A biomimetic nano-suspension based on orthoester designed for the inhibition of postoperative tumor recurrence.

The CheckMate 9ER (CM9ER) trial demonstrated thesuperiority of cabozantinib plus nivolumab (CaboNivo) over sunitinib (SUN) in patients with untreated advanced renal cell carcinoma (aRCC). We conducted a post hoc analysis using CM9ER data (median follow-up 67.6months) and two-stage estimation (TSE) to assess the efficacy of CaboNivo versus SUN, adjusting for the impact of subsequent treatment. Patients in the intention-to-treat (ITT) CM9ER population who discontinued their randomized study therapy were included in step 1 of the TSE, which used accelerated failure time modeling to estimate the extent that subsequent therapy extended survival in each treatment arm. Step 2 adjusted the CM9ER ITT population overall survival (OS) estimates to account for this impact; an adjusted hazard ratio (HR)for OS was then calculated to evaluate the relative impact of CaboNivo versus SUN without the effects of subsequent treatment. In total, 540 patients from CM9ER (CaboNivo, n = 264; SUN, n = 276) discontinued treatment and were included in the analysis, of whom 297 (CaboNivo, n = 129; SUN, n = 168) initiated subsequent systemic therapy. Patient characteristics were balanced between ITT and TSE populations. Median (interquartile range) time from randomization to treatment discontinuation was 22.2 (9.92-31.51) months for CaboNivo and 9.6 (3.48-18.62) months for SUN. The TSE-adjusted median (95% confidence interval [CI]) OS was 42.7 (38.4-49.1) months for CaboNivo and 21.3 (18.1-24.9) months for SUN (HR [95% CI] 0.53 [0.43-0.65; p < 0.001]), compared with unadjusted estimates of 46.5 (40.6-53.7) months and 35.5 (29.2-42.8) months, respectively (HR [95% CI] 0.79 [0.65-0.96; p = 0.0196]). Removing the effect of subsequent therapy strengthened the relative OS benefit of CaboNivo versus SUN in CM9ER. Consistent with clinical practice, these results further support first-line CaboNivo as a standard of care for aRCC.Graphical abstract available for this article. NCT03141177.

Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial.

2624P Artificial intelligence (AI)-powered immune phenotype (IP) predicts differential benefit from nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in advanced clear cell renal cell carcinoma (ccRCC)

Abstract The multi-stimuli-responsive nanohydrogels provide a powerful strategy for enhancing drug utilization, preservation, controlled release, and minimizing systemic toxicity. Herein, we designed and developed a new multi-stimuli-responsive magnetic graphene oxide (MGO) integrated carboxymethyl cellulose/κ-carrageenan (CMC/CG/MGO) nanogels (NGs) for colon-specific delivery of sunitinib (SU). The physicochemical properties of the CMC/CG/MGO NGs were investigated by various analytical techniques of XRD, FTIR, TGA VSM, DLS, BET, and FESEM/TEM. The in-vitro SU release results exhibited that the CMC/CG/MGO NGs have a sustained release behavior with good pH, magnetic field, and near-infrared (NIR) light-dependent properties. The integrated photothermal agent MGO endowed the CMC/CG NGs with efficient photothermal properties, enabling precise SU release control under NIR laser irradiation. The CMC/CG/MGO/SU NGs displayed a good photothermal conversion effect (η = 38.5%). Besides, the CMC/CG/MGO NGs were not cytotoxic (cell viability &gt; 73% at 15.6–500 ppm) for the L929 fibroblast and Caco-2 cell lines. The MTT results also revealed that the CMC/CG/MGO/SU NGs exhibited enhanced anti-cancer activity compared to free SU under NIR laser irradiation. These results highlight the potential of CMC/CG/MGO/SU NGs as a promising candidate for remotely controlled multi-stimuli-responsive drug delivery. Graphical abstract

Unravelling the cardioprotective effects of calcitriol in Sunitinib-induced toxicity: A comprehensive in silico and in vitro study.

4505 Background: First-line nivolumab plus ipilimumab (NIVO+IPI) provided substantial long-term survival benefits over sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CheckMate 214 trial. We now report final efficacy and safety data in the intent-to-treat (ITT) population and by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk. Methods: Pts with clear cell aRCC were randomized 1:1 to NIVO 3 mg/kg + IPI 1 mg/kg Q3W×4 then NIVO (3 mg/kg or 240 mg Q2W or 480 mg Q4W); or SUN 50 mg once daily for 4 weeks on, 2 weeks off. Efficacy endpoints included overall survival (OS), and independent radiology review committee (IRRC)-assessed progression-free survival (PFS) and objective response rate (ORR) in intermediate/poor-risk (I/P; primary), ITT (secondary), and favorable-risk (FAV; exploratory) pts. Response was assessed using RECIST v1.1. Results: With 9 years median follow-up, OS was improved with NIVO+IPI vs SUN in ITT (HR 0.71) and I/P (HR 0.69) pts. The probability of OS at 108 months was 31% vs 20% in ITT pts and 30% vs 19% in I/P pts, respectively. In pts with FAV risk, the HR for OS improved from 1.45 at first report (Motzer NEJM 2018) to 0.80 at 9 years, showing a delayed benefit with NIVO+IPI vs SUN. OS probabilities at 108 months were 35% vs 22% in FAV pts, respectively (Table). The probability of PFS at 96 months with NIVO+IPI vs SUN was 23% vs 9% in ITT pts, 25% vs 9% in I/P pts, and 13% vs 11% in FAV pts. The probability of remaining in response through 96 months with NIVO+IPI vs SUN was 48% vs 19% in ITT pts, 50% vs 23% in I/P pts, and 36% vs not available (NA) in FAV pts. No new treatment-related deaths occurred in either arm. Additional subgroup analyses will be presented. Conclusions: In the longest and final phase 3 follow-up (9 years) of a first-line checkpoint inhibitor combination in aRCC, milestone rates of OS and PFS and durable response remained higher with NIVO+IPI vs SUN. No new safety signals emerged. NIVO+IPI remains a standard first-line option in aRCC. Clinical trial information: NCT02231749 . ITT I/P FAV Arm; n NIVO+IPI; 550 SUN; 546 NIVO+IPI; 425 SUN; 422 NIVO+IPI; 125 SUN; 124 mOS (95% CI), mo 53 (46–64) 38 (32–44) 47 (35–56) 26 (22–33) 78 (65–92) 67 (56–80) 108-mo OS probabilities (95% CI), % 31 (27–35) 20 (16–23) 30 (26–35) 19 (15–23) 35 (27–44) 22 (15–30) mPFS (95% CI), mo 12 (10–16) 12 (10–15) 12 (9–17) 9 (7–11) 13 (10–18) 29 (23–43) 96-mo a PFS probabilities (95% CI), % 23 (18–27) 9 (5–15) 25 (20–31) 9 (4–15) 13 (6–22) 11 (3–27) ORR per IRRC (95% CI); CR, % 39 (35–44); 12 33 (29–37); 3 42 (38–47); 12 27 (23–32); 3 30 (22–38); 13 52 (43–61); 6 mDOR (95% CI), mo 76 (59–NE) 25 (20–33) 83 (54–NE) 20 (16–26) 61 (23–NE) 33 (25–51) 96-mo a DOR probabilities (95% CI), % 48 (39–55) 19 (10–31) 50 (41–58) 23 (13–36) 36 (17–56) NA b a 96-mo probabilities reported due to small numbers of pts at risk at 108 mo. b No pts remain at risk. CR, complete response; DOR, duration of response; m, median; NE, not estimable.

4511 Background: The CM 9ER trial demonstrated increased objective response rate (ORR), progression-free and overall survival in patients with aRCC treated with NIVO+CABO compared to sunitinib (SUN). For vascular modulating therapies (e.g. CABO and SUN) and immunotherapies (like NIVO), the state of the TME and activity of stromal cells can modulate tumor response to therapy. Methods: We investigated how the TME and circulating factors were associated with response to NIVO+CABO using pre-treatment tumor PD-L1 staining, human interpretable features (HIF) derived from H&amp;E tissue sections, circulating immune cell populations quantified by flow cytometry, and circulating extracellular matrix (ECM) markers quantified by competitive ELISAs from 150 patients (23% of ITT) enrolled in CM 9ER. We employed principal component analysis, varimax rotation, and Feature Set Enrichment Analysis (FSEA) to identify a subset of biological measurements capturing 85% of the data variability. We constructed a logistic regression model to associate the most variable features with patient response (ORR per BICR) to NIVO+CABO or SUN therapy. Results: An unbiased clustering and feature extraction approach was used to identify measurements contributing to multi-modal variability in the TME across 150 patients (~4000 biological measurements reduced to 16 highly informative measurements): PD-L1 staining, 4 ECM markers, 4 PBMC markers, and 7 H&amp;E HIF features. A final binary logistic regression model was built employing lasso regularization to associate these 16 features to short-term response to NIVO+CABO or SUN while minimizing spurious associations. Based on these regression models, the ECM marker VICM, a citrullinated fragment of vimentin released by matrix metalloproteases, and which measures macrophage activity and immune status, was prognostic across both therapies. Logistic regression models that integrated highly informatic features had AUCs of 0.76 for NIVO+CABO model and 0.72 for the SUN model. Within the NIVO+CABO arm, this integrative model uncovered high VICM (and therefore anti-tumor macrophage polarization), high PD-L1 staining, high plasma cell numbers and high cancer cell numbers at the epithelial stromal interface, low levels of circulating fragment of C-terminal type VIa3 collagen (Pro-C6), and low percentages of circulating regulatory (Foxp3+ CD4+) T cells as determinants of therapeutic response. Conclusions: Taken together, these findings indicate that the state of the tumor microenvironment and circulating factors together have an effect on patient responsiveness to NIVO+CABO in aRCC and provides a framework for integrative analysis for biomarker discovery.

Mild antiresorptive activity of an anti-vascular endothelial growth factor A antibody and sunitinib in a rat model of bone resorption.

Chemotherapy-induced cognitive impairment, commonly referred to as chemobrain, is a well-documented adverse outcome of anticancer treatments. While the neurotoxicity of doxorubicin (DOX) has been extensively studied, targeted therapies such as sunitinib (SUN) remain largely unexplored concerning this outcome. This study aimed to compare the neurotoxic effects of DOX and SUN in dopaminergic neuronal cells and to explore the involvement of oxidative stress and autophagy as potential mechanisms underlying their cytotoxicity. Human neuronal SH-SY5Y cells were differentiated into a dopaminergic phenotype and exposed to clinically relevant concentrations of DOX (0.1-10 µM) and SUN (1-10 µM) for 24 or 48 h. To investigate the involvement of oxidative stress in their cytotoxicity, redox modulators [N-acetylcysteine (NAC); dimethyl fumarate (DMF); sulforaphane (SFN); and cheirolin (CH)] were tested alongside DOX and SUN for their potential protective effects. The role of autophagy in SUN-induced toxicity was assessed using 3-methyladenine (3-MA; an early-stage inhibitor); chloroquine (CH; a late-stage inhibitor); and rapamycin (RAP; an autophagy inducer). Additionally, LC3-I and LC3-II expression levels were determined. Both DOX and SUN exhibited time- and concentration-dependent cytotoxicity and induced mitochondrial membrane depolarization. NAC conferred partial protection against SUN toxicity but enhanced DOX's cytotoxicity at the lowest concentration tested. DMF and SFN had dual effects, depending on the drug's concentration, while CH exhibited a consistent protective effect towards the cytotoxicity induced by both drugs. Regarding autophagy, 3-MA partially protected against SUN-induced toxicity, whereas CLQ and RAP exacerbated it. LC3-II levels were increased in some conditions, suggesting that SUN-induced toxicity involves autophagy. This study shows that SUN, though less studied in chemobrain, has a cytotoxic profile similar to DOX, which is a known contributor to chemobrain, in SH-SY5Y cells. These findings highlight the need for further research on neuroprotective strategies targeting oxidative stress and autophagy to reduce chemobrain in cancer patients and survivors.

Sunitinib (SU), a multi-targeted tyrosine kinase inhibitor, has anticancer function but its clinical use is often limited by cardiovascular complications. Baicalin (BA) has demonstrated various pharmacological activities including antioxidant, anti-inflammatory and antiviral properties, but its potential roles in SU-induced cardiotoxicity have not been reported. In this study, we aimed to investigate the effect of BA in SU-induced cardiotoxicity in vivo by using renal carcinoma patient-derived xenograft (PDX) model. Female Nod Scid mice with renal carcinoma PDX were treated with vehicle, SU (50mg/kg/d), BA (100mg/kg/d), or BA combined with SU for 6 weeks. The tumor volume and weight of tumor-bearing mice were measured, and cardiovascular functions were evaluated by testing the Heart index and blood biochemical indicators, and by hematoxylin and eosin (H&E), Masson and Tunel staining. The results showed that SU therapy and combination therapy effectively inhibited the growth of renal tumors. Combination therapy inhibited SU-induced increase of creatine kinase (CK) and lactate dehydrogenase (LDH), and ameliorated the heart parameters. Moreover, BA effectively protected SU-induced cardiac dysfunction by decreasing injury, apoptosis, and fibrosis. Collectively, our results demonstrate that BA can be as a potential cardioprotective approach for cardiovascular complications during SU regimen.

The development of novel and effective treatment strategies, particularly through drug combinations, can significantly enhance therapeutic outcomes. This study explores the innovative combination of resveratrol (RES), a phenolic compound, with sunitinib (SUNI), a multitarget tyrosine kinase inhibitor, for targeting human colon adenocarcinoma cell line HT-29. We identified a synergistic effect at a SUNI:RES ratio of 1:8, based on their half-maximal inhibitory concentration values. Increasing the dosage of the combined treatment led to a notable reduction in cell viability, observed in both two-dimensional (2D) and three-dimensional cell cultures. To improve RES therapeutic efficacy, drug-loaded polymeric nanoparticles (PLGA-RES) were successfully fabricated with an average diameter of 178.4 ± 4.6 nm. The combination of PLGA-RES and free SUNI at the optimal ratio exhibited enhanced anticancer activity, reducing cell viability by approximately 25 and 15% more than PLGA-RES and free SUNI alone, respectively, in 2D cultures. Moreover, this combination therapy demonstrated superior effectiveness in treating HT-29 spheroids over 24 and 48 h. These findings highlight the potential of this combined approach to improve colorectal cancer treatment outcomes.

Background/Objectives: Cancer remains one of the leading causes of mortality worldwide. Despite significant advancements in treatment strategies and drug development, survival rates remain low and the adverse effects of conventional therapies severely impact patients' quality of life. This study evaluates the therapeutic potential of plant-derived extracts in hepatocellular carcinoma treatment, with a focus on minimizing side effects while enhancing efficacy. Methods: This research investigates the in vitro synergistic effect of silver bio-nanoparticles synthesized from Clematis vitalba, Melissa officinalis, and Taraxacum officinale extracts (Clematis vitalbae extractum-CVE, Melissae extractum-ME, Taraxaci extractum-TE) in combination with liver cancer drugs, sunitinib (SNTB) and imatinib (IMTB), on HepG2 (human hepatocellular carcinoma) and HUVEC (human umbilical vein endothelial) cell lines. The silver nanoparticles (AgNPs) were characterized using UV-Vis spectroscopy, dynamic light scattering (DLS), zeta potential analysis, and scanning electron microscopy (SEM). The antitumor effects were evaluated through cell viability assays after 24 and 48 h of exposure, with additional cytotoxicity tests on HUVEC cells. Results: Results indicated that Melissa officinalis-derived silver nanoparticles (ME AgNPs) and Clematis vitalba extract with silver nanoparticles (CVE AgNPs) significantly reduced HepG2 cell viability. Their efficacy improved when combined with conventional therapies (SNTB + ME AgNPs 1:1 vs. SNTB: 20.01% vs. 25.73%, p = 0.002; IMTB + ME AgNPs 1:1 vs. IMTB: 17.80% vs. 18.08%, p = 0.036; SNTB + CVE AgNPs 1:1 vs. SNTB: 18.73% vs. 25.73%, p = 0.000; SNTB + CVE AgNPs 1:2 vs. SNTB: 26.62% vs. 41.00%, p = 0.018; IMTB + CVE AgNPs 1:1 vs. IMTB: 12.99% vs. 18.08%, p = 0.001). Taraxacum extract exhibited similar cytotoxicity to its nanoparticle formulation but did not exceed the efficacy of the extract alone at 24 h. Selectivity index assessments confirmed that AgNPs-based formulations significantly improve cytotoxicity and selectivity to HepG2 cells. Among the tested extracts, CVE demonstrated the strongest antitumor effect, enhancing the efficacy of synthetic drugs (CI < 1). SNTB + TE AgNPs (5% EtOH) also demonstrated consistent synergy at high doses, while SNTB + CVE AgNPs provided broad-range synergy, making it suitable for dose-escalation strategies. Conclusions: These findings underscore the potential of nanoparticle-based formulations in combination therapies with targeted kinase inhibitors such as sunitinib and imatinib. Future research should focus on in vivo validation and clinical trials to confirm these findings.

Sunitinib (SUN) is a chemotherapeutic agent showing renal toxicity that limits its clinical applications. The present research aimed to clarify the potential ameliorative effects of secukinumab (SEC) and dapagliflozin (DAPA) against SUN-induced renal toxicity and the underpinning molecular mechanisms. For this purpose, adult Wistar albino rats were received SUN (25 mg/kg 3 times/week, po) and co-treated with SEC (3 mg/kg/every 2 weeks, subcutaneously) or DAPA (10 mg/kg/day, po) for 4 weeks and compared with age-matched control group (CON). Markers of kidney functions were assessed in serum samples. Kidneys were harvested for biochemical and histological examination. Compared to CON group, SUN-treated rats displayed signs of kidney dysfunction along with renal histological changes that were ameliorated by SEC or DAPA. Both drugs significantly lowered the renal levels of IL-17, but SEC exerted more inhibitory effect than DAPA. Additionally, SUN-subjected rats showed significant increases in the renal expression of NLRP3 inflammasome and the other inflammatory mediators including IL-1β, END-1, and MCP-1. This was associated with marked decline of the renal levels of beclin-1. Co-treatment with SEC or DAPA significantly suppressed NLRP3-induced inflammation while enhanced beclin-1-mediated autophagy. The modulatory effect of DAPA on NLRP3 and beclin-1 was superior to that of SEC. Moreover, both drugs significantly and similarly attenuated the enhanced cleaved caspase-3 expression and interstitial fibrosis in renal tissue of SUN-subjected rats. Collectively, these findings may repurpose SEC and DAPA as candidate therapies to alleviate the renal toxicity of SUN and to rescue the renal functionality in SUN-treated cancer cases.

437 Background: CheckMate 214 established nivolumab and ipilimumab (NIVO+IPI) as a first line standard of care regimen with superior survival and durable response versus sunitinib (SUN) in advanced RCC. Previous studies have shown that high levels of circulating KIM-1 are associated with worse prognosis and reduction in KIM-1 levels is associated with benefit from adjuvant immunotherapy. In this post-hoc analysis we evaluated whether KIM-1 levels at baseline and after 1 cycle of NIVO+IPI or SUN are associated with treatment outcomes in CheckMate 214. Methods: Patients with advanced RCC were randomized to NIVO+IPI or SUN as previously described. Serum KIM-1 was measured at baseline and 3 wks after first treatment dose using an enzyme based electrochemiluminescence assay. The association between KIM-1 levels and clinical outcomes was evaluated using Kaplan-Meier and Cox proportional hazards analyses. Results: We analyzed serum from 821 patients (75% of the CM 214 ITT population). Median KIM-1 at baseline was 660.4 pg/mL. Across both arms, higher KIM-1 levels were associated with shorter overall survival (OS) independent of IMDC risk group, nephrectomy status, and tumor burden. Benefit for NIVO+IPI versus SUN was seen across KIM-1 tertiles. Decrease in KIM-1 from baseline to C2D1 was strongly associated with progression free survival (PFS) and OS among patients treated with NIVO+IPI (Median PFS 70.8 months vs 4.2 months for patients with &gt;30% decrease vs &gt;30% increase in KIM-1, with median OS 85.4 vs 26.6 months, overall response rate (ORR) 69.3 % vs 13.9%), but not in patients treated with SUN. Conclusions: In CheckMate 214, increased levels of baseline circulating KIM-1 were associated with worse clinical outcomes both in NIVO+IPI and SUN arms. The extent of reduction in serum KIM-1 just 3 wks after single cycle of NIVO+IPI was associated with long term efficacy of this IO doublet. Circulating KIM-1 may be a useful minimally invasive biomarker for monitoring patients on RCC immunotherapy. KIM-1 change at 3 weeks (prior to second dose of NIVO+IPI) and association with outcomes (NIVO+IPI arm). 3 week KIM-1 change N (%) ORR, % (95% CI) mPFS, months (95% CI) mOS, months (95% CI) &gt;30% Decrease 140 (31.7) 69.29 (60.94-76.80) 70.80 (17.84- NA) 85.36 (63.08- NA) &gt;10-30% Decrease 87 (19.7) 36.78 (26.69-47.80) 11.43 (6.28-18.20) 66.14 (40.44-80.10) &lt;10% Change 86 (19.5) 30.23 (20.79-41.08) 15.41 (10.32-20.73) 52.70 (30.26-70.67) &gt;10-30% Increase 56 (12.7) 23.21 (12.98-36.42) 7.13 (4.17-16.79) 40.34 (23.82-58.41) &gt;30% Increase 72 (16.3) 13.89 (6.87-24.06) 4.17 (3.02-8.08) 26.61 (18.79-38.44)

523 Background: Tyrosine kinase (TKI) and immune checkpoint inhibitors (CPI) are first-line options in metastatic renal cell carcinoma (mRCC). Most patients (pts) experience adverse events (AE) and 20-30% discontinue therapies due to AEs. We tested whether proactive onco-coaching (POC) improved quality of life (QoL) in patients with medical treatment. Methods: Adult treatment-naïve mRCC pts who were candidates for sunitinib (SU), axitinib + avelumab (AA) or axitinib + pembrolizumab (AP) were eligible. Treatment and modifications were at the physician's discretion. Pts were 1:1 randomized to POC by a trained nurse (8 visits of structured interviews educating on preventive, preemptive and supportive measures, and phone call follow-up for a total of 24 wks) or standard of care (SOC). Primary endpoint was the fraction of pts with QoL improvement (QOLI) by ≥3 points (minimal important difference: MID) of the FKSI-15 score. Secondary endpoints consisted of patient reported outcomes (PRO: FACT-G, EQ-5D), time to QOLI, efficacy, survival and safety (CTCTAE 4.03). The planned sample size was 430 pts. Log rank analyses were employed for time to event endpoints and Fisher exact tests for categorical data. Results: Between 2016 and 2023, 113 pts were included. Median age was 72 and 68y (POC vs. SOC). 44% had a Charlson Comorbidity Index (CCI) ≥2. MSKCC good/intermediate/poor risk were 21/61/12%. 86% had clear cell histology. Of 110 treated patients, 39% and 61% received SU or AXI-CPI (AA or AP). FKSI-15-completion rate was 85%. 80 pts (73%) had ≥2 PRO assessments and were evaluable for the primary endpoint. There was no difference in QOLI between POC and SOC (43.6% vs. 41.5%; p=0.95). Mean baseline FKSI-15 score was similar between arms, as were ORR (38.2 [95% CI 25.4-52.3] vs. 34.5% [95% CI 22.2-48.6]; p=0.96) and PFS (11.1 [95% CI 8.3- 18.9] vs. 9.2 mo [95% CI 5.6-14.6]; p=0.21). Overall survival was favored by POC (median 49.6 [95% CI 30.6- 61.6] vs. 25.4 mo [95% CI 17.8-NC]; p=0.11). Stratification by CCI had no relevant effect on OS in the POC arm (p=0.26), while pts. with CCI ≥2 had poorest OS in the SOC arm (15.7 vs. 33.4 mo; p=0.002). Treatment related AEs of any or ≥3 grade affected 96.4% and 52.7% with POC and 85.5% and 36.4% with SOC. Discontinuation due to toxicity between POC vs. SOC occurred for TKI in 7.3 vs. 9.1% and for CPI in 18.2 vs. 5.5% pts. Conclusions: Target patient accrual was not reached, and POC did not improve the rate of QoL responders or treatment efficacy. However, there was a trend towards a considerable extension of OS in the POC group, suggesting an overall beneficial impact of proactive coaching compared to standard reactive therapy management. Comorbid patients putatively benefit most from pro-active coaching, which warrants further studies. Clinical trial information: NCT03013946 .

Background: Sunitinib (SU) is used to treat kidney cancer. However, it can also cause cardiotoxicity. This study is performed to investigate whether rivaroxaban (RIV) attenuates SU-induced cardiotoxicity (SIC).Methods and Materials: AC16 cells and primary cardiomyocytes of neonatal mouse were treated with different concentrations (2–10 μM) of SU for 24 h or with 6 μM SU and 10 μg/mL RIV for 24 h. The viability of cardiomyocytes was evaluated using the cell counting kit-8 (CCK-8) assay, and the apoptosis rate was evaluated using flow cytometry. The activity of caspase-3 was determined. The levels of malondialdehyde (MDA), glutathione (GSH), and superoxide dismutase (SOD) were also measured. The potential targets and downstream pathways of RIV in SIC treatment were investigated using network pharmacology, molecular docking, and molecular dynamics simulation. qPCR and western blotting were used to detect the regulatory effects of SU and RIV on mRNA and protein expression of MAPK pathway-related genes, respectively.Results: RIV treatment alleviated SU-induced cardiomyocyte injury by promoting viability and inhibiting apoptosis, oxidative stress, and the inflammatory response in AC16 cells and primary cardiomyocytes. Caspase 3 (CASP3), signal transducer and activator of transcription 3 (STAT3), SRC proto-oncogene, nonreceptor tyrosine kinase (SRC), ATP-binding cassette subfamily G member 2 (ABCG2), and ATP-binding cassette subfamily B member 1 (ABCB1) were candidate targets of RIV in SIC. The binding affinities between RIV and CASP3, STAT3, SRC, ABCG2, and ABCB1 were all less than −7.5 kcal/mol, indicating that RIV could bind stably to these targets. Bioinformatics analyses suggested that the mitogen-activated protein kinase (MAPK) pathway was involved in the mechanism by which RIV alleviated SIC. RIV treatment decreased the mRNA expression of CASP3 and increased the mRNA expression of STAT3, SRC, ABCG2, and ABCB1 in AC16 cells and primary cardiomyocytes. RIV also inhibited the SU-induced activation of the MAPK pathway.Conclusion: RIV exerts a protective effect against SU-induced cardiomyocyte injury by inhibiting the MAPK signaling pathway. RIV therapy may be a promising strategy to inhibit SU's cardiotoxicity in cancer patients.

P183 Nivolumab Plus Ipilimumab (NIVO+IPI) vs Sunitinib (SUN) for first-line treatment of advanced Renal Cell Carcinoma (aRCC): Efficacy across number of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk factors with 8-year follow-up from the phase 3 CheckMate 214 trial

TPS97 Background: Gastrointestinal stromal tumor (GIST) is soft-tissue sarcoma of the gastrointestinal tract. Most GISTs harbor mutations in KIT or PDGFRA, recognized as key drivers of GIST development and progression. Imatinib (IM), which inhibits KIT/PDGFRA tyrosine kinase, exerts significant clinical activity in GIST, but most GISTs develop resistance to IM, mainly due to secondary kinase-domain mutations in KIT. Therefore, standard therapies for patients (pts) with IM-refractory GIST have room for improvement. Heat shock protein 90 (HSP90) is one of the molecular chaperones. Many of HSP90's client proteins, such as KIT, PDGFRA, and BRAF, have been identified as cancer-related proteins required for tumor development, and their activation, especially in mutant forms, is dependent on HSP90.Therefore, HSP90 inhibitors have a potential to overcome IM-resistance. Pimitespib (PIMI) is a novel HSP90 inhibitor, approved in Japan for pts with fourth line GIST based on the results of the phase 3 study (CHAPTER-GIST-301). We reported at ESMO 2023 (1917MO) that PIMI effectively inhibited tumor growth in an IM-resistant xenograft model, and further enhanced the anti-tumor activity when given with IM, and that PIMI + IM was well tolerated with no dose-limiting toxicity and suggested preliminary efficacy in pts resistant to IM in a dose-escalation part (DEP) of CHAPTER-GIST-101 study. Methods: The CHAPTER-GIST-101 study (NCT05245968) is a global phase 1 study in pts with IM-refractory advanced GIST in the second-line setting, consisting of three parts: the DEP, its expansion part (ExP), and another DEP for Chinese pts. The DEP used a 3+3 design to determine the maximum tolerated dose of PIMI (120 mg/day or 160 mg/day, orally, on 5 days on/2 days off) in combination with IM (400 mg/day once daily) and the ExP is for the efficacy and safety with determined dose of 120 mg/day PIMI + IM. The ExP is a global, open-label, randomized, part evaluating the efficacy and safety of PIMI in combination with IM, PIMI monotherapy, and standard therapy sunitinib (SU) in each arm of 20 pts. Pts are randomized 1:1:1 to receive either PIMI 120 mg on 5 days on/2 days off with IM 400 mg once daily, PIMI 160 mg on 5 days on/2 days off followed by IM 400 mg once daily after discontinuation of PIMI, or SU 50 mg on 4 weeks on/2 weeks off. The primary endpoint is progression-free survival (PFS) by the independent radiological review. The secondary endpoints include investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, PK and safety. Exploratory pharmacogenomics analysis is also planned. After the DLT evaluation for the DEP, enrollment for the ExP began in March 2023 in Japan, Singapore, Taiwan and Australia, and for the DEP for Chinese pts is also ongoing in China to evaluate tolerability and efficacy of this combination. Clinical trial information: NCT05245968 .

Asophisticated electrochemical sensoris presented employing a glassy carbon electrode (GCE) modified with a novel composite of synthesized graphitic carbon nitride (g-C3N4) and CoNiO2 bimetallic oxide nanoparticles (g-C3N4/CoNiO2). The sensor's electrocatalytic capabilities for Sunitinib (SUNI) oxidation were demonstratedexceptional performance with a calculated detection limit (LOD) of 52.0nM. The successful synthesis and integrity of the composite were confirmed through meticulous characterization using various techniques. FT-IR analysis affirmed the successful synthesis of g-C3N4/CoNiO2 by providing insights into its molecular structure. XRD, FE-SEM, SEM-EDX, and BET analyses collectively validated the material's structural integrity, surface morphology, and electrocatalytic performance. Optimization of key analytical parameters, such as loading volume, concentration, electrolyte solution type, and pH, enhanced the electrocatalytic sensing capabilities of g-C3N4/CoNiO2. The synergistic interaction between g-C3N4 and CoNiO2 bimetallic oxide nanoparticles executed the sensor highly effective in the electrical oxidation of SUNI. Across a concentration range of 0.1-83.8µMSUNI, the anodic peak current exhibited a linear increasewith good precision. Application of the newly developed g-C3N4/CoNiO2 system to detect SUNI in a variety of samples, including urine, human serum, and capsule dosage forms, obtained satisfactory recoveries ranging from 97.1 to 103.0%. This methodology offers a novel approach to underscore the potential of the developed sensor for applications in biological and pharmaceutical monitoring.