Combination Of Agonists Research Articles

Chemotherapy in synergy with innate immune agonists enhances T cell priming for checkpoint inhibitor treatment in pancreatic cancer

BackgroundThe combination of conventional chemotherapy and immune checkpoint inhibitors (ICIs) has been unsuccessful for pancreatic ductal adenocarcinoma (PDAC). Administration of maximum tolerated dose of chemotherapy drugs may have immunosuppressive effects.MethodsWe thus tested, by using the preclinical model of PDACs including the genetically engineered mouse KPC spontaneous pancreatic tumor model and the pancreatic KPC tumor orthotopic implant model, the combinations of synthetic innate immune agonists including STING and NLRP3 agonist, respectively, and ICIs with or without chemotherapy.ResultsWe found that innate agonists potentiate the role of chemotherapy in inducing effector T cells and subsequently to prime the tumor microenvironment (TME) better for ICI treatments. Triple combination of chemotherapy, innate agonists, and ICIs is superior to single modalities or double modalities in antitumor efficacies. Adding chemotherapy to innate agonists enhances the infiltration of overall CD8+ T cells and the memory cytotoxic subtype. NLRP3 agonist has a less effect than STING agonist on driving the T cell exhaustion. Adding chemotherapy to innate agonists enhances the infiltration of dendritic cells (DCs) in the tumors and CD86+ mature DCs in tumor draining lymph nodes. RNA sequencing analysis of the pancreatic tumors demonstrates the role of the combination of STING/NLRP3 agonist and chemotherapy, but not either treatment modality alone, in upregulating the T cell activation signaling. The NLRP3 agonist-mediated T cell activation is likely through regulating the nitrogen metabolism pathways.ConclusionThis study supports the clinical testing of both STING and NLRP3 agonists, respectively, in combination with chemotherapy to sensitize PDAC patients for ICI treatments.

Abstract P012: PSMA-RLT and targeting the cGAS-STING pathway as a combination approach for Prostate Cancer

Abstract The VISION trial showed that 177Lu-PSMA-617 radioligand therapy (RLT) effectively reduced PSA levels and improved survival in patients with late-stage prostate cancer1. However, there is still a need to identify strategies to enhance and sustain RLT efficacy. Alpha therapy and combination of immunotherapy and radiation are emerging strategies. Herein, we focused on strategies to amplify the immune system activation to intensify the effects of PSMA-RLT in prostate cancer by combining 225Ac-PSMA-617 RLT with a STING agonist (diABZI). We compared the efficacy of alpha RLT in mice bearing STING-proficient or STING-deficient PC cell line (RM1-PGLS or Myc-CaP) alone or in combination with a STING agonist. Furthermore, we assessed the efficacy of RLT in STING knockout (Sting -/-) mice injected with RM1-PGLS. Method: Male C57BL/6 wt or STING-deficient or FVB mice were subcutaneously injected with 0.1 × 10⁶ RM1-PGLS cells in a 100 µl mixture of PBS and Matrigel (1:1) or 2 × 10⁶ MycCap cells. PSMA expression was assessed in vivo using PET/CT imaging 1h after intravenous injection of 68Ga-PSMA-617 to validate target expression prior to treatment. Once tumors reached 100 mm³, animals were treated intravenously with 30 kBq of 225Ac-PSMA. C57BL/6 mice bearing RM1 PGLS tumors and FVB mice bearing MycCap were treated with RLT alone or in combination with diABZI (1.5 mg/kg), 24h post RLT. Tumor growth and therapeutic efficacy were monitored weekly by CT. Results: In an immunocompetent syngeneic model (C57BL/6 mice bearing RM1-PGLS tumors) we observed a synergistic effect of STING agonist and RLT. At 28 days post-treatment, survival rates were: 0% for NT, 66% for RLT alone, 70% DiABZI and 89% for the combination. Contrastingly, in the MycCap model, the combination of RLT and STING agonist did not improve survival compared to the control group with 0% survival at 22 days. Same survival rate was observed with the STING agonist. Only the RLT group showed 30% of survival at day 22.In the STING-deficient host model, we observed 75% tumor-free mice (6/8). At day 22, the median survival was 50% for the control group compared to 100% for the RLT group. Rechallenged RLT-treated mice did not regrow tumors for more than a year after rechallenging. Conclusion and discussion: STING agonist and RLT synergize in certain models of PCa.Based on our results, STING proficiency in the tumor cells seems to be a critical determinant for RLT-response. Our data in the STING -/- mice suggest that host STING could have deleterious effects. We hypothesize that the acute inflammation triggered by STING activation may stimulate the accumulation of MDSCs (myeloid-derived suppressor cells), which are associated with immune suppression which may restrain the efficacy of RLT. Given this, our next strategy will focus on preventing MDSC activation to maintain the beneficial immune activation within the tumor microenvironment. The dual role of STING in both immune recruitment and activation, as well as in immunosuppression, makes it a complex mechanism that requires further exploration. Citation Format: Beatrice Louis, Marco Taddio, Clara Diaz Garcia Prada, Mathis Richard, Rachel Dove, Khalid Rashid, Evan Abt, Ethan Rosser, Thuc Le, Katharina Lueckerath, Caius Radu, Johannes Czernin, Christine Mona.PSMA-RLT and targeting the cGAS-STING pathway as a combination approach for Prostate Cancer.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P012

Combination of rTMS and oxytocin agonist attenuate depression-like behavior after postpartum depression in mice.

The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) categorizes postpartum depression (PPD) as a subtype of Major Depressive Disorder (MDD) with peripartum onset, generally arising within the initial trimester following delivery. This acute psychiatric condition is characterized by feelings of worthlessness, insomnia, extreme anxiety, or maternal neglect. Intranasal oxytocin (OT) and transcranial magnetic stimulation (TMS) have the potential to address impaired social cognition; nonetheless, their neuronal underpinnings, along with their safety and efficacy, are little comprehended. This study examines the effects of rTMS stimulation with an oxytocin agonist or antagonist in a PPD model. We employed the maternal separation with early weaning (MSEW) strategy for 21days to attain our objective. Oxytocin acetate (agonist) and atosiban (antagonist) were administered by injection twice daily for three consecutive days following the model according to the established protocol. A single session of rTMS involved the application of high-frequency stimulation (20Hz) one hour following the final injection. Behavioral testing and brain collection were conducted 12h post-rTMS. The results indicated that treatment with OT followed by rTMS stimulation decreased neuronal cell death and microglial activation, meanwhile enhancing synaptic plasticity through the upregulation of PSD95, Synapsin I, and Synaptophysin. Simultaneously, both OT therapy and repetitive transcranial magnetic stimulation demonstrated a significant capacity to alter autophagy activity and astrocyte function. Nonetheless, OTA therapy followed by rTMS did not exhibit the same pattern of outcomes. Our findings indicate that the combination of rTMS stimulation and an oxytocin agonist in a PPD model may mitigate depression-like behavior.

Ginsenoside RG3 Synergizes With STING Agonist to Reverse Cisplatin Resistance in Gastric Cancer.

This study investigates the synergistic inhibitory effects of combining the stimulator of interferon genes (STING) agonist cyclic diadenylate monophosphate (c-di-AMP) and ginsenoside RG3 on cisplatin (DDP)-resistant gastric cancer (GC) cells. The objective is to identify novel therapeutic targets and offers insights for the clinical management of DDP resistance. Various techniques were employed, including western blot, MTT assay, colony formation assay, scratch assay, transwell assay, tubule formation assay, flow cytometry, Hoechst 33342 fluorescence staining, and invivo experiments, to investigate the potential mechanisms and effects of the combined application of the STING agonist and ginsenoside RG3 in reversing cisplatin resistance in gastric cancer. The combination markedly suppressed key malignant behaviors, including proliferation, migration, invasion, and angiogenesis of SGC-7901/DDP cells. Additionally, this treatment inhibited the epithelial-mesenchymal transition (EMT) process and stem cell-like characteristics of SGC-7901/DDP cells, while downregulating the expression of resistance-related proteins. The STING agonist effectively suppresses the growth and proliferation of gastric cancer cells. Ginsenoside RG3, well-documented for its multifaceted properties, including antioxidant, anti-aging, and anti-cancer effects, is widely used in cancer treatment and in managing chemotherapy-related side effects. Furthermore, RG3 enhances anti-tumor immunity by regulating signal transduction. This study comprehensively evaluated the efficacy of the STING agonist and RG3 combination through invitro and invivo experiments, demonstrating significant inhibition of malignant progression and reversal of drug resistance in gastric cancer. These findings offer a robust theoretical foundation for clinical applications and highlight new therapeutic targets for future research.

Luteinizing hormone-releasing hormone receptor agonists and antagonists in prostate cancer: effects on long-term survival and combined therapy with next-generation hormonal agents.

Prostate cancer is a leading cause of cancer-related death in men worldwide. Luteinizing hormone-releasing hormone receptor (LHRH-R) agonists and antagonists are known to achieve castration-level testosterone suppression; however, long-term data comparing the survival benefits of these therapies are insufficient to inform treatment decisions. Furthermore, the advent of next-generation hormonal agents (NHAs), such as abiraterone and enzalutamide, have shifted the paradigm of managing prostate cancer. Although LHRH-R agonists and antagonists remain the cornerstone treatment across various stages of prostate cancer, they are increasingly administered with NHAs, because the combination treatment confers a survival advantage. Nevertheless, the differences in efficacy and safety profiles among various combinations of LHRH-R agonists and antagonists and NHAs remain unclear. Hence, this narrative review is aimed at providing a comprehensive overview of the long-term outcomes of various LHRH-R agonists and antagonists. Key data from major clinical studies are summarized, categorized by disease stage. LHRH-R agonists and antagonists, particularly goserelin, have demonstrated long-term survival benefits in patients with localized and locally advanced prostate cancer. The clinical outcomes of different LHRH-R agonists and antagonists in combination with NHAs have also been evaluated. Among the various combinations, goserelin plus abiraterone appears to have a manageable safety profile with relatively low rates of hot flushes and fatigue. Overall, long-term survival data and safety profiles should be considered in selecting optimal combination therapies for prostate cancer treatment.

The combination of a glucagon-like peptide-1 and amylin receptor agonists reduces alcohol consumption in both male and female rats.

Combining different pharmaceuticals may be beneficial when treating disorders with complex neurobiology, including alcohol use disorder (AUD). The gut-brain peptides amylin and GLP-1 may be of potential interest as they individually reduce alcohol intake in rodents. While the combination of amylin receptor (AMYR) and glucagon-like peptide-1 receptor (GLP-1R) agonists have been found to decrease feeding and body weight in obese male rats synergistically, their combined impact on alcohol intake is unknown. Therefore, the effect of the combination of an AMYR (salmon calcitonin (sCT)) and a GLP-1R (dulaglutide) agonist on alcohol intake in rats of both sexes was explored in two separate alcohol-drinking experiments. The first alcohol-drinking experiment evaluated the potential of adding sCT to an ongoing dulaglutide treatment, whereas the second alcohol-drinking experiment examined the effect when adding sCT and dulaglutide simultaneously. When adding sCT to an ongoing dulaglutide treatment, a reduction in alcohol intake was observed in both male and female rats. However, when combining sCT and dulaglutide simultaneously, an initial reduction in alcohol intake was observed in rats of both sexes, whereas tolerance towards treatment was observed. In both alcohol-drinking experiments, this treatment combination consistently decreased food consumption and body weight in males and females. While the treatment combination did not affect inflammatory mediators, the gene expression of AMYR or GLP-1R, it changed fat tissue morphology. Further investigation needs to be done on the combination of AMYR and GLP-1R agonists to assess their combined effects on alcohol intake.

Cooperative tumor inhibition by CpG-oligodeoxynucleotide and cyclic dinucleotide in head and neck cancer involves T helper cytokine and macrophage phenotype reprogramming

Head and neck cancer ranks as the sixth most common cancer worldwide, highlighting the critical need for the development of new therapies to enhance treatment efficacy. The activation of innate immune receptors given their potent immune stimulatory properties aid in the eradication of cancer cells. In this study, we investigated the immune mechanism and anti-tumor function of a Toll-like receptor 9 (TLR9) agonist, CpG-oligodeoxynucleotide-2722 (CpG-2722), in combination with cyclic dinucleotides, which are agonists of stimulator of interferon genes (STING). Our results revealed that CpG-2722 stimulation increased the expression of Th1 pro-inflammatory cytokines. Stimulation by STING agonists exhibited lower expression of Th1 cytokines but higher expression of Th2 cytokines compared to CpG-2722. However, the combination of these two agonists significantly enhanced Th1 cytokines while reducing Th2 cytokines. Moreover, in vivo experiment showed that both CpG-2722 and 2'3'-c-di-AMP suppressed head and neck tumor growth, with their combination proving more effective than the use of these agonists alone. The combined treatment cooperatively promoted the production of Th1 cytokines and type I interferons, while suppressing Th2 cytokines in the tumors as observed in vitro. Additionally, it led to the accumulation of M1 macrophages, dendritic cells, and T cells, shaping a favorable tumor microenvironment for T cell-mediated tumor killing. The anti-tumor activity of the CpG-2722 and 2'3'-c-di-AMP combination depends on the macrophage presence but does not directly activate M1 macrophage polarization, instead working through a reprogrammed cytokine profile. Furthermore, this combination shows a cooperative anti-tumor activity with anti-PD-1 in treating head and neck tumors. Overall, these findings highlight a Th response and macrophage phenotype reprograming involved functional mechanism underlying the cooperative activity of the combination of TLR9 and STING agonists in the immunotherapy of head and neck cancer.

The interaction of adenosine and dopamine in modulating the consequences of central nervous system oxygen toxicity.

Hyperbaric oxygen (HBO) refers to pure oxygen with a pressure greater than 1 atmospheres absolute (ATA), and when the pressure is too high, it can cause convulsive attacks. Adenosine and dopamine have been shown to be closely associated with HBO induced convulsion seizures, and their receptors exhibited a coexisting relationship of mutual antagonism on the membrane of nerve cells. We explored the influence of adenosine and dopamine interplay on the occurrence of oxygen convulsion. Rats were individually exposed to HBO of 6 ATA and treated with adenosine, dopamine, and their receptor modulators separately and jointly, with the latency of convulsion onset recorded. Additionally, after administering adenosine to rats and exposing them to HBO for 30 min, the content of dopamine and its metabolites, as well as the activity of enzymes related to their metabolism, were measured. The results revealed that dopamine was effective in resisting convulsion (> 60 min vs 32.53±5.31 min, P=0.000), and low-dose adenosine partially counteracted its effect (> 60 min vs 28.18±6.24 min, P=0.002). The combined use of adenosine A1 and dopamine D1 receptor modulators significantly impacted the incidence of convulsion. The activation or inhibition of A2A receptor had a particularly significant impact on convulsion, while modulating D2 receptor did not affect their effects. The combination of A1 agonist and D2 agonist was highly effective in resisting convulsion (> 60 min vs 32.53±5.31 min, P=0.000). Exposure to HBO accelerated the metabolism of dopamine to its end products, which may be related to the enhanced activity of monoamine oxidase (MAO). Adenosine can inhibit MAO activity (0.0766±0.0150 U/mg.prot vs 0.1055±0.0086 U/mg.prot, P=0.004), maintaining a higher level of dopamine (1.820±0.379 mg/g vs 0.602±0.087 mg/g, P=0.000). The study demonstrated that dopamine plays a significant role in oxygen convulsion, and adenosine can affect dopamine metabolism. The interaction between them can have a crucial impact on the occurrence of oxygen convulsion. The findings offer a novel perspective for further investigating the mechanism of oxygen convulsion and exploring effective preventive strategies.

Proximal tubule cell maturation rate and function are controlled by PPARα signaling in kidney organoids

Human pluripotent stem cell-derived kidney organoids are expected to be a useful tool for new drug discoveries, however, the immaturation of kidney organoids causes difficulties in recapitulating renal pharmacokinetics using organoids. Here, we performed time-course single-cell RNA sequencing of kidney organoids and revealed cell heterogeneity in the maturation rate of the proximal tubule. An unbiased analysis to identify upstream targets of genes that are expressed differentially between cells with low and high maturation rates revealed a higher activation of PPARα signaling in rapidly maturing cells. Treatment with a combination of a PPARα agonist and an RXRα agonist induced genes related to proximal tubule maturation and increased the capacity for protein uptake as well as the sensitivity to nephrotoxicity by cisplatin. This method to promote the maturation rate of proximal tubule cells has the potential to be utilized in microphysiological systems to recapitulate proximal tubule functions and to screen nephrotoxic drugs.

Efficient Dendritic Cell Activation by a Layered Double Hydroxide‐Loaded Dual Adjuvant Cocktail

AbstractOne of the main goals of present vaccine investigations is to develop a potent and efficient adjuvant strategy. The combination of multiple agonists to different pattern recognition receptor families offers great opportunities to achieve strong immune responses in a synergy manner. Here, we employed layered double hydroxide nanomaterials with BSA coating (LB) to integrate CpG and 3pRNA dual adjuvant cocktail, together with ovalbumin antigen. With LB loading, CpG and 3pRNA led to a quick internalization and enhanced induction of dendritic cell (DC) maturation. Meanwhile, this nanoadjuvant cocktail facilitated antigen crosspresenting in activated DCs. Taken together, these results may inspire the investigation of agonists combination and LDH‐based nanoadjuvants.

Combinatorial effects of cannabinoid receptor 1 and 2 agonists on characteristics and proteomic alteration in MDA-MB-231 breast cancer cells.

Breast cancer is the most common cancer diagnosed in women worldwide. However, the effective treatment for breast cancer progression is still being sought. The activation of cannabinoid receptor (CB) has been shown to negatively affect breast cancer cell survival. Our previous study also reported that breast cancer cells responded to various combinations of CB1 and CB2 agonists differently. Nonetheless, the mechanism underlying this effect and whether this phenomenon can be seen in other cancer characteristics remain unknown. Therefore, this study aims to further elucidate the effects of highly selective CB agonists and their combination on triple-negative breast cancer proliferation, cell cycle progression, invasion, lamellipodia formation as well as proteomic profile of MDA-MB-231 breast cancer cells. The presence of CB agonists, specifically a 2:1 (ACEA: GW405833) combination, prominently inhibited colony formation and induced the S-phase cell cycle arrest in MDA-MB-231 cells. Furthermore, cell invasion ability and lamellipodia formation of MDA-MB-231 were also attenuated by the exposure of CB agonists and their 2:1 combination ratio. Our proteomic analysis revealed proteomic profile alteration in MDA-MB-231 upon CB exposure that potentially led to breast cancer suppression, such as ZPR1/SHC1/MAPK-mediated cell proliferation and AXL/VAV2/RAC1-mediated cell motility pathways. Our findings showed that selective CB agonists and their combination suppressed breast cancer characteristics in MDA-MB-231 cells. The exposure of CB agonists also altered the proteomic profile of MDA-MB-231, which could lead to cell proliferation and motility suppression.

Combination of multivalent DR5 receptor clustering agonists and histone deacetylase inhibitors for treatment of colon cancer

Death Receptor 5 (DR5) targeted therapies offer significant promise due to their pivotal role in mediating the extrinsic pathway of apoptosis. Despite DR5 overexpression in various malignancies and the potential of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), clinical applications of anti-DR5 monoclonal antibodies (mAbs) have been hampered by suboptimal outcomes potentially due to lack of receptor clustering.To address the limitation, we developed N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-based conjugates integrating multiple copies of DR5-targeting peptide (cyclic WDCLDNRIGRRQCVKL; cDR5) to enhance receptor clustering and apoptosis. Three conjugates with variable number of cDR5 were prepared and denoted as PH-cDR5 (high valence), PM-cDR5 (medium valence) and PL-cDR5 (low valence). Our studies in TRAIL-sensitive and resistant cancer cell lines demonstrated that the HPMA copolymer-peptide conjugates (P-cDR5) significantly improved DR5 receptor clustering and induced apoptosis effectively. In TRAIL-sensitive colon cancer cells (COLO205, HCT-116), P-cDR5 showed efficacy comparable to anti-DR5 mAb Drozitumab (DRO), but P-cDR5 outperformed DRO in TRAIL-resistant cells (HT-29), highlighting the importance of efficient receptor clustering. In COLO205 cells PM-cDR5 exhibited an IC50 of 94 pM, while PH-cDR5 had an even lower IC50 of 15 pM (based on cDR5 equivalent concentration), indicating enhanced potency of the multivalent HPMA copolymer-based system with a flexible polymer backbone in comparison with the IC50 for TRAIL at 0.12 nM. Combining P-cDR5 with valproic acid, a histone deacetylase inhibitor, resulted in further enhancement of apoptosis inducing efficacy, along with destabilizing mitochondrial membranes and increased sensitivity of TRAIL-resistant cells. These findings suggest that attaching multiple cDR5 peptides to a flexible water-soluble polymer carrier not only overcomes the limitations of previous designs but also offers a promising avenue for treating resistant cancers, pointing toward the need for further preclinical exploration and validation of this innovative strategy.

Bidirectional regulation of the cGAS-STING pathway in the immunosuppressive tumor microenvironment and its association with immunotherapy.

Adaptive anti-tumor immunity is currently dependent on the natural immune system of the body. The emergence of tumor immunotherapy has improved prognosis and prolonged the survival cycle of patients. Current mainstream immunotherapies, including immune checkpoint blockade, chimeric antigen receptor T-cell immunotherapy, and monoclonal antibody therapy, are linked to natural immunity. The cGAS-STING pathway is an important natural immunity signaling pathway that plays an important role in fighting against the invasion of foreign pathogens and maintaining the homeostasis of the organism. Increasing evidence suggests that the cGAS-STING pathway plays a key role in tumor immunity, and the combination of STING-related agonists can significantly enhance the efficacy of immunotherapy and reduce the emergence of immunotherapeutic resistance. However, the cGAS-STING pathway is a double-edged sword, and its activation can enhance anti-tumor immunity and immunosuppression. Immunosuppressive cells, including M2 macrophages, MDSC, and regulatory T cells, in the tumor microenvironment play a crucial role in tumor escape, thereby affecting the immunotherapy effect. The cGAS-STING signaling pathway can bi-directionally regulate this group of immunosuppressive cells, and targeting this pathway can affect the function of immunosuppressive cells, providing new ideas for immunotherapy. In this study, we summarize the activation pathway of the cGAS-STING pathway and its immunological function and elaborate on the key role of this pathway in immune escape mediated by the tumor immunosuppressive microenvironment. Finally, we summarize the mainstream immunotherapeutic approaches related to this pathway and explore ways to improve them, thereby providing guidelines for further clinical services.

Retrospective review of seven patients with obesity simultaneously treated with a combination of a glucagon-like peptide-1 receptor agonist and a meal replacement product

BackgroundThe use of meal replacement products (MRPs) to obtain a caloric deficit while maintaining micro- and macronutrient requirements, has a long tradition in obesity medicine. Limitations include low compliance, variability in efficacy, adverse events (related to acute changes in nutrient intake), and risk of weight regain when discontinued, and their popularity has declined after the emergence of potent GLP-1 receptor analogues (GLP1-RAs). However, GLP-1RAs have limitations, including dose-dependent risk for adverse events (AEs), high cost, as well as weight regain when discontinued. Although concomitant use of MRPs and GLP-1RAs could address some of the limitations, there is a scarcity of data reported on this. Herein we report real world clinical experience of such combined use. MethodsThis retrospective case evaluation involved people with obesity that concomitantly used MRPs (Optifast) and a GLP-1RA and were followed at one of three weight management centers in Australia or South Africa. Parameters collected were gender, age, co-morbidities, height, weight, frequency/amount of MRPs used, dose/type of GLP-1RA used, duration of combined use, and occurrence of AEs. Written informed consent for use of data was obtained from each individual, and the data were managed in an anonymized form and summarized descriptively. ResultA total of seven (5 females) individuals (mean [min, max] age 49 [30,66] years, BMI 44.8 [30.7, 57.9] kg/m2) initiated either semaglutide (n=4) or liraglutide (n=3) concomitantly with daily MRPs (starting number of servings/day 2.7 [1,6]) for a duration of 12 [4, 25] months. Change in weight/BMI/% TBW was -32.0 (-9.6, -77.8) kg/-10.3 (-3.4, -24.5) kg/m2/-24.2 %. Five individuals experienced ≥1 GLP-1RA related AE (nausea, reflux, burping, diarrhea, constipation). One individual discontinued GLP-1RA, whereas two persons discontinued the use of MRPs. ConclusionsMRPs can be initiated concomitantly with a GLP-1 RA for weight management. This might enhance weight-loss effectiveness, with potential additional benefits that should be elucidated in further and larger studies.

Adverse event reporting of combining SGLT2 inhibitor and GLP1 receptor agonist: A real-world study from FAERS

Background and aimsWe evaluate whether the combination of sodium-glucose cotransporter-2 inhibitor(SGLT2i) and glucagon-like peptide-1 receptor agonist(GLP1RA) disproportionally increases the reporting of adverse events compared with SGLT2i or GLP1RA monotherapy in the FDA adverse event reporting system (FAERS). Methods and resultsAdverse events related to SGLT2i and GLP1RA were screened and selected, then data from the FAERS was underwent thorough disproportionality analysis. The proportional reporting ratio(PRR) of SGLT2i-related adverse events were compared between patients using SGLT2i alone and those using both SGLT2i and GLP1RA. Similarly, the PRR of GLP1RA-related adverse events were compared between patients using GLP1RA alone and those using both SGLT2i and GLP1RA. The results showed that the PRR of SGLT2i-related adverse events including diabetic ketoacidosis(DKA), ketosis, reproductive tract adverse events, urinary tract infection, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using SGLT2i alone, and the signal of fracture was not detected. Likewise, the PRR of GLP1RA-related adverse events including gastrointestinal adverse events, gallbladder and biliary tract disease, pancreatitis, and other adverse events, decreased in individuals using both SGLT2i and GLP1RA compared with those using GLP1RA alone, the PRR of hyperlipasaemia and hyperamylasaemia increased in the combination therapy and no signal of depression, suicidal and self-injurious behaviour was detected. ConclusionAdverse events reporting are not disproportionally higher among those using both SGLT-2i and GLP1RA compared with SGLT2i or GLP1RA monotherapy.

Abstract PR-10: Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy

Abstract Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a dismal 5-year overall survival (OS) rate of 3%. Current standard of care provides only modest anti-cancer impact. Preclinical models show that combinations of myeloid agonists can induce strong anti-tumor activity in PDAC tumors resistant to immunotherapy, including immune checkpoint blockade (anti-CTLA4, anti-PD1). This study combines odetiglucan, a beta glucan pathogen-associated molecular pattern (PAMP), with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody, in the maintenance setting after cytotoxic chemotherapy induction. Preliminary findings are presented as the study was closed early for financial reasons. Methods: Patients with mPDAC who had not progressed after 4-8 months of 1L chemotherapy were enrolled and received weekly odetiglucan (4 mg/kg) plus every 3-week dosing of CDX-1140 (1.5 mg/kg). The primary endpoints were safety, MTD and RP2D, with secondary endpoints including DOR, PFS, ORR, and OS. Tissue and blood samples were collected at baseline and during treatment to evaluate immune pharmacodynamic responses. Results: A total of 5 patients received treatment on study including 4 patients who were efficacy evaluable and 1 patient who withdrew due to adverse event (arthralgia) after beginning treatment. Treatment-related emergent adverse events were seen in all patients with most common AEs including grade 1-2 arthralgia, chills, and fatigue. Grade 3 AEs included arthralgia (n=1), fatigue (n=1), and leukopenia (n=2). The ORR included 1 PR, 1 SD, and 2 PD. Two patients remained on treatment for >100 days. The pharmacodynamic profile was consistent with the mode of action of odetiglucan and CDX-1140, including a reduction in peripheral Dectin-1 expressing monocytes and transient decreases in peripheral B cells. Patients with disease control (PR or SD, n=2) compared to patients with progression (PD, n=2) showed expansion of peripheral Ki67+ CD8+ T cells following treatment. Analysis of a paired tumor biopsy from 1 patient with PD confirmed penetration of odetiglucan into a liver metastasis with expansion of CD11b+ macrophages and a reduction of cytokeratin+ tumor content, but without significant changes in T cell infiltration. Conclusions: The combination of odetiglucan and CDX-1140 was feasible and safe when administered as maintenance therapy in patients with mPDAC whose disease had not progressed on 1L chemotherapy. Treatment produced encouraging activity with changes in immunological correlates associated with disease control. These early results support further investigation combining odetiglucan with a CD40 agonist in mPDAC. Citation Format: Mark H O'Hara, Max Wattenberg, Ignacio Garrido-Laguna, Eileen M O'Reilly, Michael Yellin, Tibor Keler, Michele Gargano, Nick Niles, Jeremy Drees, Nandita Bose, Gregory L Beatty. Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy [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 PR-10.

Abstract B061: Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy

Abstract Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a dismal 5-year overall survival (OS) rate of 3%. Current standard of care provides only modest anti-cancer impact. Preclinical models show that combinations of myeloid agonists can induce strong anti- tumor activity in PDAC tumors resistant to immunotherapy, including immune checkpoint blockade (anti-CTLA4, anti-PD1). This study combines odetiglucan, a beta glucan pathogen- associated molecular pattern (PAMP), with CDX-1140, a fully human Ig2K agonistic monoclonal CD40 antibody, in the maintenance setting after cytotoxic chemotherapy induction. Preliminary findings are presented as the study was closed early for financial reasons. Methods: Patients with mPDAC who had not progressed after 4-8 months of 1L chemotherapy were enrolled and received weekly odetiglucan (4 mg/kg) plus every 3-week dosing of CDX-1140 (1.5 mg/kg). The primary endpoints were safety, MTD and RP2D, with secondary endpoints including DOR, PFS, ORR, and OS. Tissue and blood samples were collected at baseline and during treatment to evaluate immune pharmacodynamic responses. Results: A total of 5 patients received treatment on study including 4 patients who were efficacy evaluable and 1 patient who withdrew due to adverse event (arthralgia) after beginning treatment. Treatment-related emergent adverse events were seen in all patients with most common AEs including grade 1-2 arthralgia, chills, and fatigue. Grade 3 AEs included arthralgia (n=1), fatigue (n=1), and leukopenia (n=2). The ORR included 1 PR, 1 SD, and 2 PD. Two patients remained on treatment for >100 days. The pharmacodynamic profile was consistent with the mode of action of odetiglucan and CDX-1140, including a reduction in peripheral Dectin-1 expressing monocytes and transient decreases in peripheral B cells. Patients with disease control (PR or SD, n=2) compared to patients with progression (PD, n=2) showed expansion of peripheral Ki67+ CD8+ T cells following treatment. Analysis of a paired tumor biopsy from 1 patient with PD confirmed penetration of odetiglucan into a liver metastasis with expansion of CD11b+ macrophages and a reduction of cytokeratin+ tumor content, but without significant changes in T cell infiltration. Conclusions: The combination of odetiglucan and CDX-1140 was feasible and safe when administered as maintenance therapy in patients with mPDAC whose disease had not progressed on 1L chemotherapy. Treatment produced encouraging activity with changes in immunological correlates associated with disease control. These early results support further investigation combining odetiglucan with a CD40 agonist in mPDAC. Citation Format: Mark H O'Hara, Max Wattenberg, Ignacio Garrido-Laguna, Eileen M O'Reilly, Michael Yellin, Tibor Keler, Michele Gargano, Nick Niles, Jeremy Drees, Nandita Bose, Gregory L Beatty. Phase 1b study of maintenance soluble beta-glucan (Odetiglucan) in combination with a CD40 agonistic monoclonal antibody (CDX-1140) in patients with metastatic pancreatic adenocarcinoma that had not progressed on first-line chemotherapy [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 B061.

Class Effect Unveiled: PPARγ Agonists and MEK Inhibitors in Cancer Cell Differentiation.

Epithelial-to-mesenchymal transition (EMT) plays a major role in breast cancer progression and the development of drug resistance. We have previously demonstrated a trans-differentiation therapeutic approach targeting invasive dedifferentiated cancer cells. Using a combination of PPARγ agonists and MEK inhibitors, we forced the differentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells, we demonstrated a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrangement, and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFβ, with Cobimetinib showing the most prominent effects. A metastasis ex vivo culture from a patient diagnosed with triple-negative breast cancer demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobimetinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and the dedifferentiation phenotype in aggressive breast cancer subtypes. Combining differentiation treatments with standard therapeutic approaches may offer a strategy to overcome drug resistance.

Targeting Death Receptor 5 (DR5) for the imaging and treatment of primary bone and soft tissue tumors: an update of the literature.

Death Receptor 5 (DR5) is expressed on the surface of primary bone and soft tissue sarcoma cells, and its activation induces cell death primarily through apoptosis. The combination of DR5 agonists and commonly used chemotherapeutic agents, such as doxorubicin, can promote cell death. Currently, clinical trials are investigating the effectiveness of DR5 activation using new biological agents, such as bi-specific or tetravalent antibodies, in improving the survival of patients with relapsed or refractory cancers. Furthermore, investigations continue into the use of novel combination therapies to enhance DR5 response, for example, with inhibitor of apoptosis protein (IAP) antagonist agents [such as the second mitochondria-derived activator of caspase (SMAC) mimetics] and with immune checkpoint inhibitor anti-programmed death-ligand 1 (anti-PD-L1) or anti-programmed cell death-1 (anti-PD-1) antibodies. Other therapies include nanoparticle-mediated delivery of TRAIL plasmid DNA or TRAIL mRNA and stem cells as a vehicle for the targeted delivery of anti-cancer agents, such as TRAIL, to the tumor. Scoping review of the literature from November 2017 to March 2024, utilizing PubMed and Google Scholar. New agents under investigation include nanoTRAIL, anti-Kv10.1, multimeric IgM, and humanized tetravalent antibodies. Developments have been made to test novel agents, and imaging has been used to detect DR5 in preclinical models and patients. The models include 3D spheroids, genetically modified mouse models, a novel jaw osteosarcoma model, and patient-derived xenograft (PDX) animal models. There are currently two ongoing clinical trials focusing on the activation of DR5, namely, IGM-8444 and INBRX-109, which have progressed to phase 2. Further modifications of TRAIL delivery with fusion to single-chain variable fragments (scFv-TRAIL), directed against tumor-associated antigens (TAAs), and in the use of stem cells focus on targeted TRAIL delivery to cancer cells using bi-functional strategies. In vitro, in vivo, and clinical trials, as well as advances in imaging and theranostics, indicate that targeting DR5 remains a valid strategy in the treatment of some relapsed and refractory cancers.

Incretin hormone agonists: Current and emerging pharmacotherapy for obesity management.

Obesity continues to be a significant global health challenge, affecting over 800 million individuals worldwide. Traditional management strategies, including dietary, exercise, and behavioral interventions, often result in insufficient and unsustainable weight loss. Lifestyle modification remains the cornerstone of obesity management, providing the foundation for other strategies. While options such as bariatric surgery remain an effective intervention for severe obesity, it is associated with its own set of risks and is typically reserved for patients who have not achieved the desired results with pharmacotherapy and lifestyle interventions. Incretin hormone agonists represent a significant advancement in the pharmacotherapy of obesity, offering substantial weight reduction and cardiometabolic benefits. Agents like liraglutide, semaglutide, and tirzepatide supported by key clinical trials such as Satiety and Clinical Adipose Liraglutide Evidence (SCALE), Semaglutide Treatment Effect in People with Obesity (STEP) program trials, and Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1) have demonstrated remarkable efficacy in promoting weight loss and improving metabolic outcomes. Additionally, novel therapies, including dual and triple incretin agonists, are under investigation and hold the potential for further advancements in obesity treatment. These novel therapies can be categorized by their mechanisms of action and route of administration into oral glucagon-like peptide-1 (GLP-1) receptor agonists, triple agonists (targeting GLP-1, glucose-dependent insulinotropic polypeptide [GIP], and glucagon receptors), and glucagon receptor-GLP-1 receptor co-agonists. Other innovative approaches include oral GIP-GLP-1 receptor co-agonists, and the combination of long-acting amylin receptor agonists with GLP-1 receptor agonists. The ongoing development of incretin-based therapies and the expanding availability of currently available agents are expected to enhance clinical outcomes further and reduce the burden of obesity-related health complications. This review aims to discuss the mechanisms and efficacy of current and emerging incretin hormone agonists for obesity management.