1-like phenotype results in nerve injury, further accentuating Lar@NP-OMV-induced nerve intervention to inhibit nerve-triggered proliferation and migration of pancreatic cancer cells and angiogenesis. Leveraging this strategy, Lar@NP-OMVs significantly reduce nerve infiltration and neurite growth promoted by gemcitabine within the tumour microenvironment, leading to augmented chemotherapy efficacy in pancreatic cancer. This study sheds light on a potential avenue for nerve-targeted therapeutic intervention for enhancing pancreatic cancer therapy.

Rapidly-manufactured CD276 CAR-T cells exhibit enhanced persistence and efficacy in pancreatic cancer

BackgroundPancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer.MethodsIn the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T.ResultsWe found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48–72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal.ConclusionsIn this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.

Resistance to gemcitabine is mediated by the circ_0036627/miR-145/S100A16 axis in pancreatic cancer.

The development of gemcitabine (GEM) resistance severely limits the treatment efficacy in pancreatic cancer (PC) and increasing evidence highlights the vital roles of circular RNAs (circRNAs) in the tumorigenesis, progression and drug resistance of PC. However, the circRNAs underlying GEM resistance development of PC remains to be clarified. The current research aims to unveil the roles of circ_0036627 in dictating the aggressiveness and GEM sensitivity in PC. We reported the increased expression of circ_0036627 in PC tissues and PC cell lines. Elevated circ_0036627 expression level was correlated with advanced tumour grade and poor overall survival in PC patients. Functional assays and in vivo experiments demonstrated that circ_0036627 overexpression was required for the proliferation, migration invasion and GEM resistance in PC cells. circ_0036627 knockdown suppressed tumour development invivo. The molecular analysis further showed that circ_0036627 increased S100A16 expression by sponging microRNA-145 (miR-145), a tumour-suppressive miRNA that could significantly attenuate PC cell proliferation, migration, invasion and GEM resistance. Furthermore, our findings suggested that S100A16 acted as an oncogenic factor to promote aggressiveness and GEM resistance in PC cells. In conclusion, the current findings provide new mechanistic insights into PC aggressiveness and GEM resistance, suggesting the critical role of circ_0036627/miR-145/S100A16 axis in PC progression and drug resistance development and offering novel therapeutic targets for PC therapy.

Nanotechnology-Based Strategy for Enhancing Therapeutic Efficacy in Pancreatic Cancer: Receptor-Targeted Drug Delivery by Somatostatin Analog

A novel nanotechnology-based drug delivery system (DDS) targeted at pancreatic cancer cells was developed, characterized, and tested. The system consisted of liposomes as carriers, an anticancer drug (paclitaxel) as a chemotherapeutic agent, and a modified synthetic somatostatin analog, 5-pentacarbonyl-octreotide, a ligand for somatostatin receptor 2 (SSTR2), as a targeting moiety for pancreatic cancer. The cellular internalization, cytotoxicity, and antitumor activity of the DDS were tested in vitro using human pancreatic ductal adenocarcinoma (PDAC) cells with different expressions of the targeted SSTR2 receptors, and in vivo on immunodeficient mice bearing human PDAC xenografts. The targeted drug delivery system containing paclitaxel exhibited significantly enhanced cytotoxicity compared to non-targeted DDS, and this efficacy was directly related to the levels of SSTR2 expression. It was found that octreotide-targeted DDS proved exceptionally effective in suppressing the growth of PDAC tumors. This study underscores the potential of octreotide-targeted liposomal delivery systems to enhance the therapeutic outcomes for PDAC compared with non-targeted liposomal DDS and Paclitaxel-Cremophor® EL, suggesting a promising avenue for future cancer therapy innovations.

Abstract 6534: Overcoming B regulatory cell induced STING resistance by dual functional albumin nanomedicine to prolong survival of pancreatic cancer

Abstract Pancreatic cancer is the most lethal form of cancer with a 5-year survival at 11% and lacks treatment options. Immunotherapy, specifically anti-PD-1/PD-L1 antibody, proves ineffective for pancreatic cancer patients due to the immunosuppressive tumor microenvironment (TME). STING agonist has emerged as the most effective immune modulator to regulate immunosuppressive TME to enhance the efficacy of immunotherapy across many different cancer types. However, two challenges hinder the use of STING agonist in pancreatic cancer: (A) STING agonist strongly stimulates induction of B regulatory cells (Bregs) in pancreatic tumor and lymph node, leading to an intrinsic resistance to STING agonist and a severe compromised efficacy. (B) Most STING agonists are used by local intra-tumor injection in clinical trials, which only shrinks the local tumors without inhibiting distal tumors or metastasis, whereas it is also not feasible for intra-tumor injection for pancreatic cancer in clinical trials. In response, we developed a first-in-class dual functional drug (SH-273) to overcome STING resistance by eliminating Bregs in both tumors and lymph nodes for long-term efficacy in pancreatic cancer. SH-273 has dual function to stimulates STING function (EC50 100 nM) and inhibits PI3Kγ (IC50 7 nM) that eliminate Bregs to overcome STING resistance. Interestingly, SH-273 achieved dual function with an opposite mechanism in regulating IRF3 phosphorylation in myeloid cells (increase) vs. in Bregs (decrease). In addition, we developed an albumin nanoparticle of SH-273 (Nano-273) for systemic delivery to enhance drug targeting to tumor and lymph node to activate systemic anticancer immunity. 3D imaging results indicated that albumin nano formulation greatly enhanced drug lymphoid draining and pancreatic tumor penetrating. Nano-273, combined with anti-PD-1, achieved long-term median survival of 200 days in LSL-KrasG12D; LSL-Trp53R172H/+; Pdx1cre/+ (KPC) mice (a substantial 67% increase from 120 days without treatment). The 80-day survival extension is significant as KPC mice mimic human pancreatic cancers with Kras/P53 mutations that are unresponsive to other available therapies. Single cell RNA-sequencing and flow cytometry revealed that Nano-273, combined with anti-PD-1, reduces Bregs by 5 to 7-fold while increasing other B cell subtypes by 4-fold in both pancreatic tumors and lymph nodes, compared to control group or group treated with STING agonist alone. These findings suggest that Nano-273 overcomes STING resistance by eliminating Bregs and induced systemic immunity to achieve long-term anti-tumor efficacy in pancreatic cancer. Citation Format: Chengyi Li, Shuai Mao, Hongyi Zhao, Djibo Mahamadou, Zhongwei Liu, Hanning Wen, Miao He, Meilin Wang, Jinsong Tao, Bo Wen, Trang Hoang, Binyamin Jacobovitz, Fei Wen, Wei Gao, Duxin Sun. Overcoming B regulatory cell induced STING resistance by dual functional albumin nanomedicine to prolong survival of pancreatic cancer [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 6534.

Abstract 34: Improving CAR T cell efficacy in pancreatic cancer using an in vivo CRISPR Cas9 screen

Abstract Introduction: Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable success in the treatment of certain hematologic malignancies. However, efficacy against solid tumors has remained limited and is associated with relatively low T cell persistence. Here, we perform an in vivo CAR T cell CRISPR screen in pancreatic adenocarcinoma using a curated guide library to identify genes that enhance CAR T cell persistence in vivo. Material and Methods: The Mario library consists of 1180 total guide RNAs targeting 135 genes that have been shown to modulate T cell functions in other models. To generate Mario-CART cells, primary human T cells were transduced with two lentiviral vectors, the first encoding an anti-mesothelin CAR and the second containing a fixed guide targeting the TCR alpha gene constant region (TRAC) as well as the Mario library. Mario-CART cells were transduced at low MOI, expanded in vitro and selected for loss of CD3 expression using magnetic selection, to enrich for cells that had a successful gene-edited event. Purified Mario-CART cells were intravenously injected into NSG mice bearing subcutaneous pancreatic adenocarcinoma (ASPC1). Tumor and spleen were harvested 2 or 4 weeks after Mario-CART injection, and engrafted T cells were isolated by CD45 positive selection. Genomic DNA was prepared from retrieved cells and illumina sequencing was used to evaluate guide abundance to identify gene knockouts that had been enriched after tumor exposure in vivo. Results: The transcription factor, GATA3, was consistently identified as the most enriched hit across two donor T cells when Mario-CART was recovered at the 2-week timepoint. When compared to control or a depleted hit, GATA3 KO CAR showed early improvements in tumor clearance in vivo. However, relapse occurred at similar timepoints across groups. At the 4-week timepoint, the most enriched guides comprised a different set, including genes involved in transforming growth factor beta and JAK-STAT signaling pathways as well as T cell trafficking. In vivo anti-tumor control data are being collected. Conclusions: Our findings highlight the dynamic nature of CART-tumor interactions. Gene knockouts that confer enhancements may change over time with varying context (such as in vitro vs in vivo conditions). It may be difficult to identify single gene knockouts that enhance CAR-T cell functions across different conditions and over time, but rather it may be necessary to exert more dynamic functional control of CAR T cells to enhance their function in different settings. Citation Format: Tamina Kienka, Felix Korell, Nelson Knudsen, Kathleen Yates, Andi Cheng, Debattama Sen, Marcela Maus, Robert Manguso. Improving CAR T cell efficacy in pancreatic cancer using an in vivo CRISPR Cas9 screen [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 34.

Tumour-associated neutrophils: Potential therapeutic targets in pancreatic cancer immunotherapy.

Pancreatic cancer (PC) is a highly malignant tumour of the digestive system with poor therapeutic response and low survival rates. Immunotherapy has rapidly developed in recent years and has achieved significant outcomes in numerous malignant neoplasms. However, responses to immunotherapy in PC are rare, and the immunosuppressive and desmoplastic tumour microenvironment (TME) significantly hinders their efficacy in PC. Tumour-associated neutrophils (TANs) play a crucial role in the PC microenvironment and exert a profound influence on PC immunotherapy by establishing a robust stromal shelter and restraining immune cells to assist PC cells in immune escape, which may subvert the current status of PC immunotherapy. The present review aims to offer a comprehensive summary of the latest progress in understanding the involvement of TANs in PC desmoplastic and immunosuppressive functions and to emphasise the potential therapeutic implications of focusing on TANs in the immunotherapy of this deleterious disease. Finally, we provide an outlook for the future use of TANs in PC immunotherapy.

Development of Potent Dual BET/HDAC Inhibitors via Pharmacophore Merging and Structure-Guided Optimization.

Bromodomain and extra-terminal domain (BET) proteins and histone deacetylases (HDACs) are prime targets in cancer therapy. Recent research has particularly focused on the development of dual BET/HDAC inhibitors for hard-to-treat tumors, such as pancreatic cancer. Here, we developed a new series of potent dual BET/HDAC inhibitors by choosing starting scaffolds that enabled us to optimally merge the two functionalities into a single compound. Systematic structure-guided modification of both warheads then led to optimized binders that were superior in potency to both parent compounds, with the best molecules of this series binding to both BRD4 bromodomains as well as HDAC1/2 with EC50 values in the 100 nM range in cellular NanoBRET target engagement assays. For one of our lead molecules, we could also show the selective inhibition of HDAC1/2 over all other zinc-dependent HDACs. Importantly, this on-target activity translated into promising efficacy in pancreatic cancer and NUT midline carcinoma cells. Our lead molecules effectively blocked histone H3 deacetylation in pancreatic cancer cells and upregulated the tumor suppressor HEXIM1 and proapoptotic p57, both markers of BET inhibition. In addition, they have the potential to downregulate the oncogenic drivers of NUT midline carcinoma, as demonstrated for MYC and TP63 mRNA levels. Overall, this study expands the portfolio of available dual BET/class I HDAC inhibitors for future translational studies in different cancer models.

The Extracellular Niche and Tumor Microenvironment Enhance KRAS Inhibitor Efficacy in Pancreatic Cancer.

Pharmacologic inhibition of KRAS elicits varied responses in pancreatic cancer 2D cell lines, 3D organoid cultures, and xenografts, underscoring the importance of mechanotransduction and the tumor microenvironment in regulating therapeutic responses.

Abstract B087: Mutant-p53 amplifies Cxcl1 expression from distal enhancers blunting immune checkpoint inhibition efficacy in pancreatic cancer

Abstract Pancreatic ductal Adenocarcinoma (PDAC) is an aggressive malignancy complicated by poor early diagnosis and a lack of response to traditional treatments. It is characterized by a desmoplastic stroma, a lack of infiltration and activation of T cells, and a low mutational burden. The genetic landscape of PDAC is defined by activating KRAS mutations (~90%) and p53 alterations (~70%), but the molecular switches perturbed by these genetic aberrations remain unclear. p53 missense mutations, unlike mutations resulting in the loss of p53, are considered to acquire tumor-supporting functions. But these novel functions remain uncharacterized. The ambiguity in the molecular mechanism of mutant-p53 is further exacerbated by the existence of various types of p53 mutations. The majority of p53 mutations are missense mutations in the DNA binding domain. The repertoire of transcription factors (TFs) it can interact with and the vast regulatory landscape of each TF—composed of gene promoters and distal enhancers—present obstacles in understanding the molecular mechanisms promoting PDAC. In this study, we examined how a common p53 missense mutation in PDAC plays a role in weakening the Immune checkpoint Inhibitors (ICIs) efficacy. Using cells derived from a genetically engineered mouse model (GEMM) of PDAC with activating KRAS mutation (KrasG12D/+) and a p53 missense mutation (p53R172H/-), we found that the PDAC tumorigenesis and resistance to ICIs are dependent on the mutant-p53. We used isogenic p53-null PDAC cells and the restoration of p53R172H in p53-null cells to demonstrate the role of p53R172H in controlling the expression of immunosuppressive chemokine genes such as Cxcl1. p53R172H deletion attenuated PDAC tumor growth, increased the influx of cytotoxic T-cells, and sensitized the tumor to ICIs. The p53R172H-mediated TME reprogramming was replicated by the deletion of the Cxcl1 gene, suggesting the anti-tumorigenic effect of p53R172H was mediated by the Cxcl1 gene. We probed the mechanism of Cxcl1 expression dependence on p53R172H. We found that in conjunction with NF-kB, p53R172H occupies the distal transcription regulatory elements (dTREs) of the Cxcl1 gene harboring NF-kB binding sites. Strikingly, deletion of the Cxcl1 dTREs in PDAC cells recapitulates the phenotypes of p53R172H deletion and Cxcl1 deletion in terms of tumor size, immune landscape of the TME, and ICI responsiveness. Furthermore, we examined the interplay between p53R172H and NF-kB and found that the p53R172H physically interacts with the NF-kB subunit RelA and facilitates its nuclear translocation. Overall, we characterize how a common p53 mutation in PDAC co-opts non-coding regulatory DNA to augment the expression of selective chemokine genes and establishes an immunosuppressive TME to shield the therapeutic benefits of ICIs. Citation Format: Dig B. Mahat, Heena Kumra, Emily Metcalf, Sarah Castro, Kim Nguyen1, Arundeep Singh, William W. Ho, Ivy Chen, Brandon Sullivan, Leon Yim, Enrico Moiso, Vikash Chauhan, Hernandez Moura Silva, Stefani Spranger, Rakesh Jain, Phillip A. Sharp. Mutant-p53 amplifies Cxcl1 expression from distal enhancers blunting immune checkpoint inhibition efficacy in pancreatic cancer [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 B087.

Chimeric Antigen Receptor T Cell Therapy for Pancreatic Cancer: A Review of Current Evidence.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of malignant and non-malignant disorders. CARs are synthetic transmembrane receptors expressed on genetically modified immune effector cells, including T cells, natural killer (NK) cells, or macrophages, which are able to recognize specific surface antigens on target cells and eliminate them. CAR-modified immune cells mediate cytotoxic antitumor effects via numerous mechanisms, including the perforin and granzyme pathway, Fas and Fas Ligand (FasL) pathway, and cytokine secretion. High hopes are associated with the prospective use of the CAR-T strategy against solid cancers, especially the ones resistant to standard oncological therapies, such as pancreatic cancer (PC). Herein, we summarize the current pre-clinical and clinical studies evaluating potential tumor-associated antigens (TAA), CAR-T cell toxicities, and their efficacy in PC.

Responsive Nanomaterial Delivery Systems for Pancreatic Cancer Management

AbstractPancreatic cancer is characterized by a high mortality rate and unfavorable prognosis. This is primarily attributed to poor accumulation of therapeutic agents at the target site due to the presence of a highly complex tumor microenvironment surrounding the pancreatic cancer tissue. However, a promising avenue for targeted drug delivery has emerged in the form of stimuli‐responsive materials. These advanced nanocarriers, encompassing both external and internal stimuli‐responsive nanoparticles, can be formulated to control the release of therapeutic agents precisely in response to specific activation. By harnessing external stimuli such as light, ultrasound, or magnetic fields, as well as intrinsic biological triggers including pH, redox potential, hypoxia, and temperature, these nanomaterials exhibit ‘intelligent’ and selective responses within complex biological environments. These responsive nanoparticles have been shown to address challenges associated with poor vascularity and thick desmoplastic stromal layers, which are hallmarks of pancreatic cancer, by promoting enhanced drug accumulation and release at the target site relative to conventional therapy. This work explores the design strategies for advanced stimuli‐responsive nanomaterials, integrating both internal and external stimuli, with the potential to enhance drug delivery efficacy in pancreatic cancer. It addresses the challenges and prospects in their development and offers insights for future clinical applications.

Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer

BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC...

HIMB1636-MMAE, a Novel TROP2-Targeting Antibody-Drug Conjugate Exerting Potent Antitumor Efficacy in Pancreatic Cancer.

Herein, we first prepared a novel anti-TROP2 antibody-drug conjugate (ADC) hIMB1636-MMAE using hIMB1636 antibody chemically coupled to monomethyl auristatin E (MMAE) via a Valine-Citrulline linker and then reported its characteristics and antitumor activity. With a DAR of 3.92, it binds specifically to both recombinant antigen (KD ∼ 0.687 nM) and cancer cells and could be internalized by target cells and selectively kill them with IC50 values at nanomolar/subnanomolar levels by inducing apoptosis and G2/M phase arrest. hIMB1636-MMAE also inhibited cell migration, induced ADCC effects, and had bystander effects. It displayed significant tumor-targeting ability and excellent tumor-suppressive effects in vivo, resulting in 5/8 tumor elimination at 12 mg/kg in the T3M4 xenograft model or complete tumor disappearance at 10 mg/kg in BxPc-3 xenografts in nude mice. Its half-life in mice was about 87 h. These data suggested that hIMB1636-MMAE was a promising candidate for the treatment of pancreatic cancer with TROP2 overexpression.

1656P Targeting NPC1L1 rescues anti-tumor immunity and improves immunotherapeutic efficacy in pancreatic cancer

1656P Targeting NPC1L1 rescues anti-tumor immunity and improves immunotherapeutic efficacy in pancreatic cancer

A Long-Term and Sustainable Response to Orapali in a BRCA2 Mutant Advanced Pancreatic Cancer: A Case Report

Pancreatic cancer is a highly malignant cancer characterized by high mutation rates of oncogenes and tumor suppressor genes and genomic instability. It has a poor prognosis owing to early metastasis and rapid growth. Therefore, new drugs or treatments are urgent to be required. Poly ADP-Ribose polymerase (PARP) inhibitors have shown therapeutic efficacy in pancreatic cancer driven by defects in homologous recombinant (HRD). Here we report a case of advanced pancreatic cancer with BRCA2 mutation. The patient came to our hospital due to abnormal enlargement of the left supraclavicular lymph node. Further examination revealed pancreatic cancer with multiple retroperitoneal lymph nodes metastases and lung metastases. Pathological and immunohistochemical results of supraclavicular lymph node confirmed it was pancreatic cancer metastasis. Next generation sequencing (NGS) demonstrated that BRCA2 germline mutation. Subsequently, gemcitabine combined with cisplatin as first line therapy was commenced for the patient. The tumors were significant reduced after 6 cycles of treatment. Then, the patient was given orapali (PARP inhibitors) to maintain treatment. Surprisingly, the efficacy has lasted for about 20 months (from Dec 2021 to Aug 2023) and no signs of disease progression have been found. Our case shows that orapali provides a more efficient and low-toxic treatment for patient with BRCA2 mutation advanced pancreatic cancer, which is expected to change the treatment pattern of advanced pancreatic cancer.

The Tango between Cancer-Associated Fibroblasts (CAFs) and Immune Cells in Affecting Immunotherapy Efficacy in Pancreatic Cancer.

The lack of response to therapy in pancreatic ductal adenocarcinoma (PDAC) patients has contributed to PDAC having one of the lowest survival rates of all cancer types. The poor survival of PDAC patients urges the exploration of novel treatment strategies. Immunotherapy has shown promising results in several other cancer types, but it is still ineffective in PDAC. What sets PDAC apart from other cancer types is its tumour microenvironment (TME) with desmoplasia and low immune infiltration and activity. The most abundant cell type in the TME, cancer-associated fibroblasts (CAFs), could be instrumental in why low immunotherapy responses are observed. CAF heterogeneity and interactions with components of the TME is an emerging field of research, where many paths are to be explored. Understanding CAF-immune cell interactions in the TME might pave the way to optimize immunotherapy efficacy for PDAC and related cancers with stromal abundance. In this review, we discuss recent discoveries on the functions and interactions of CAFs and how targeting CAFs might improve immunotherapy.

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.

Serum CA724 has no diagnostic value for gastrointestinal tumors.

This study aimed to explore the predictive values of serum carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 199, CA125 and CA724 in the diagnosis of gastrointestinal tumors. Among patients treated for gastrointestinal tumors at the First Affiliated Hospital of Wannan Medical College between December 2020 and March 2022, 572 patients were reviewed as the tumor group, and 700 healthy subjects from the physical examination center of the same hospital were reviewed as the control group. We evaluated the correlation between serum CEA, CA199, CA125, CA724 levels and pathological features in 572 patients with gastrointestinal tumors.The levels of serum CEA, CA199, CA125 and CA724 were compared between the two groups, and the area under the receiver operating characteristic (ROC) curve (AUC) was used to evaluate the diagnostic efficacy of these markers alone and in combination. Serum CEA level was correlated with tumor stage and metastasis, and CA199 was correlated with tumor stage, lymph node involvement and metastasis. CA125 and CA724 have no correlation with tumor pathological features. The levels of serum CEA, CA199 and CA125 were significantly increased in the tumor group compared with the control group, while serum CA724 levels did not significantly differ between groups (p > 0.05). In addition, in patients with gastric cancer (GC), esophageal cancer (EC), pancreatic cancer (PC), gallbladder cancer (GBC) or colorectal cancer (CRC), the serum CEA, CA199 and CA125 levels were significantly higher than those in the control group (p < 0.05). However, serum CA724 levels were increased only in CRC patients (p < 0.05). ROC curve evaluation results showed that while CA199, CA125 and CA724 alone had poor diagnostic efficacy in the tumor group, CEA was better. Specifically, CEA had better diagnostic efficacy in GC, PC, GBC and CRC; additionally, CA199 and CA125 had better diagnostic efficacy in PC. However, CA724 showed no diagnostic value in the tumor group and the single gastrointestinal tumor group. For diagnosis with multiple-marker combinations, CEA + CA199 + CA125 had the best diagnostic performance (AUC = 0.776, AUC = 0.650, AUC = 0.896, AUC = 0.840, AUC = 0.793) in the GC, EC, PC, GBC and CRC groups, and the sensitivity of multiple-marker combined detection was better than that of single-marker detection. Serum CA724 has no diagnostic value for gastrointestinal tumors, and it cannot evaluate the pathological status of tumors. Serum CEA has excellent diagnostic efficacy in GC, PC, GBC and CRC, and its expression level is related to tumor stage and metastasis. Additionally, CA199 and CA125 have good diagnostic efficacy in PC. Among them, CA199 level was related to tumor stage, lymph node involvement and metastasis, and CA125 level was not related to pathological status. In addition, the multiple-marker combination CEA + CA199 + CA125 has the best diagnostic efficacy in GC, EC, PC, GBC and CRC.

Targeting UBE2T Potentiates Gemcitabine Efficacy in Pancreatic Cancer by Regulating Pyrimidine Metabolism and Replication Stress

Although small patient subsets benefit from current targeted strategies or immunotherapy, gemcitabine remains the first-line drug for pancreatic cancer (PC) treatment. However, gemcitabine resistance is widespread and compromises long-term survival. Here, we identified ubiquitin-conjugating enzyme E2T (UBE2T) as a potential therapeutic target to combat gemcitabine resistance in PC. Proteomics and metabolomics were combined to examine the effect of UBE2T on pyrimidine metabolism remodeling. Spontaneous PC mice (LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre; KPC) with Ube2t-conditional knockout, organoids, and large-scale clinical samples were used to determine the effect of UBE2T on gemcitabine efficacy. Organoids, patient-derived xenografts (PDX), and KPC mice were used to examine the efficacy of the combination of a UBE2T inhibitor and gemcitabine. Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes really interesting new gene 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice. Collectively, UBE2T-mediated p53 degradation confers PC gemcitabine resistance by promoting pyrimidine biosynthesis and alleviating replication stress. This study offers an opportunity to improve PC survival by targeting UBE2T and develop a promising gemcitabine sensitizer in clinical translation setting.