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Abstract Background The associations between different types of diabetes, characterized by distinct pathophysiology and genetic architecture, and pancreatic ductal adenocarcinoma (PDAC) risk are not understood. Methods We investigated associations of genetic susceptibility to type 2 diabetes (T2D), 8 T2D mechanistic clusters, type 1 diabetes (T1D), and maturity-onset diabetes of the young (MODY) with PDAC risk. We used genome-wide association study (GWAS) summary-level statistics for T2D (242 283 cases, 1 569 734 controls), T1D (18 942 cases, 501 638 controls), and PDAC (10 244 cases and 360 535 controls) in individuals of European ancestry. Results Two-sample Mendelian randomization (MR) using the Robust Adjusted Profile Score (MR-RAPS) method indicated that genetically predicted T2D was associated with PDAC risk (OR = 1.10; 95% CI = 1.05 to 1.15), particularly the T2D obesity (OR = 1.28; 95% CI = 1.15 to 1.42) and lipodystrophy (OR = 1.25; 95% CI = 1.03 to 1.51) clusters. No association was observed for T1D with PDAC risk (OR = 1.01; 95% CI = 0.99 to 1.02). Pathway/gene-set analysis using the summary-based Adaptive Rank Truncated Product (sARTP) method revealed a significant association between the MODY gene-sets and PDAC risk (P = 1.5 × 10−8), which remained after excluding 20 known PDAC GWAS loci (P = 7.6 × 10−4). HNF1A, FOXA3, and HNF4A were the top contributing genes after excluding the previously identified GWAS loci regions. Conclusions Our results from this genetic association study support that T2D, particularly the obesity and lipodystrophy mechanistic clusters, and MODY genomic susceptibility regions play a role in the etiology of PDAC.

Background: Diabetic cardiomyopathy is a common complication of diabetes, which can progress to symptomatic heart failure. Current conventional medical therapy does not reverse the deleterious features of diabetic cardiomyopathy. The natriuretic peptide-cGMP system has been proven to provide a cardioprotective role in diabetic rats. Therefore, we developed CRRL094, a n bispecific peptide that simultaneously activates the natriuretic peptide system and glucagon-like peptide-1 (GLP-1) receptor. In this study, we aimed to characterize the cardioprotective role of CRRL094 and elucidate its downstream molecular mechanisms. Methods: In vitro, human cardiomyocytes (HCMs) were pretreated with PBS or CRRL094 (5 µM) for 6 hours, then exposed to high glucose treatment (HGT, 25 mM) for 48 hours. HCM hypertrophy was determined by assessing mRNA levels of hypertrophic gene markers (NPPA and NPPB) using real-time PCR. Lipid droplet staining was performed using BODIPY 493/503 dye and fluorescence images were analyzed. The protein levels of CIDEC (lipid droplet-related gene) and phosphorylation-AMPK and total AMPK (a key regulator of lipid metabolism) were analyzed by Western blot. In vivo, a type 2 diabetes (DM2) rat model was established by low-dose intraperitoneal Streptozotocin (STZ) injection and a high-fat diet in Wistar rats (male, 4- to 6-week-old). Diabetes was confirmed by fasting blood glucose > 350 mg/dL. Rats were then allocated to two groups: saline-treated controls (n=6) or CRRL094-treated (30 pmol/kg/min; n=6), with treatment delivered via osmotic pumps for 28 days. Heart tissues were collected and analyzed. Results: HGT in HCMs significantly increased the mRNA levels of NPPA and NPPB, whereas CRRL094 significantly attenuated markers of hypertrophy. Further, HGT increased lipid accumulation in HCMs, which was decreased with CRRL094 treatment. Moreover, CRRL094 increased p-AMPK protein levels and decreased CIDEC protein levels in HCMs under HGT. In a DM2 rat model, chronic CRRL094 therapy was associated with suppression of NPPA and NPPB, downregulation of CIDEC, and upregulation of p-AMPK expression in the heart tissue. Conclusion: CRRL094 protects against HGT-induced hypertrophy and inhibits lipid accumulation through regulating the AMPK/CIDEC pathway in vitro and in vivo . These findings support CRRL094 as a novel therapeutic candidate to prevent diabetic cardiomyopathy.

Introduction: Diabetes mellitus (DM) is strongly associated with metabolic and cardiorenal derangements. Natriuretic peptides (NPs), and glucagon-like peptide 1 receptor agonists (GLP-1 RA) have well-established cardiometabolic and cardiorenal protective effects. We developed a novel bispecific biologic, CRRL 101, which agonizes guanylyl cyclase A (GCA) NP receptors and GLP-1 receptors. In this study, we sought to evaluate the in vitro effects and in vivo impact of CRRL 101 in a DM rat model. Methods: In vitro experiments evaluated the impact of CRRL 101 treatment of GCA receptor transfected human embryonic kidney (HEK) cells and INS-1 rat pancreatic beta cells. In vivo experiments were conducted by inducing DM in Wistar rats (male, 6-8-week-old) by intraperitoneal Streptozotocin (STZ) injection (65 mg/kg). One week after STZ injection, DM was confirmed (fasting blood glucose > 350 mg/dL). Rats were then divided into 3 groups: saline control (n=6), 1 pmol/kg/min CRRL-101 (“1pmol” n= 4), and 10 pmol/kg/min CRRL-101 (“10 pmol” n=5). Treatment was infused for 120 min after which rat blood and urine were collected. Data were analyzed using GraphPad Prism 10.0.0. Results: In vitro, there was a marked increase in cyclic GMP (cGMP) levels (pmol/mL) in HEK treated with 10 -6 M CRRL 101 (mean difference ± SEM:1.603 ± 0.29 p = 0.0048). In INS-1 cells treated with CRRL 101 at 10 -6 M in a 20 mM glucose medium, cAMP levels (pmol/mL) markedly increased (16.7 ± 1.47 vs 23.19 ± 1.51 p=0.0036) and insulin levels (ng/mL) doubled (4.4 ng/mL ± 0.44 vs 9.5 ng/mL ± 0.34 in 20 mM glucose p < 0.0001). Similar increases were observed at lower doses (10 -7 M, 10 -8 M) of CRRL 101. In vivo , after 120 minutes of treatment, mean plasma cGMP levels were 6.5x greater in both groups (mean difference± SEM) (1pmol: 38.89 ± 7.93, p = 0.016; 10pmol: 39.40 ± 4.84 p=0.001). Plasma insulin (ng/mL) more than doubled with both doses (1pmol: 0.39 ± 0.148, p = 0.039; 10 pmol: 0.198 ± 0.051, p = 0.004) with no significant increase with placebo ( 0.03 ± 0.08, p = 0.67). Rate of natriuresis (mEq/min) more than doubled with peptide administration vs placebo (1 pmol: 0.36 ± 0.093 p = 0.014; 10 pmol: 0.38 ± 0.13, p = 0.034). Conclusions: Our novel bispecific biologic, CRRL 101, activates GC-A, increasing plasma cGMP and inducing natriuresis, and stimulates GLP-1R, raising cAMP and plasma insulin. Chronic administration studies to eludicate its therapeutic efficacy are warranted.

Abstract Background Lung adenocarcinoma in never-smokers is a major public health burden, especially among East Asian women. Polygenic risk scores (PRSs) are promising for risk stratification but are primarily developed in European-ancestry populations. We aimed to develop and validate single- and multi-ancestry PRSs for East Asian never-smokers to improve lung adenocarcinoma risk prediction. Methods PRSs were developed using genome-wide association study summary statistics from East Asian (8002 cases; 20 782 controls) and European (2058 cases; 5575 controls) populations. Single-ancestry models included a PRS with 25 single nucleotide variants (PRS-25), PRS clumping and thresholding (CT), and LDpred2; multi-ancestry models included LDpred2 plus European PRS-128, PRS-CSx, and clumping and thresholding, super learning, empirical Bayes (CT-SLEB). Performance was evaluated in independent East Asian data from the Female Lung Cancer Consortium and externally validated in the Nanjing Lung Cancer Cohort. We assessed predictive accuracy via area under the curve operating procedure (AUC), with 10-year and (ages 30-80 years) absolute risks estimates. Results The best multi-ancestry PRS, using East Asian and European data via CT-SLEB, outperformed the best East Asian-only (LDpred2; AUC = 0.629, 95% confidence interval [CI] = 0.618 to 0.641), achieving an AUC of 0.640 (95% CI = 0.629 to 0.653) and odds ratio of 1.71 (95% CI = 1.61 to 1.82) per standard deviation increase. Nanjing Lung Cancer Cohort validation confirmed robust performance (AUC = 0.649, 95% CI = 0.623 to 0.676). The top 20% PRS group had a 3.92-fold higher lung adenocarcinoma risk than the bottom 20%. Further, the top 5% PRS group reached a 6.69% lifetime absolute risk. Notably, this group reached the average population 10-year lung adenocarcinoma risk at age 50 years (0.42%) by age 41 years, 9 years earlier. Conclusions Multi-ancestry PRS approaches enhance lung adenocarcinoma risk stratification in East Asian never-smokers, with consistent external validation, suggesting future clinical utility.

Abstract Background Cabozantinib is indicated for hepatocellular carcinoma (HCC) following first-line (1L) sorafenib, but the 1L standard has shifted to immuno-oncology (IO)-based regimens. This study evaluated real-world outcomes among patients with advanced HCC receiving second-line (2L) cabozantinib following 1L therapies, including newer regimens. Patients and Methods US claims data were used to identify adults with advanced HCC initiating 2L cabozantinib monotherapy (index date). Patients were stratified into three 1L treatment cohorts: IO monotherapy/IO + IO combination therapy; IO + non–IO combination therapy; or tyrosine kinase inhibitor (TKI) monotherapy. Real-world time to treatment discontinuation (rwTTD), real-world time to next treatment or death (rwTNTD), real-world overall survival (rwOS), and cabozantinib dosing were assessed collectively and by cohort. Adverse events were assessed before/after cabozantinib initiation. Results Among 148 patients who received 2L cabozantinib, 28 were in the IO monotherapy/IO + IO combination therapy cohort, 54 in the IO + non–IO combination therapy cohort, and 66 in the TKI monotherapy cohort. Median rwTTD among all patients was 3.2 months; median rwTNTD was 7.6 months; 12-month rwOS rate was 61.6%. There were no significant differences in these outcomes among the three cohorts. Overall, 44.6% of patients initiated 2L cabozantinib at 60 mg/day, of whom 39.4% required a dose reduction; 37.8% initiated at 40 mg/day, of whom 16.1% had a dose reduction. Adverse event rates were similar before/after cabozantinib initiation. Conclusions Cabozantinib shows consistent effectiveness and safety in the 2L HCC setting following prior TKIs or IO-based regimens in real-world clinical practice. These findings may inform 2L treatment decisions.

8501 Background: TROPION-Lung02 (NCT04526691) evaluated the TROP2-directed antibody-drug conjugate (ADC) Dato-DXd plus pembro combination with or without Pt-CT in aNSCLC. Here we report primary analyses of pts receiving combination therapy in the 1L setting. Methods: Pts across 6 cohorts were dosed with Dato-DXd (4 or 6 mg/kg) plus pembro 200 mg alone (doublet) or with pembro plus Pt-CT (triplet; cisplatin 75 mg/m 2 or carboplatin AUC 5) Q3W. PD-L1 expression (tumor proportion score) was assessed locally by immunohistochemistry (22C3 assay). Primary objectives were safety and tolerability; efficacy was a secondary objective. Results: As of Apr 29, 2024, 96 pts received either the doublet (n=42) or triplet (n=54) combination as 1L therapy; 29% and 15% of pts were ongoing, respectively. Median ages were 65 (doublet) and 64 years (triplet). Median treatment durations were 9.7 and 5.8 months, respectively. Stomatitis (doublet, 57%; triplet, 33%) and nausea (doublet, 42%; triplet, 48%), primarily Gr 1–2, were the most common adverse events (AEs) across both regimens. Treatment related serious AEs occurred in 5 (12%) and 12 (22%) pts in each cohort and no deaths related to study drug were seen. Efficacy outcomes, including by histology, are summarized in the Table. Biomarker analyses, including efficacy by PD-L1 status, will be presented. Conclusions: In this largest data set to date evaluating an ADC combined with an anti-PD-1/L1 agent in the 1L setting, the combination of Dato-DXd plus pembro treatment both with and without Pt-CT elicited durable antitumor activity in pts with aNSCLC. Tolerability of the combinations was as expected, based on known profiles of the individual agents. Clinical trial information: NCT04526691 . All 1L (n=96) 1L, Nonsquamous (n=75) 1L, Squamous (n=21) Response, n (%) Doublet (n=42) Triplet (n=54) Doublet (n=33) Triplet (n=42) Doublet (n=9) Triplet (n=12) Confirmed objective response rate 23 (55) 30 (56) 17 (52) 24 (57) 6 (67) 6 (50) Complete response 1 (2) 2 (4) 1 (3) 2 (5) 0 0 Partial response 22 (52) 28 (52) 16 (49) 22 (52) 6 (67) 6 (50) Stable disease 14 (33) 18 (33) 12 (36) 14 (33) 2 (22) 4 (33) Progressive disease 3 (7) 2 (4) 3 (9) 1 (2) 0 1 (8) Disease control rate a 37 (88) 48 (89) 29 (88) 38 (91) 8 (89) 10 (83) Median duration of response, mo (95% CI) 20.1 (9.7–NE) 13.7 (5.7–NE) 24.9 (9.7–NE) 18.0 (8.0–NE) 12.0 (5.5–NE) 5.5 (4.1–NE) Median PFS, mo (95% CI) 11.2 b (8.2–21.3) 6.8 c (5.5–11.1) 11.2 (6.1–21.3) 10.8 (5.5–17.3) 10.2 (0.4–NE) 6.7 (1.0–8.2) a Proportion of pts with confirmed CR + PR + SD at 12 wks. b.c Median (95% CI) PFS follow-up, mo: b 17.3 (11.3−26.8); c 23.5 (17.3−27.9). mo, months; NE, not evaluable.

BACKGROUND: Cardiomyocyte oxidative stress significantly contributes to the progression of hypertension-induced heart failure, highlighting the need for targeted therapies. We developed a novel peptide, NPA7, that coactivates the GC-A (guanylyl cyclase A)/cGMP and MasR (Mas receptor)/cAMP pathway. This study aimed to test NPA7’s ability to inhibit oxidative stress by modulating the p62 (Sequestosome 1)-KEAP1 (Kelch-like ECH-associated protein 1)-NRF2 (nuclear factor erythroid 2-related factor 2) pathway in human cardiomyocytes (HCMs) and a rat model of hypertension. METHODS: Oxidative stress was induced in HCMs using H 2 O 2 with phosphate-buffered saline or NPA7 treatment. Intracellular reactive oxygen species levels were assessed via dihydroethidium staining. Western blotting analysis measured p62, KEAP1, and NRF2 protein levels, while GSH/GSSG (glutathione/glutathione disulfide) ratios and antioxidant gene expression were analyzed. HCMs were transfected with small interfering RNA targeting GC-A, MasR, or p62 before NPA7 and H 2 O 2 treatment. In vivo, spontaneously hypertensive rats received saline or NPA7, with normotensive Wistar Kyoto rats as control and cardiac oxidative stress, KEAP1 protein levels, NOX2 (NADPH oxidase 2), and p67 (NADPH oxidase subunit p67-phox) mRNA levels were measured. RESULTS: NPA7 reduced H 2 O 2 -induced reactive oxygen species levels and increased GSH/GSSG ratio in HCMs. Silencing GC-A (guanylyl cyclase A receptor) and MasR (Mas receptor) reversed NPA7’s effects. NPA7 activated the KEAP1-NRF2 pathway, enhancing NRF2’s antioxidant target gene expression. In p62 knockdown HCMs, NPA7-induced KEAP1 degradation and NRF2 activation were diminished. Reactive oxygen species levels were elevated in spontaneously hypertensive rat versusWistar Kyoto rats’ hearts, however, NPA7 treatment reduced myocardial reactive oxygen species, suppressed KEAP1 protein, and decreased NOX2 and p67 mRNA levels. CONCLUSIONS: NPA7 exhibits antioxidant properties in HCMs and spontaneously hypertensive rat hearts by targeting GC-A and MasR through the p62-KEAP1-NRF2 pathway, supporting a novel therapeutic approach against cardiovascular disease–related oxidative stress.

Background: Tyrosine kinase inhibitors (TKIs), such as sunitinib, are highly effective in treating cancers. However, they have severe cardiovascular (CV) side effects that include cardiotoxicity via cardiomyocyte injury and death resulting in myocardial dysfunction. There are no FDA-approved drugs to prevent or treat cardiotoxicity, which have been linked mechanistically to mitochondrial dysfunction and oxidative stress, highlighting the need for new therapeutics. Two recognized CV protective pathways are the particulate guanylyl cyclase A receptor (GC-A)/cGMP and the Mas receptor (MasR)/cAMP pathways. We recently engineered NPA7 a novel peptide that activates both pathways. Aim: Here we investigated NPA7’s ability to protect against sunitinib-induced cardiotoxicity in human cardiomyocytes (HCMs) and defined its role on mitochondrial function. Methods: HCMs were treated with DMSO or sunitinib (10 µM) together with PBS or NPA7 (10 µM). Intracellular reactive oxygen species (ROS) was assessed by DHE staining. CCK8 assay was performed to measure cell viability. TOM20 staining were performed by immunofluorescence and the mitochondrial length was analyzed. The protein levels of mitochondrial dynamics markers (fission: MFF, Fis1; fusion: OPA1 and MFN1) proteins were measured by western blot. Cell surface area was assessed by phalloidin staining with mRNA levels of hypertrophic gene markers (NPPA and MYH7) in HCMs using real-time PCR. Results: Sunitinib increased DHE staining and intracellular ROS in HCMs, which was decreased with NPA7 treatment. NPA7 enhanced HCM cell viability in the presence of sunitinib. TOM20 staining showed a marked reduction in mitochondrial length in sunitinib group, compared to DMSO group, whereas NPA7 treatment rescued mitochondria length (DMSO= 6.15 ± 0.94 μm, Sunitinib= 2.42 ± 0.63 μm, NPA7= 5.4 ± 1.19 μm; P < 0.05). Moreover, NPA7 inhibited mitochondrial fission protein levels (MFF and Fis1) and increased mitochondrial fusion protein levels (OPA1, MFN1) in HCMs treated with sunitinib. Sunitinib treatment notably increased HCM cell surface area and hypertrophic gene markers (NPPA and MYH7), whereas NPA7 abolished these markers of hypertrophy. Conclusions: We report, for the first time, that NPA7 protects against sunitinib induced oxidative stress, mitochondrial fragmentation, hypertrophy and cell death in HCMs. These data support a novel therapeutic approach against TKI-induced cardiotoxicity with NPA7 to which no therapies exist.