Combination Therapy For Pancreatic Cancer Research Articles

CASP1 is a target for combination therapy in pancreatic cancer

Gemcitabine (GEM) is commonly used as the first-line chemotherapeutic agent for treating pancreatic cancer (PC) patients. However, drug resistance is a major hurdle in GEM-based chemotherapy for PC. Recent studies have shown that pyroptosis, a type of programmed death, plays a significant regulatory role in cancer development and therapy. In this study, we observed an increase in the expression of Caspase-1(CASP1)/Gasdermin-D (GSDMD) in PC and found that high expression of CASP1 and GSDMD was associated with poor overall survival (OS) and progression-free survival (PFS) of PC patients. Knockdown of either CASP1 or GSDMD resulted in the inhibition of cell viability and migration in PC cells. More importantly, the knockdown of CASP1 or GSDMD enhanced GEM-induced cell death in PC cells. Interestingly, subsequent investigations demonstrated that enzymatically active CASP1 promoted GEM-induced cell death in PC cells. The activation of CASP1 by the DPP8/DPP9 inhibitor (Val-boroPro, VbP) increased GEM-induced cell death by inducing pyroptosis. These findings suggest that inhibiting CASP1 to suppress its oncogenic effects or activating it to promote cell pyroptosis both enhance the sensitivity of PC cells to GEM therapy.

Study on the effect of a triple cancer treatment of propolis, thermal cycling-hyperthermia, and low-intensity ultrasound on PANC-1 cells.

To reduce side effects and enhance treatment efficacy, study on combination therapy for pancreatic cancer, a deadly cancer, has gained much attraction in recent years. In this study, we propose a novel triple treatment combining propolis and two physical stimuli-thermal cycling-hyperthermia (TC-HT) and low-intensity ultrasound (US). The study found that, after the triple treatment, the cell viability of a human cancer cell line PANC-1 decreased to a level 80% less than the control, without affecting the normal pancreatic cells. Another result was excessive accumulation of reactive oxygen species (ROS) after the triple treatment, leading to the amplification of apoptotic pathway through the MAPK family and mitochondrial dysfunction. This study, to the best of our knowledge, is the first attempt to combine TC-HT, US, and a natural compound in cancer treatment. The combination of TC-HT and US also promotes the anticancer effect of the heat-sensitive chemotherapy drug cisplatin on PANC-1 cells. It is expected that optimized parameters for different agents and different types of cancer will expand the methodology on oncological therapy in a safe manner.

Triple combination therapy for pancreatic cancer remodels stroma and improves survival

Triple combination therapy for pancreatic cancer remodels stroma and improves survival

Retracted: Antitumor Effects of 10058-F4 and Curcumin in Combination Therapy for Pancreatic Cancer In Vitro and In Vivo.

[This retracts the article DOI: 10.1155/2022/1620802.].

Preclinical evaluation of pentagamavunone-1 as monotherapy and combination therapy for pancreatic cancer in multiple xenograft models

We previously reported that pentagamavunone-1 (PGV-1) effectively inhibited cell proliferation in many types of human tumors, including pancreatic cancer, by inducing M phase (prometaphase) arrest, senescence, and apoptosis with few side effects. However, a detailed evaluation of the effects of PGV-1 on pancreatic cancer cells in an in vivo setting has not yet been conducted. The present study investigated the potential efficacy of PGV-1 as both monotherapy and combination therapy for pancreatic cancer using multiple xenograft mouse assays. A cell-line derived xenograft model (CDX-M) with pancreatic cancer cell line and a patient-derived xenograft mouse model (PDX-M) using resected pancreatic cancer samples without neoadjuvant chemotherapy were established in both heterotopic and orthotopic manners. PGV-1 effectively suppressed tumor formation at the heterotopic and orthotopic sites in CDX-M than in untreated mice. Combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation than monotherapy with PGV-1 or gemcitabine when administered after tumor formation. Monotherapy with PGV-1 or gemcitabine less effectively suppressed tumor formation in PDX-M than in CDX-M, whereas combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation. PGV-1 as monotherapy and combination therapy with gemcitabine effectively inhibited tumor formation and has potential as an anticancer candidate for pancreatic cancer.

PP038 Drug repurposing and gemcitabine-based combination therapy for pancreatic cancer

PP038 Drug repurposing and gemcitabine-based combination therapy for pancreatic cancer

Nardoguaianone L Isolated from Nardostachys jatamansi Improved the Effect of Gemcitabine Chemotherapy via Regulating AGE Signaling Pathway in SW1990 Cells.

Pancreatic cancer is the seventh leading cause of cancer-related death worldwide and is known as “the king of cancers”. Currently, gemcitabine (GEM) as the clinical drug of choice for chemotherapy of advanced pancreatic cancer has poor drug sensitivity and ineffective chemotherapy. Nardoguaianone L (G-6) is a novel guaiane-type sesquiterpenoid isolated from Nardostachys jatamansi DC., and it exhibits anti-tumor activity. Based on the newly discovered G-6 with anti-pancreatic cancer activity in our laboratory, this paper aimed to evaluate the potential value of the combination of G-6 and GEM in SW1990 cells, including cell viability, cell apoptosis, colony assay and tandem mass tags (TMT) marker-based proteomic technology. These results showed that G-6 combined with GEM significantly inhibited cell viability, and the effect was more obvious than that with single drug. In addition, the use of TMT marker-based proteomic technology demonstrated that the AGE-RAGE signaling pathway was activated after medication-combination. Furthermore, reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) assays were used to validate the proteomic results. Finally, apoptosis was detected by flow cytometry. In conclusion, G-6 combined with GEM induced an increase in ROS level and a decrease in MMP in SW1990 cells through the AGE-RAGE signaling pathway, ultimately leading to apoptosis. G-6 improved the effect of GEM chemotherapy and may be used as a potential combination therapy for pancreatic cancer.

Metronomic Dosing for Pancreatic Cancer Combination Therapy Treatment Association With Reduced Neutropenia

PURPOSE Metronomic dosing for pancreatic cancer combination therapy treatment association with reduced neutropenia. METHODS This research aims to evaluate the use of combination therapy for shrinking tumor size in patients with metastatic pancreatic cancer using gemzar/paclitaxel combination therapy for treatment. Patients with pancreatic cancer were treated and observed in a cancer outpatient clinic. Gemzar/Paclitaxel combination therapy was used in lower than recommended dose. Patients were educated on the risk of neutropenia associated with combination chemotherapy. Labs were repeated every month to assess the tumor size, metastasis of tumor growth to other organs and neutropenia associated with combination chemotherapy. RESULTS Patient in the clinic undergoing chemotherapy showed that using gemzar/paclitaxel combination therapy has reduced chance of neutropenia when used with low dose intervals in metastatic pancreatic cancer. CONCLUSION We observed that using metronomic dosing in patients using combination therapy for pancreatic cancer shows decreased neutropenia compared to others who did not receive metronomic dosing on combination treatment with gemzar/paclitaxel. While neutropenia is decreased, patients also have decline in the metastasis of the tumor to other organs and shrinkage in the size of tumor.

Inhibition of PRMT5 Disrupts Cell Cycle Progression and DNA Damage Signaling, Revealing a Potential Novel Combination Therapy for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers and remains a therapeutic challenge. There is an urgent need for novel therapeutic strategies for PDAC, and the targeting of pathways highly relevant to its pathobiology is critical. PDAC cells often possess defects in DNA damage repair (DDR) pathways that are not present in healthy cells, which can be exploited for therapeutic strategies. Protein arginine methyltransferase 5 (PRMT5) is a type II histone arginine methyltransferase involved in various cellular processes, such as cell cycle progression and DDR. In PDAC tumors, PRMT5 expression is elevated and predicts shorter overall survival and disease‐free patient survival than those with lower PRMT5 expression. Here, we examined the effect of PRMT5 inhibition on PDAC in vitro, the impact of its inhibition on cell cycle and DDR, as well as potential synergy between PRMT5 inhibition and DNA damage‐inducing ionizing radiation (IR) as a novel therapeutic strategy for PDAC. Treatment of PDAC cells withthe PRMT5 inhibitor (PRMT5i), EPZ015938, resulted in a dose‐dependent decrease of cell growth by time‐lapse live‐cell imaging and clonogenic survival assays. Flow cytometry‐based cell cycle analysis showed that PDAC cells treated with EPZ015938 had increased numbers in G2/M, suggesting that PRMT5 inhibition triggers a G2/M arrest. Using a phospho‐protein array of cell cycle control proteins, we found higher levels of WEE1, P‐S216‐CDC25C, and P‐Y15‐CDC2, supporting G2/M arrest following treatment with EPZ015938. The phospho‐protein array also revealed an increase in P‐S15‐TP53, a signal of DNA damage mediated by the DNA damage sensors, ATM/ATR, along with a decrease in ATM. We confirmed the ATM downregulation at the transcript level by quantitative RT‐PCR. Pathway‐specific qPCR array analysis displayed differential expression of DDR genes related to ATM and G2/M DNA damage checkpoint regulation, further implicating a mechanistic role for these pathways in response to PRMT5i. The downregulation of ATM combined with the presence of G2/M arrest and signals of DNA damage led us to examine the related ATR pathway. In protein lysates from PDAC cells treated with PRMT5i followed by western blot, we found increased phosphorylation of ATR at S1981 and H2A.X at S139. This suggests that PRMT5 inhibition activates DDR in PDAC cells via ATR. To harness the potential vulnerability presented by PRMT5i‐mediated G2/M arrest, we combined PRMT5i treatment with ionizing radiation (IR) exposure to find that the combination of EPZ015938 and IR displayed a greater reduction in PDAC cell growth in vitro over individual treatments. In conclusion, we find that PRMT5 is a critical player in DNA damage via modulation of the ATM/ATR pathways, and combined PRMT5i and IR have beneficial anti‐tumor effects in vitro, revealing an exciting avenue for further exploration as a potential new therapeutic strategy in PDAC.

Antitumor Effects of 10058-F4 and Curcumin in Combination Therapy for Pancreatic Cancer In Vitro and In Vivo.

Background Pancreatic cancer (PC) stands out as one of the most lethal cancers. Due to late diagnosis, only a fraction of patients can be resected. Although it still has significant adverse effects and poor results, the treatment is connected with better overall survival than the prior treatment. Thus, new alternative therapy for advanced PC is needed. Materials/Methods. The impact of 10058-F4 and curcumin combination therapy on apoptosis and cell growth in SW1990 pancreatic cancer cells were determined in vitro using the CCK-8 assay and flow cytometry of Annexin V-FITC/PI, and the in vivo antitumor effect was determined utilizing SW1990-bearing pancreatic tumor mouse models induced by subcutaneous implantation. Results At concentrations of (10 mol/L+2 mol/L), 10058-F4+curcumin obtained the highest rate of SW1990 cell death, and they had a beneficial effect on SW1990 pancreatic tumor-bearing animals. Furthermore, c-Myc, Akt phosphorylation, and the expression of apoptosis-related molecular were reduced, and the combination therapy modified the expression of apoptosis-related molecular. Conclusions In vitro and in vivo, the combination of 10058-F4 plus curcumin has antipancreatic cancer actions that are substantially effective.

Codelivery of Doxorubicin/PI3K Inhibitor Nanomicelle Linked with Phenylboronic Acid for Enhanced Cytotoxicity to Pancreatic Cancer

Multidrug combination therapy for pancreatic cancer is widely applied in clinical practice. In this study, we used phenylboronic acid and polyethylene glycol as materials of nanomicelles, loaded with the PI3K/mTORC1 dual inhibitor PF04691502 (PF) to inhibit the resistance and metastasis of pancreatic cancer and increase the sensitivity of doxorubicin (DOX). We prepared the PPD nanoparticles (NPs) with a small PDI and a uniform morphology by controlling the DOX substitution degree (size of 164.8 ± 3.6 nm and zeta potential of −16.9 ± 0.4 mV). We determined the rates of PF and materials through the combination experiment of free drugs and the obtained PF@PPD NPs (size of 200.8 ± 2.6 nm and zeta potential of −13.9 ± 0.3 mV). The drug loadings of DOX and PF in the nanomicelle were 14.8 ± 0.4% and 9.5 ± 0.3%, respectively. And the drug release in vitro was slow (29.17 ± 2.00% for DOX and 39.22 ± 2.49% for PF). The cell assay showed that the NPs had a good curative effect and migration on BxPC‐3 cells, and it could be continuously taken up by cells. The PF@PPD NPs displayed a dose‐dependent cytotoxicity with less cell viability (20.38 ± 1.11%) and higher uptake in BxPC‐3 cells compared with the free drug. The combined medication or PF@PPD NPs reduced tumor metastasis, indicating that PF@PPD NPs had the potential for clinical application.

FDI-6 and olaparib synergistically inhibit the growth of pancreatic cancer by repressing BUB1, BRCA1 and CDC25A signaling pathways

Inducing homologous recombination (HR) deficiency is a promising strategy to broaden the indication of PARP1/2 inhibitors in pancreatic cancer treatment. In addition to inhibition kinases, repression of the transcriptional function of FOXM1 has been reported to inhibit HR-mediated DNA repair. We found that FOXM1 inhibitor FDI-6 and PARP1/2 inhibitor Olaparib synergistically inhibited the malignant growth of pancreatic cancer cells in vitro and in vivo. The results of bioinformatic analysis and mechanistic study showed that FOXM1 directly interacted with PARP1. Olaparib induced the feedback overexpression of PARP1/2, FOXM1, CDC25A, CCND1, CDK1, CCNA2, CCNB1, CDC25B, BRCA1/2 and Rad51 to promote the acceleration of cell mitosis and recovery of DNA repair, which caused the generation of adaptive resistance. FDI-6 reversed Olaparib-induced adaptive resistance and inhibited cell cycle progression and DNA damage repair by repressing the expression of FOXM1, PARP1/2, BUB1, CDC25A, BRCA1 and other genes-involved in cell cycle control and DNA damage repair. We believe that targeting FOXM1 and PARP1/2 is a promising combination therapy for pancreatic cancer without HR deficiency.

PARP Inhibitor Upregulates PD-L1 Expression and Provides a New Combination Therapy in Pancreatic Cancer.

Despite recent improvements in treatment modalities, pancreatic cancer remains a highly lethal tumor with mortality rate increasing every year. Poly (ADP-ribose) polymerase (PARP) inhibitors are now used in pancreatic cancer as a breakthrough in targeted therapy. This study focused on whether PARP inhibitors (PARPis) can affect programmed death ligand-1 (PD-L1) expression in pancreatic cancer and whether immune checkpoint inhibitors of PD-L1/programmed death 1 (PD-1) can enhance the anti-tumor effects of PARPis. Here we found that PARPi, pamiparib, up-regulated PD-L1 expression on the surface of pancreatic cancer cells in vitro and in vivo. Mechanistically, pamiparib induced PD-L1 expression via JAK2/STAT3 pathway, at least partially, in pancreatic cancer. Importantly, pamiparib attenuated tumor growth; while co-administration of pamiparib with PD-L1 blockers significantly improved the therapeutic efficacy in vivo compared with monotherapy. Combination therapy resulted in an altered tumor immune microenvironment with a significant increase in windiness of CD8+ T cells, suggesting a potential role of CD8+ T cells in the combination therapy. Together, this study provides evidence for the clinical application of PARPis with anti-PD-L1/PD-1 drugs in the treatment of pancreatic cancer.

Efficacy and safety of gemcitabine-capecitabine combination therapy for pancreatic cancer: A systematic review and meta-analysis of randomized controlled trials.

Background:Recent randomized controlled trials revealed the combination of gemcitabine and capecitabine (GemCap) regime shows promising efficacy in pancreatic cancer patients. Here, we conducted a meta-analysis to compare the efficacy and safety of gemcitabine (Gem) with GemCap for pancreatic cancer.Methods:The database of MEDLINE (PubMed), EMBASE, Cochrane Central Controster of Controlled Trials, Web of Science was searched for relevant randomized controlled trials before 8 April, 2020. The outcomes were overall survival (OS), 12-month survival rate, progress free survival (PFS), partial response rate (PRR), objective response rate (ORR), and Grade 3/4 toxicities.Results:Five randomized controlled trials involving 1879 patients were included in this study. The results showed that GemCap significantly improves the OS (hazard ratio = 1.15, 95% CI: 1.037-1.276, P = .008), PFS (hazard ratio = 1.211, 95% CI 1.09-1.344, P = 0), PRR (relative risk (RR) = 0.649, 95% CI 0.488-0.862, P = .003), ORR (RR = 0.605, 95% CI 0.458-0.799, P = 0), and the overall toxicity (RR = 0.708, 95% CI 0.620-0.808, P = .000) compared to Gem alone. However, no significant difference was found in 12-month survival.Conclusions:Despite a higher incidence of Grade 3/4 toxicity, GemCap was associated with better outcomes of OS, PFS, PRR, ORR, as compared with Gem, which is likely to become a promising therapy for pancreatic cancer.

Targeting of elevated cell surface phosphatidylserine with saposin C-dioleoylphosphatidylserine nanodrug as individual or combination therapy for pancreatic cancer.

Pancreatic cancer is one of the deadliest of cancers with a five-year survival of roughly 8%. Current therapies are: surgery, radiation and chemotherapy. Surgery is curative only if the cancer is caught very early, which is rare, and the latter two modalities are only marginally effective and have significant side effects. We have developed a nanosome comprised of the lysosomal protein, saposin C (SapC) and the acidic phospholipid, dioleoylphosphatidylserine (DOPS). In the acidic tumor microenvironment, this molecule, SapC-DOPS, targets the phosphatidylserine cancer-biomarker which is predominantly elevated on the surface of cancer cells. Importantly, SapC-DOPS can selectively target pancreatic tumors and metastases. Furthermore, SapC-DOPS has exhibited an impressive safety profile with only a few minor side effects in both preclinical experiments and in phase I clinical trials. With the dismal outcomes for pancreatic cancer there is an urgent need for better treatments and SapC-DOPS is a good candidate for addition to the oncologist’s toolbox.

Abstract 1732: Hybrid-nanoengineering of an effective combination therapy for pancreatic cancer

Abstract Introduction: A novel proprietary nano-combination therapy (Hybrid-Nanoengineering) combination of paclitaxel and bioavailable curcumin (nano-paclitaxel-curcumin or NPC) has been created and shown to be stable as a dry powder and was effective in treating pancreatic cancer in preclinical models. Experimental Methods: The highly aggressive L3.6PL model of orthotopic pancreatic cancer is typically lethal within 30 days. Three L3.6PL tumor spheroids were introduced into the pancreas of each of 40 nude mice with a vehicle control and treatment group. On 5 of the 20 mice in each treatment group 5x105 cells were implanted to act as sentinels for the orthotopic growth. After 5 days, treatment was initiated with 10 mg/kg (paclitaxel equivalent) every 4 days. The NPC was resuspended with saline to a 1 mg/ml final concentration and the vehicle group received saline (VC) in an equivalent volume. The NPC dose was adjusted on day 17 to 20 mg/kg, q4d as there was no observed flank tumor growth inhibition. Treatment was continued for 25 days before treatment was halted on day 42. Results 1: Tumor response was low at the initial 10 mg/kg dose and after 12 days when the flank tumors had reached ~600 mm3, the treatment was adjusted to 20 mg/kg, q4d. 17/20 of the VC control animals died or were euthanized by day 42, whereas in the NPC group 13/20 animals survived for an unexpected 65% survival rate with this aggressive tumor. The mean orthotopic tumor weight was 2.53 g and 0.81 g for the VC and NPC groups respectively, indicating a significant reduction in tumor volume with treatment in addition to the significant survival benefit with the NPC drug treatment. Results 2: At day 42 a decision to halt the combination therapy was made and two groups of 5 were randomized from the surviving NPC group animals. One group received a nano-curcumin (NC) at 40 mg/kg, q4d and one no treatment (C) for an additional 23 days. Tumors were excised and the average tumor volumes were 1.39 g for the "C" group and 0.54 g for the "NC" animals. Discussion: The NPC formulation provided dramatic and unexpected survival benefit at a relatively low dose of paclitaxel and was well tolerated by the mice already burdened with an aggressive pancreatic tumor. In fact, by allowing the tumors to escape initially at the 10 mg/kg, q4d dose, and reaching nearly 600 mm3 (flank sentinel tumors), this was an extreme challenge and the 20 mg/kg, q4d dose provided a significant benefit to overall survival, tumor burden and animal health. In a previous study with Panc-1 xenograft tumors, a clear benefit was shown with the nano-paclitaxel-curcumin over nab-paclitaxel with similar tumor volumes at half the dose (not shown). Citation Format: Mewa Singh, Michael R. Briggs. Hybrid-nanoengineering of an effective combination therapy for pancreatic cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1732.

Beta 1 integrin signaling mediates pancreatic ductal adenocarcinoma resistance to MEK inhibition

Pancreatic cancer, one of the deadliest human malignancies, has a dismal 5-year survival rate of 9%. KRAS is the most commonly mutated gene in pancreatic cancer, but clinical agents that directly target mutant KRAS are not available. Several effector pathways are activated downstream of oncogenic Kras, including MAPK signaling. MAPK signaling can be inhibited by targeting MEK1/2; unfortunately, this approach has been largely ineffective in pancreatic cancer. Here, we set out to identify mechanisms of MEK inhibitor resistance in pancreatic cancer. We optimized the culture of pancreatic tumor 3D clusters that utilized Matrigel as a basement membrane mimetic. Pancreatic tumor 3D clusters recapitulated mutant KRAS dependency and recalcitrance to MEK inhibition. Treatment of the clusters with trametinib, a MEK inhibitor, had only a modest effect on these cultures. We observed that cells adjacent to the basement membrane mimetic Matrigel survived MEK inhibition, while the cells in the interior layers underwent apoptosis. Our findings suggested that basement membrane attachment provided survival signals. We thus targeted integrin β1, a mediator of extracellular matrix contact, and found that combined MEK and integrin β1 inhibition bypassed trametinib resistance. Our data support exploring integrin signaling inhibition as a component of combination therapy in pancreatic cancer.

Abstract A31: Investigating the effect of myeloid Arg1 deletion on tumor growth and CD8+ T-cell infiltration and activation in pancreatic cancer

Abstract PDA is characterized by an extensive fibroinflammatory stroma. This fibroinflammatory stroma is mainly composed of fibroblasts and tumor-infiltrating immune cells. The most abundant infiltrating immune cells are myeloid cells. Myeloid cells including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells, and granulocytes are required for PDA tumor growth and maintenance. Myeloid cells have the ability to suppress antitumor T-cell responses in PDA, as depletion of myeloid cells restores CD8+ T-cell immunity. Our previous characterization of myeloid cells infiltrating the neoplastic pancreas has revealed that myeloid cells express high levels of Arginase 1 (Arg1), an enzyme that depletes the amino acid L-arginine from the microenvironment and a signature marker of immunosuppressive macrophages and TAMs. In turn, L-arginine is required for CD8+ T-cell activation. An increase in Arginase levels has been reported also in other cancers, including lung, gastrointestinal, and bladder cancer. Thus, Arg1 expression in myeloid cells might be a key mediator of immune suppression, although this possibility has not been investigated directly in pancreatic cancer. Based on these observations, we test the hypothesis that myeloid cell polarization in the tumor microenvironment mediates immune suppression in PDA through expression of Arginase 1. The objective of this study is to provide novel insights into the role of Arg1 in pancreatic cancer, and the overall goal is to identify new therapeutic targets for combination therapy in pancreatic cancer. We used a genetically engineered mouse model (LysM-Cre;Arg1f/f) to delete the Arg1 gene, specifically from the myeloid cell compartment (LysM+ cells), including macrophages and neutrophils. We orthotopically implanted primary mouse pancreatic cancer cell lines into C57BL/6 LysM-Cre;Arg1f/f and wild-type (WT) mice. We evaluated tumor growth and CD8+ T-cell infiltration and activation between LysM-Cre;Arg1f/f and WT control mice. We used MRI imaging to determine tumor volume, and we used immunofluorescence and mass cytometry analysis to investigate changes in immune cell infiltration. We confirmed Arg1 depletion in LysM-Cre;Arg1f/f mice by Western blotting, co-immunofluorescence, and mass cytometry. We observed a decreasing trend in tumor growth and volume in LysM-Cre;Arg1f/f mice, an increase in iNOS expression (a marker of inflammatory macrophages), and an increase in CD8+ T-cell number and activity compared to the WT. These results support the notion that Arg1 might be a moderator of immune suppression in pancreatic cancer. Citation Format: Rosa E. Menjivar, Christopher Halbrook, Ashley Velez, Fatima Lima, Carlos Espinoza, Stefanie Galban, Yaqing Zhang, Costas Lyssiotis, Marina Pasca di Magliano. Investigating the effect of myeloid Arg1 deletion on tumor growth and CD8+ T-cell infiltration and activation in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A31.

Sustained co-delivery of gemcitabine and cis-platinum via biodegradable thermo-sensitive hydrogel for synergistic combination therapy of pancreatic cancer

Pancreatic cancer is one of the most devastating cancers with poor prognosis and no significant change in the survival rate over the past decades. Localized targeted drug delivery through interventional endoscopic ultrasonography-guided fine-needle injection (EUS-FNI) is an attractive and minimally invasive strategy for inoperable pancreatic cancer. An injectable in-situ formed long-lasting drug delivery system is a promising alternative for the localized treatment of pancreatic cancer via EUS-FNI. Here, a biodegradable thermo-sensitive copolymer hydrogel for the co-delivery of anticancer agents gemcitabine (GEM) and cis-platinum (DDP) was developed. This hydrogel is a free flowable liquid at room temperature that changes into a semi-solid hydrogel following injection in response to the physiological temperature. Both in vitro and in vivo drug release behaviors indicate sustained drug release of this delivery system. Synergistic cellular proliferation inhibition and desirable apoptosis promotion have been found when pancreatic cancer Bxpc-3 cells were co-cultured with this GEM-DDP/hydrogel system. After a single intratumoral injection, the dual-drug loaded hydrogel formulation exhibited superior anti-tumor efficacy and minimized systemic side effect on pancreatic cancer xenograft mouse model in comparison to the intravenously injected free GEM and DDP combination. In addition, a strong synergistic therapeutic effect of the GEM-DDP/hydrogel system against pancreatic cancer has been found in vitro and in vivo compared to the single-drug loaded hydrogel composites. The obtained findings suggest this developed thermo-sensitive copolymer hydrogel system as a potential universal carrier for the localized targeted delivery of multi-drugs, for use in a variety of inoperable solid tumors.

Abrogation of Pancreatic Cancer Using a Brain Malady Drug

Pancreatic cancer is the fourth preeminent cause of cancer-related deaths with a poor prognosis. Desmoplasia and drug resistance are few of the pivotal hurdles in pancreatic cancer management. Unlike breast cancer, awareness about pancreatic cancer still lacks in all the aspects. Our extensive bioinformatic and clinical data mining led us to notice an abnormal upregulation of a membrane protein Sphingosine-1-Phosphate Receptor-1 (S1PR1) in pancreatic cancer. S1PR1 is an important lipid signalling receptor whose ligand is a bioactive lipid, Sphingosine-1-phosphate. We were curious to know what happens to the cancer cell if we block this active lipid signaling. So, we targeted this protein using its antagonist, FTY720, which is already in the market for a known brain disorder called multiple sclerosis. FDA accreditation and known ADMET patters prompted us to choose this pre-existing drug. Accordingly, time-consuming clinical trials could be bypassed leading to rapid repurposing for pancreatic cancer. Our in vitro studies on numerous pancreatic cancer cell lines displayed a dose-dependent increase in cell death with low toxicity on normal cells. Although, gemcitabine is the first line chemotherapeutic drug for pancreatic cancer, the emergence of resistance among the patients was observed which leads to metastasis. In particular, combination therapy is an imminent approach to tackle the trouble of drug resistance. Indeed, an amalgamation of FTY720 and gemcitabine showed the enhanced anticancer effects on ex vivo experiments. Furthermore, two animal models showed the conspicuous abatement in tumor chunk as a result of blended drug treatment for 30 days. Besides, reduction of significant cell proliferation markers in the tumor microenvironment was observed. We found that FTY720 alone and also in commixture with gemcitabine effectively ameliorated the activity of PP2A which is the known target of FTY720. STAT3 is a transcription factor, which plays a remarkable role in carcinogenesis. We also observed a reduced S1PR1-STAT3 loop in vivo along with its downstream survival proteins due to strong affinity of FTY720 on the S1PR1 receptor. Since the combination of FTY720+Gem showed an astonishing role in abatement of tumor size than solitary treatment, the exact role of this combination strategy was explained by exploring the role of FTY720, which may act as a trooper for gemcitabine to cross the desmoplasia, an enlarged collagen area. As expected, we found a reduction in desmoplastic markers in the FTY720 treatment group. It infers that FTY720 loosens up the tumor tissue so that gemcitabine can readily reach the cancer cells. In conclusion, we propose that FTY720 can be a propitious molecule in pancreatic cancer management in combination with other chemotherapeutic drugs. Support or Funding Information University Grants Commision, Government of India and Department of Biotechnology, Government of India. The Mechanism of action of the combination therapy in pancreatic cancer. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.