Vascular Endothelial Growth Factor Receptor Research Articles

Targeted therapy and immunotherapy for gastric cancer: rational strategies, novel advancements, challenges, and future perspectives

Gastric cancer (GC) is one of the most common malignant tumors worldwide, and its treatment has been a focus of medical research. Herein we systematically review the current status of and advancements in targeted therapy and immunotherapy for GC, which have emerged as important treatment strategies in recent years with great potential, and summarize the efficacy and safety of such treatments. Targeted therapies against key targets in GC, including epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR), have shown remarkable therapeutic efficacies by inhibiting tumor progression and/or blood supply. In particular, markable breakthroughs have been made in HER2-targeting drugs for HER2-positive GC patients. To address intrinsic and acquired resistances to HER2-targeting drugs, novel therapeutic agents including bispecific antibodies and antibody–drug conjugates (ADC) targeting HER2 have been developed. Immunotherapy enhances the recognition and elimination of cancer cells by activating body anticancer immune system. Programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies are the most commonly used immunotherapeutic agents and have been used with some success in GC treatment. Innovative immunotherapy modalities, including adoptive immune cell therapy, tumor vaccines, and non-specific immunomodulators therapy, and oncolytic viruses have shown promise in early-stage clinical trials for GC. Clinical trials have supported that targeted therapy and immunotherapy can significantly improve the survival and quality of life of GC patients. However, the effects of such therapies need to be further improved and more personalized, with advancement in researches on tumor immune microenvironment. Further studies remain needed to address the issues of drug resistance and adverse events pertaining to such therapies for GC. The combined application of such therapies and individualized treatment strategies should be further explored with novel drugs developed, to provide more effective treatments for GC patients.

Clioquinol inhibits angiogenesis by promoting VEGFR2 degradation and synergizes with AKT inhibition to suppress triple-negative breast cancer vascularization

Inhibition of angiogenesis, either as monotherapy or in conjunction with other treatments, holds significant promise in cancer treatment. However, the limited efficacy of clinically approved anti-angiogenic agents underscores the urgent need for the development of novel drugs and therapeutic strategies. In this study, we demonstrate the highly selective inhibitory effects of clioquinol, a topical antifungal and antibiotic agent, on the angiogenic activity of endothelial cells (ECs) in a series of in vitro angiogenesis assays. Moreover, clioquinol effectively suppressed blood vessel formation in ex vivo aortic ring and in vivo Matrigel plug assays. Mechanistic studies revealed that clioquinol directly binds to the ATP-binding site of vascular endothelial growth factor receptor 2 (VEGFR2), promoting its degradation through both proteasome and lysosome pathways. This led to the down-regulation of the downstream extracellular signal-regulated kinase (ERK) pathway. In addition, the combination with the AKT inhibitor MK-2206 synergistically boosted the anti-angiogenic efficacy of clioquinol in vitro and in an in vivo dorsal skinfold chamber model of triple-negative breast cancer (TNBC), leading to the suppression of TNBC growth. Accordingly, clioquinol, either alone or in combination with AKT inhibitors, represents a promising therapeutic agent for future anti-angiogenic cancer treatment.

In vitro and in vivo evaluation of the cyclophosphamide effect along with oncolytic Newcastle disease virus (NDV): An animal preclinical research

AbstractBackgroundBreast cancer is a major cause of mortality globally. Oncolytic virotherapy is a promising treatment modality that directly destroys cancer cells and induces an immune response against them. Among natural oncolytic viruses, Newcastle disease virus (NDV) has shown selective tumor cell infection.Materials and methodsIn this study, we investigated the efficacy of variable doses of NDV and cyclophosphamide on 4T1 cancer cell line and BALB/c mouse tumors for the first time.ResultsCompared with the control group, the combination treatment group with NDV and cyclophosphamide showed a significant increase in the expression levels of P21, P27, and P53 genes by 38%, 46%, and 81%, respectively (p < 0.05). In contrast, the expression levels of CD34, integrin α5, vascular endothelial growth factor (VEGF), and vascular endothelial growth factor receptor (VEGFR) genes significantly decreased by 47%, 45%, 42%, and 23%, respectively (p < 0.05). The reactive oxygen species (ROS) generation assay evaluated with 2′,7′‐dichlorodihydrofluorescein diacetate (DCFH‐DA) staining showed a significant increase in ROS levels within 4T1 cells treated with NDV compared with the untreated group after 24 h (p < 0.01). Furthermore, Annexin V/propidium iodide (PI) double staining analysis showed that the proportion of apoptotic cells in the NDV‐treated group decreased by 0.61% and 1.63% after 6 h and 12 h, respectively (p < 0.05). After 12 days, tumor volume in the NDV‐treated groups decreased by 72%−87% compared with a 48% increase in the control group, reflecting a net reduction in tumor volume relative to the control group (p < 0.001).ConclusionThese findings demonstrate that NDV in combination with chemotherapy drugs may be a promising therapeutic option for cancer patients. However, several other factors need to be considered. These results indicate that NDV may have potential effects on cancer treatment.

Discovery of Novel Pyrimidine Based Small Molecule Inhibitors as VEGFR-2 Inhibitors: Design, Synthesis, and Anti-cancer Studies.

Receptor tyrosine kinases (RTKs) are potent oncoproteins in cancer that, when mutated or overexpressed, can cause uncontrolled growth of cells, angiogenesis, and metastasis, making them significant targets for cancer treatment. Vascular endothelial growth factor receptor 2 (VEGFR2), is a tyrosine kinase receptor that is produced in endothelial cells and is the most crucial regulator of angiogenic factors involved in tumor angiogenesis. So, a series of new substituted N-(4-((2-aminopyrimidin-5-yl)oxy)phenyl)-N-phenyl cyclopropane- 1,1-dicarboxamide derivatives as VEGFR-2 inhibitors have been designed and synthesized. Utilizing H-NMR, C13-NMR, and mass spectroscopy, the proposed derivatives were produced and assessed. HT-29 and COLO-205 cell lines were used for the cytotoxicity tests. The effective compound was investigated further for the Vegfr-2 kinase inhibition assay, cell cycle arrest, and apoptosis. A molecular docking examination was also carried out with the Maestro-12.5v of Schrodinger. In comparison to the reference drug Cabozantinib (IC50 = 9.10 and 10.66 μM), compound SP2 revealed promising cytotoxic activity (IC50 = 4.07 and 4.98 μM) against HT-29 and COLO-205, respectively. The synthesized compound SP2 showed VEGFR-2 kinase inhibition activity with (IC50 = 6.82 μM) against the reference drug, Cabozantinib (IC50 = 0.045 μM). Moreover, compound SP2 strongly induced apoptosis by arresting the cell cycle in the G1 phase. The new compounds' potent VEGFR-2 inhibitory effect was noted with key amino acids Asp1044, and Glu883, and the hydrophobic interaction was also observed in the pocket of the VEGFR-2 active site by using a docking study. The results demonstrate that at the cellular and enzyme levels, the synthetic compounds SP2 are similarly effective as cabozantinib. The cell cycle and apoptosis data demonstrate the effectiveness of the suggested compounds. Based on the findings of docking studies, cytotoxic effects, in vitro VEGFR-2 inhibition, apoptosis, and cell cycle arrest, this research has given us identical or more effective VEGFR-2 inhibitors.

Vascular endothelial growth factor receptor (VEGFR) -tyrosine kinase inhibitors combined with programmed death receptor-1 (PD-1) inhibitors as third- or later-line treatment in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): A retrospective study.

68 Background: Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) shows a low response to programmed death receptor-1 (PD-1) inhibitors. Recent studies suggest that combining vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs) with PD-1 inhibitors may enhance the anti-cancer activity for mCRC patients. Multiple antiangiogenic drugs have been approved by the FDA and NMPA for the treatment of later-line mCRC. Nevertheless, the effects of various anti-angiogenic drugs when used in combination with immunotherapy for mCRC treatment is not yet fully established. Methods: We conducted a non-interventional, retrospective study. Data were compiled from patients with mCRC at Shandong Cancer Hospital. Eligible patients must have received a combination of anti-angiogenic drugs and PD-1 inhibitors following at least two lines of standard treatment. The treatment period spanned from August 2019 to April 2024. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Results: At the cut-off date (April 29th, 2024), 79 eligible patients were available for analysis. Of these, 49 patients received fruquintinib in combination with PD-1 inhibitors (F group), 30 patients received investigator-selected other anti-angiogenic agents in combination with PD-1 inhibitors (NF group). The baseline characteristics of the two groups were well balanced. The median overall survival (OS) was significantly longer in the F group compared to the NF group (hazard ratio [HR]: 0.36, 95% CI 0.14-0.96, P=0.042). The median OS was not reached (95% CI 21.1-NA) in the F group, whereas it was 19.1 months (95% CI 12.6-NA) in the NF group. Subgroup analyses of OS were generally consistent with benefit in the whole population across nearly all subgroups. In contrast to NF group, individuals in F group demonstrated a significant enhancement in overall survival (OS) when patients had received prior bevacizumab (HR: 0.26, 95% CI 0.07-0.75, P=0.015), had no prior treatment with cetuximab (HR: 0.23, 95% CI 0.26-0.97, P=0.045), or had experienced surgical resection at baseline (HR: 0.34, 95% CI 0.12-0.95, P=0.041). The median PFS between two groups showed no statistically significant difference (HR: 0.65, 95% CI 0.38-1.13, P=0.127), F group 6.1 months (95% CI 4.6-10.3) versus NF group 4.4 months (95% CI, 3.0-7.5). Conclusions: Fruquintinib demonstrated improved OS over other anti-angiogenic agents when combined with immunotherapy for third or later-line MSS mCRC treatment.

Meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of hemorrhage and venous thromboembolism (VTE) events in patients with gastrointestinal (GI) cancers treated with fruquintinib.

118 Background: Fruquintinib is a novel cancer therapy that was recently approved by the US FDA as a third-line treatment for metastatic colorectal cancer (mCRC). It works by inhibiting the vascular endothelial growth factor receptors, that leads to blocking of angiogenesis which is essential for the tumor proliferation. Close monitoring is always crucial in order to promptly detect and manage any adverse events. This study aims to assess the risk of hemorrhagic and VTE events in patients with GI cancers treated with fruquintinib. Methods: A comprehensive literature search was conducted using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers reporting hemorrhage or VTE events as an adverse event were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients were included. Data were pooled from three phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one phase II RCT, all reporting VTE events including deep vein thrombosis and pulmonary embolism and hemorrhage. FRESCO, FRESCO-2, and the phase II trials involved patients with mCRC, comparing fruquintinib to placebo. FRUTIGA trial incorporated patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. High-grade hemorrhage incidence was higher in the fruquintinib arm compared to the control arm (29.00% vs 21.18%, RR 1.62; 95% CI: 1.26-2.08, P=0.0001). In the mCRC subgroup, high-grade hemorrhage rate was also higher and statistically significant in the fruquintinib arm 20.87% vs 11.22% (RR 1.84; 95% CI: 1.25-2.70; P=0.002). Incidence of any grade or high grade VTE events was neither statistically significant in GI cancer population or mCRC subgroup. Incidence of any grade VTE events in GI cancer group and mCRC subgroup was 2.74% vs 2.15% (RR, 1.23; 95% CI: 0.53-2.88; P=0.63) and 2.68% vs 1.53% (RR, 0.95; 95% CI: 0.09-9.67; P=0.97), respectively. Rate of high grade VTE events in GI cancer cohort was 1.67% vs 0.67% (RR, 1.96; 95% CI: 0.52-7.36; P=0.32), while in mCRC subgroup was 1.79% vs 0.76% (RR, 1.08; 95% CI: 0.06-19.98; P=0.96). Conclusions: This meta-analysis demonstrates that patients with GI cancers, including mCRC, treated with fruquintinib have higher incidence of high-grade hemorrhage. These findings underscore the importance of individualized risk assessment, especially for patients predisposed to hemorrhagic complications. No increased risk of VTE events was noted in patients treated with fruquintinib compared to placebo.

Meta-analysis of phase II/III randomized controlled trials (RCTs) to determine the incidence of hypertension and proteinuria in patients with gastrointestinal (GI) cancers treated with fruquintinib.

119 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors which impedes angiogenesis associated with tumor growth. On November 8th, 2023, the US FDA approved fruquintinib for use as a third-line treatment for metastatic colorectal cancer (mCRC). With the introduction of novel cancer therapies, monitoring for adverse events is critical. This meta-analysis aims to assess the risk of hypertension (HTN) and proteinuria in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive search of MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024, identifying Phase II/III RCTs that employed fruquintinib in GI cancers and reported HTN and proteinuria as adverse effects. The Mantel-Haenszel method was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Heterogeneity was assessed using Cochran’s Q-statistic, and a random effects model was applied. Results: Our analysis included 1872 patients, 1131 (60%) of whom received fruquintinib, from three Phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one Phase II RCT. FRESCO, FRESCO-2, and the phase II trials compared fruquintinib to placebo in patients with mCRC. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. The incidence of any-grade HTN was higher in the fruquintinib group, 34.92% vs 7.55% (RR 3.96; 95% CI: 3.05-5.13; P<0.00001); the rate of high-grade HTN was 13.96% vs 1.21% (RR 9.01; 95% CI: 4.67-17.40; P<0.00001). In the mCRC subgroup, incidence of any-grade and high-grade HTN was 43.02% vs 10.45% (RR 3.97; 95% CI: 2.95-5.33; P<0.00001), and 17.28% vs. 1.27% (RR 12.06; 95% CI: 5.19-28.01; P<0.00001), respectively. Incidence of any-grade proteinuria was also found to be statistically significant and higher in the fruquintinib arm in both GI cancer cohort and mCRC subgroup: 27.3% vs 16.19% (RR 1.89; 95% CI: 1.30-2.74; P=0.0008), and 25.22% vs 11.73% (RR 2.29; 95% CI: 1.17-4.51; P=0.02). The rate of high-grade proteinuria was not statistically significant in both cohorts. In GI cancer group, 1.85% vs 0.53% (RR, 2.49; 95% CI: 0.86-7.16; P=0.09), and mCRC subgroup 2.17% vs 0.51% (RR, 2.87; 95% CI: 0.74-11.12; P=0.13). Conclusions: This meta-analysis revealed a higher incidence of any-grade and high-grade HTN with fruquintinib in GI cancer patients, with significant association in the mCRC subgroup. Fruquintinib was also noted to be associated with increased risk of any-grade proteinuria, however, incidence of high-grade proteinuria was not different in patients treated with fruquintinib compared to placebo. Prompt identification and early management of these adverse events are crucial.

Overall survival with fruquintinib versus placebo after adjusting for subsequent anticancer therapy in patients with refractory metastatic colorectal cancer in the FRESCO-2 study.

171 Background: Fruquintinib is a highly selective, oral inhibitor of all 3 vascular endothelial growth factor receptors (VEGFRs -1, -2, and -3) that is approved by the US FDA and in the EU, UK, and Japan for previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. The phase 3 FRESCO-2 study (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival with fruquintinib + best supportive care (BSC) vs placebo + BSC. As patients may have received subsequent anticancer therapy after progression, understanding the impact on overall survival is important. This analysis examined overall survival data from FRESCO-2 after adjusting for subsequent anticancer therapy. Methods: In FRESCO-2, patients were randomized 2:1 to receive fruquintinib (5 mg) or matching placebo by mouth, once daily, 3 weeks on, 1 week off, + BSC. Eligible patients had received prior chemotherapy, anti-VEGF therapy, anti-EGFR therapies (if indicated), and TAS-102 and/or regorafenib. We assessed the impact of subsequent anticancer therapy on overall survival by excluding patients who received subsequent therapies, censoring these patients, and determining the causal hazard ratio using inverse probability of censoring weights (IPCW) and marginal structural models (MSM) to adjust for the potential bias introduced by subsequent treatments. Results: In FRESCO-2, a lower proportion of patients in the fruquintinib vs placebo arm received subsequent anticancer therapy (29.4% vs 34.3%). Among these patients, the most common subsequent anticancer therapies in the fruquintinib vs placebo arms were fluorouracil (7.7% vs 9.6%) and regorafenib (7.5% vs 7.8%). The overall survival benefit seen with fruquintinib vs placebo in the intent-to-treat population (hazard ratio [HR]: 0.66; 95% confidence intervals [CI]: 0.55–0.80) was improved when patients who had received subsequent anticancer therapy were excluded (HR: 0.45; 95% CI: 0.36–0.57) or censored (HR: 0.63; 95% CI: 0.50–0.79). In addition, the overall survival benefit seen with fruquintinib vs placebo was improved after adjusting for subsequent anticancer therapy using IPCW (HR: 0.43; 95% CI: 0.33–0.55) and MSM (HR: 0.48; 95% CI: 0.38–0.60). Patients receiving fruquintinib had similar rates of grade ≥3 adverse events, whether or not they received subsequent anticancer therapy (51.5% and 67.4%, respectively). Conclusions: Consistent with the primary analysis of the FRESCO-2 intent-to-treat population, fruquintinib improved overall survival vs placebo after adjusting for the impact of subsequent anticancer therapy. Furthermore, these analyses are robust with consistent results reported using IPCW and MSM. These findings support fruquintinib as a new treatment option for patients with previously treated mCRC. Clinical trial information: NCT04322539 .

Efficacy and safety of fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

166 Background: Maintenance therapy with bevacizumab (Bev) plus capecitabine (Cap) is widely recommended to unresectable mCRC patients (pts). Fruquintinib (Fru) is a highly selective TKI that inhibits vascular endothelial growth factor receptor (VEGFR)-1,2,3. This study is to compare the therapeutic potential of alternating treatment with fruquintinib and bevacizumab plus capecitabine as maintenance therapy for mCRC (NCT05659290). Methods: Eligible mCRC pts aged 18-75 years with stable disease or better after induction treatment with chemotherapy in combination with Bev, ECOG PS 0-2, adequate bone marrow, liver, and renal function were enrolled. Forty patients were included (20 in phase IIa, 40 in phase IIb). In phase IIa, pts were orally administered with Fru (5 mg, qd, d1-14, q3w) alternating with Bev (7.5 mg/kg, iv.gtt, d1, q3w) plus Cap (850 mg/m 2 , orally, twice daily, d1-14, q3w). In phase IIb, pts were randomly assigned (1:1) to either maintenance treatment with Fru alternating with Bev plus Cap or Bev plus Cap. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR) and safety. Results: At cutoff date of Sep 5, 2024, In phase IIa, 20 pts (14 males and 6 females) were enrolled with the median age was 59.0 years (range 27-75), ECOG PS 1 (95.0%), liver metastasis (55.0%), left-sided colon and rectal primary (70.0%). 11 pts had received at least one tumor assessment. the DCR was 100.0% (11/11) and the mPFS was immature, but 4 pts showed the PFS of ≥ 8 months (8.3, 8.6, 9.2, 13.4 m, respectively). The most common treatment-emergent adverse events (TEAEs) were proteinuria (60.0%), hypoalbuminemia (40.0%), hypertension (35.0%); The most common grade ≥ 3 adverse events were hypertension (10.0%), proteinuria (5.0%), and platelet count decreased (5.0%). After fully considering about patient′s tolerance and safety, the phase IIb of Fru was adjusted from 5mg to 3mg, these results provided further evidence that 3mg can ensure the safety and tolerance. Conclusions: Fruquintinib alternating with bevacizumab plus capecitabine as maintenance therapy after first-line treatment in mCRC showed preliminary anti-tumor activity and manageable toxicity. The phase IIb is ongoing and warrants further exploration in mCRC. Clinical trial information: NCT05659290 .

Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line treatment in patients with RAS-mutant metastatic colorectal cancer (mCRC): A multicenter, open-label, phase II study.

151 Background: Anti-angiogenic drugs combined with chemotherapy could bring good clinical benefit to patients (pts) with mCRC, but the efficacy in pts with RAS mutant mCRC was limited. Fruquintinib is a highly selective oral inhibitor of vascular endothelial growth factor receptors (VEGFRs -1, -2, and -3) and was approved for previously treated mCRC. Our study was to explore the efficacy and safety of fruquintinib combined with FOLFIRI/mFOLFOX6 in the second line treatment of RAS-mutant mCRC (NCT05634590). Methods: Eligible pts with histologically confirmed RAS-mutant mCRC who had received first-line standard chemotherapy regimens were included in the study, and pts received Fru (4 mg, p.o. qd, 3 weeks on/1 week off, q4w) plus FOLFIRI/mFOLFOX6 (d1-15, q4w) until disease progression, unacceptable toxicities, or withdrew consent. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), overall survival (OS)and safety. Results: As of Aug 30, 2024, 25 eligible pts were enrolled and received at least one time treatment. Baseline characteristics included median age (66.0 [range: 35-73]), female/male (56.0% / 44.0%), ECOG PS 1(68.0%), left-sided and right-sided colon (72.0% / 28.0%), liver metastasis (64.0%), prior anti-VEGF therapies (76.0%). 14 pts had received at least one tumor assessment. Five pts achieved partial response (PR), 9 pts achieved stable disease (SD), and the ORR was 35.7% (5/14) (95% confidence interval [CI]: 12.8-64.9), the DCR was 100.0% (14/14) (95% CI: 76.8-100.0). Compared to liver metastases, the ORR was higher without liver metastases (42.9% [95%CI 9.9-81.6]). The median PFS was 6.41 months (95% CI: 6.37 - NA), and median OS was not reached yet. In the subgroup analysis, Median PFS was also longer without liver metastases pts than with liver metastases (8.84 mo vs 6.41 mo; HR=1.230; 95%CI 0.2462-6.148; p=0.7775). Additionally, Grade ≥3 treatment-emergent adverse events (TEAEs) included platelet count decreased (18.2%), hypertension (9.1%) and neutrophil count decreased (9.1%). Conclusions: Fruquintinib combined with FOLFIRI/mFOLFOX6 as second-line in patients with RAS-mutant mCRC achieved a promising clinical benefit, with a manageable safety profile. This trial is ongoing and more updated clinical data will be presented in the future. Clinical trial information: NCT05634590 .

Meta-analysis of phase II/III randomized controlled trials (RCTs) to evaluate the incidence of hand-foot skin reaction (HFSR) or palmar-plantar erythrodysesthesia (PPE) syndrome in patients with gastrointestinal (GI) cancers treated with fruquintinib.

117 Background: Fruquintinib is a selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3 blocks the angiogenesis associated with tumor proliferation. Recently, the US FDA approved fruquintinib as a third-line treatment for metastatic colorectal cancer (mCRC). As with any other novel cancer therapies, adverse events are always a concern and all patients should be monitored in order to early detect and appropriately treat any adverse events. This meta-analysis aims to assess the risk of HFSR or PPE syndrome in patients with GI cancers treated with fruquintinib. Methods: We conducted a comprehensive literature search using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers mentioning HFSR or PPE as an adverse effect were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients, of whom 1131 (60%) received fruquintinib, from 3 phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and 1 phase II RCT were eligible for evaluation of HFSR or PPE incidence. FRESCO, FRESCO-2, and phase II trials involved patients with mCRC, they compared fruquintinib vs placebo. FRUTIGA trial involved patients with gastric or gastroesophageal junction adenocarcinoma, it compared fruquintinib + paclitaxel vs placebo + paclitaxel. The incidence of any-grade and high-grade HFSR or PPE was higher in the fruquintinib group compared to the placebo group, 27.93% vs 3.64% (RR, 7.64; 95% CI: 4.08-14.33; P<0.00001), and 8.5% vs 0% (RR, 26.0; 95% CI: 6.42-105.29; P<0.00001), respectively. In the mCRC subgroup analysis, the higher incidence of any-grade and high-grade HFSR or PPE in the fruquintinib arm was also statistically significant, 29.70% vs 2.55% (RR, 10.27; 95% CI: 5.59-18.88; P<0.00001), and 8.45% vs 0% (RR, 19.34; 95% CI: 3.84-97.36; P=0.0003), respectively. Conclusions: This meta-analysis revealed increased incidence of any-grade and high-grade HFSR or PPE in patients with GI cancers including mCRC treated with fruquintinib. In the FRESCO trial, this association was also shown to confer survival benefit in Chinese patients with mCRC. Prompt identification and providing proper supportive care is crucial in managing this adverse event and ultimately, preserving the patients’ quality of life.

Fruquintinib plus best supportive care for patients with metastatic colorectal cancer: Characterization of patients who had an overall survival of ≥10 months in the FRESCO-2 study.

142 Background: Fruquintinib (F) is a highly selective, oral tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors (VEGFRs -1, -2, -3) that is approved by the US FDA and in the EU, UK, and Japan for previously treated metastatic colorectal cancer (mCRC), regardless of biomarker status. FRESCO-2 (NCT04322539) met its primary endpoint demonstrating significantly improved overall survival (OS) with F + best supportive care (BSC) vs placebo (P) + BSC. This subgroup analysis assessed landmark survival of all FRESCO-2 patients (pts), and baseline (BL) characteristics and safety data of pts treated with F who had OS ≥10 months (mos) compared with the intent-to-treat (ITT) population (pop). Methods: Pts were randomized 2:1 to receive F 5 mg or matching P, by mouth, once daily, 3 weeks on, 1 week off, + BSC. Pts had received prior chemotherapy, anti-VEGF therapy and, if RAS wild type, anti-EGFR therapy; and had prior exposure to trifluridine/tipiracil (TAS-102) and/or regorafenib. The hazard ratio (HR) between the two treatment arms was calculated from a stratified Cox proportional hazard model with treatment group as the only covariate in the model. Results: In the ITT pop, OS was improved with F vs P (HR 0.66); OS rates (95% confidence intervals [CIs]) at 6 and 9 mos were 60.4% (55.9–64.9) vs 41.5% (35.0–48.0) and 41.1% (36.4–45.8) vs 28.2% (22.1–34.3), respectively. Progression-free survival (PFS) rates (95% CIs) at 6 and 9 mos were 23.8% (19.7–28.0) vs 1.1% (0–2.6) and 11.3% (8.1–14.6) vs 0.5% (0–1.6), respectively. Of 461 pts who received F, 113 (24.5%) had OS ≥10 mos (range 10.0–18.9) with a median duration of F treatment of 6.3 mos (range 0.7–19.1). Among pts receiving F, a higher proportion (≥10% difference) of pts with OS ≥10 mos had no liver metastases (mets) and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 at BL compared with the ITT pop (Table). In pts with OS ≥10 mos, 61.9% experienced a grade ≥3 treatment-emergent adverse event compared with 62.7% in the ITT pop. Conclusions: Longer-term OS and PFS rates at 6 and 9 mos were higher with F vs P in the FRESCO-2 ITT pop. The data show a higher proportion of pts with OS ≥10 mos had an absence of liver mets and ECOG PS 0 at BL than the ITT pop. The safety profile of F in pts with OS ≥10 mos was consistent with the ITT pop. Clinical trial information: NCT04322539 . BL characteristics of pts treated with F with OS ≥10 mos vs ITT pop. BL characteristic Pts with OS ≥10 mos (n=113) ITT pop(n=461) ECOG PS (0 / 1), % 54.0 / 46.0 42.5 / 57.5 Median time since 1 st CRC diagnosis, mos 52.0 47.2 Primary tumor location at 1 st diagnosis (colon / rectum / both), % 51.3 / 35.4 / 13.3 60.5 / 31.0 / 8.5 Primary site at 1 st diagnosis (colon left / colon right), % 42.5 / 15.9 41.6 / 21.0 Liver mets, % 58.4 73.5 Median duration of mCRC, mos 42.7 37.9 Prior lines of therapy for mCRC (≤3 / >3), % 26.5 / 73.5 27.1 / 72.9 Prior TAS-102, % 46.9 52.1 Prior regorafenib, % 12.4 8.7

Repeated sequential administration of pegylated emulsion of SU5416 and liposomal paclitaxel enhances anti-tumor effect in 4T1 breast cancer-bearing mice.

To improve vascular normalization strategy for intractable triple-negative breast cancer 4 T1, we examined the anti-tumor effects of repeated sequential administration of polyethylene glycol (PEG)-modified emulsion of SU5416 (PE-SU5416), a vascular endothelial growth factor (VEGF) receptor-2 kinase inhibitor, and PEG-modified liposomal paclitaxel (PL-PTX) in mice bearing 4 T1 cells. Three sequential administrations (Seq × 3) of PE-SU5416 and PL-PTX exhibited significantly higher anti-tumor activity than a single sequential administration (Seq × 1). The tumor vasculatures were structurally normalized until after two PE-SU5416 (PE-SU5416 × 2) or sequential (Seq × 2) administrations, while the improvement in vascular function, such as oxygen supply, blood flow, and PEG-liposomal distribution, was evident until after three administrations of PE-SU5416 (PE-SU5416 × 3) and Seq × 3. Although some discrepancies between the structural and functional improvement in tumor vasculatures were observed after PE-SU5416 × 3 and Seq × 3, cancer-associated fibroblasts (CAFs) and collagen levels were significantly reduced after PE-SU5416 × 2, PE-SU5416 × 3, Seq × 2, and Seq × 3, suggesting that a possible decrease in interstitial fluid pressure due to the reduction in CAFs and collagen would have compensated for vascular function. Furthermore, PE-SU5416 × 2, PE-SU5416 × 3, Seq × 2, and Seq × 3 significantly decreased tumor growth factor-β (TGF-β), an activator of CAFs, in tumor tissues, suggesting that the reduction in TGF-β levels by PE-SU5416 suppresses CAF activation.

Exploring Novel Therapeutics for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive obliteration of pulmonary arteries. Dysregulated bone morphogenetic protein (BMP) signaling pathway contributes to the development of PAH, and pulmonary vasodilators including endothelin receptor antagonists, phosphodiesterase 5 inhibitors, prostaglandins and soluble guanylate cyclase stimulators, dramatically improve the long-term prognosis. However, there still exist refractory patients who require continuous catecholamine support or lung transplantation, and the development of new treatment strategies targeting molecular mechanisms of PAH is highly anticipated. Sotatercept, a first-in-class activin signaling inhibitor, has recently been approved for the treatment of PAH, and it targets and restores an imbalance in activin-growth differentiation factor and BMP pathway signaling. In addition, treatment strategies targeting peroxisome proliferator-activated receptor-γ signaling, inflammatory and immune systems, DNA damage response and cellular senescence, and growth factor receptors including vascular endothelial growth factor and platelet-derived growth factor receptors, are being devised. In this review, we briefly summarize the recent advances in basic research paving the way for the development of more effective treatments for PAH and their potential in clinical therapeutic applications.

Exploring the role of circulating proteins in multiple myeloma risk: a Mendelian randomization study

Multiple myeloma (MM) is an incurable blood cancer with unclear aetiology. Proteomics is a valuable tool in exploring mechanisms of disease. We investigated the causal relationship between circulating proteins and MM risk, using two of the largest cohorts with proteomics data to-date. We performed bidirectional two-sample Mendelian randomization (MR; forward MR = causal effect estimation of proteins and MM risk; reverse MR = causal effect estimation of MM risk and proteins). Summary statistics for plasma proteins were obtained from genome-wide association studies performed using SomaLogic (N = 35,559; deCODE) and Olink (N = 34,557; UK Biobank; UKB) proteomic platforms and for MM risk from a meta-analysis of UKB and FinnGen (case = 1649; control = 727,247) or FinnGen only (case = 1085; control = 271,463). Cis-SNPs associated with protein levels were used to instrument circulating proteins. We evaluated proteins for the consistency of directions of effect across MR analyses (with 95% confidence intervals not overlapping the null) and corroborating evidence from genetic colocalization. In the forward MR, 994 (SomaLogic) and 1570 (Olink) proteins were instrumentable. 440 proteins were analysed in both deCODE and UKB; 302 (69%) of these showed consistent directions of effect in the forward MR. Seven proteins had 95% confidence intervals (CIs) that did not overlap the null in both forward MR analyses and did not have evidence for an effect in the reverse direction: higher levels of dermatopontin (DPT), beta-crystallin B1 (CRYBB1), interleukin-18-binding protein (IL18BP) and vascular endothelial growth factor receptor 2 (KDR) and lower levels of odorant-binding protein 2b (OBP2B), glutamate-cysteine ligase regulatory subunit (GCLM) and gamma-crystallin D (CRYGD) were implicated in increasing MM risk. Evidence from genetic colocalization did not meet our threshold for a shared causal signal between any of these proteins and MM risk (h4 < 0.8). Our results highlight seven circulating proteins which may be involved in MM risk. Although evidence from genetic colocalization suggests these associations may not be robust to the effects of horizontal pleiotropy, these proteins may be useful markers of MM risk. Future work should explore the utility of these proteins in disease prediction or prevention using proteomic data from patients with MM or precursor conditions.

Pharmacokinetics and Biological Activities of Notoginsenoside R1: A Systematical Review.

Panax notoginseng (PN) root is a renowned nutritional supplement, health food additive, and traditional medicine that maintains homeostasis within the human microcirculatory system. Notoginsenoside R1 (NG-R1), an active compound derived from PN root, has been reported to possess various pharmacological activities, including anti-inflammatory, antioxidant, anticancer, antimicrobial, and angiogenic effects. However, NG-R1's pharmacokinetic properties and pharmacological activities have not been systematically elucidated. In this paper, the pharmacokinetic properties of NG-R1, its pharmacological effects, mechanisms of actions, and structure-activity relationship have been reviewed. Notably, NG-R1 inhibits tumor necrosis factor [Formula: see text] (TNF-[Formula: see text] expression, enhances the expression of nuclear factor erythroid 2-related factor 2 (NRF2), and enhances the expression of vascular endothelial growth factor receptor (VEGFR). The pharmacological effects of NG-R1 are associated with the modulation of several signaling pathways, such as mitogen-activated protein kinase (MAPK)/nuclear factor [Formula: see text]-B (NF-[Formula: see text]B), NRF2/antioxidant response element (ARE), Wnt/[Formula: see text]-catenin, and phosphoinositide-3 kinase (PI3K)/protein kinase B (AKT). NG-R1 offers potentially protective effects against numerous diseases, including cardiovascular, neurological, renal, pulmonary, bone, and diabetes-related conditions. Although the pharmacological activities and diverse effects of NG-R1 have been demonstrated in various diseases, its clinical applications are limited by poor bioavailability. Several strategies have been explored to improve the pharmacokinetic profile of NG-R1, making it a promising candidate for drug development.

Design of VEGFR2 Inhibitors: Construction and Screening of Virtual Compound Libraries

Objective: The current use of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) inhibitors is often limited by low selectivity and adverse side effects, highlighting the urgent need for novel, highly selective agents targeting this receptor. Methods: Based on existing VEGFR-2 inhibitors, we employed computer-aided drug design (CADD) techniques to develop a virtual compound library using active docking fragments. Molecular docking was performed using the configuration of VEGFR-2 as the receptor protein(PDB:4ASD). Comparative analysis and screening identified the most promising inhibitor, which was subsequently validated through molecular dynamics simulations. Results:: From the virtual library, 10 potential highly active inhibitors were identified. In particular, Compound 9 demonstrated strong binding affinity with the protein configuration, forming four hydrogen bonds during docking. The calculated CODOCKER energy was 39.7315 kcal/mol, with an RMSD of 0.4634 nm and RMSF of 0.3234 nm. Compared to Sorafenib, Compound 9 exhibited superior docking selectivity and activity. Conclusion: Computational analyses suggest that Compound 9 is a promising candidate as a highly selective VEGFR-2 inhibitor. Nonetheless, due to the inherent limitations of in silico docking studies, further chemical synthesis and experimental biological validation are required to confirm its potential.

A Coordination Nanosystem Enables Endogenous Ferric Ion-Initiated Multi-Catalysis for Synergistic Tumor-Specific Ferroptosis and Gene Therapy.

Emerging evidence demonstrates that inducing ferroptosis, a nonapoptotic programmed cell death mode, holds significant potential for tumor treatment. However, current ferroptosis strategies utilizing exogenous Fenton-type heavy metal species or introducing glutathione (GSH)/glutathione peroxidase 4 (GPX4) suppressants are hampered by latent adverse effects toward organisms, while utilizing endogenous iron may cause undesirable tumor angiogenesis through specific signaling pathways. Here, aferric ion (Fe3+)-responsive and DNAzyme-delivered coordination nanosystem (ZDD) is developed to achieve a novel scheme of synergistic tumor-specific ferroptosis and gene therapy, which modulates and harnesses the endogenous iron in tumors for inducing ferroptosis while intercepting tumor angiogenesis to enhance therapeutic efficacy. Profiting from the characteristic coordination structure and components, ZDD can not only specifically capture tumor endogenous Fe3+ into the tumor cells to promote the catalytic generation of hydroxyl radicals (·OH) and superoxide anions (O2·-) under acidic environment and the catalytic GSH oxidation, arousing potent ferroptotic cell death, but also effectively deliver specific DNAzyme and release abundant zinc ion (Zn2+) as a powerful cofactor to activate the biocatalytic cleavage of vascular endothelial growth factor receptor 2 (VEGFR2) gene for angiogenesis suppression. Ultimately, the ZDD-enabled synergistic therapy prominently inhibited tumor growth and prevented metastasis, representing a promising nanotherapeutic formula for safe and efficient tumor therapy.

Stromal PDGFR-beta expression is a prognostic factor in high-grade serous ovarian cancer patients but is it also predictive for response to antiangiogenic treatment?

ObjectiveIn advanced ovarian cancer, the majority of patients receive anti-angiogenic treatment with bevacizumab. However, its use is often associated with severe side effects, and not all patients benefit from the therapy. Currently, there are no reliable biomarkers to predict response to treatment. Given their role as key regulators of angiogenesis, platelet-derived growth factor receptor-beta (PDGFR-beta) and vascular endothelial growth factor receptor-2 (VEGFR-2) are promising candidates for predictive biomarkers. This study evaluates their potential.MethodsPDGFR-beta and VEGFR-2 expression was evaluated using immunohistochemistry in a tissue microarray assay including 391 ovarian tissue samples. Correlation analyses with clinical and histopathological parameters were performed in a homogeneous cohort of 199 high grade serous ovarian cancer samples (HGSOC).ResultsIn HGSOC, strong stromal PDGFR-beta expression was associated with significantly shorter overall survival compared to weak/moderate expression. The impact of stromal PDGFR-beta expression on patient survival was however not restricted to the subgroup of patients receiving therapy with bevacizumab, and therefore cannot be considered as a predictive factor. For VEGFR-2, no or weak protein expression was found in the majority of the tumor samples. Survival analyses showed a more favorable prognosis with no or weak VEGFR-2 expression.ConclusionsHigh stromal expression levels of PDGFR-beta correlate with shorter overall survival in HGSOC. Thus, stromal PDGFR-beta might serve as a prognostic biomarker. No predictive effect in response to bevacizumab therapy could be attributed.

Synergistic effects of mTOR inhibitors with VEGFR3 inhibitors on the interaction between TSC2-mutated cells and lymphatic endothelial cells.

Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease affecting the lung, kidney, and lymphatic system with a molecular mechanism of tuberous sclerosis complex 2 (TSC2) mutations. Vascular endothelial growth factor D (VEGF-D), a ligand for vascular endothelial growth factor receptor 3 (VEGFR3), is a diagnostic biomarker of LAM and is associated with lymphatic circulation abnormalities. This study explored the interaction between LAM cells and lymphatic endothelial cells (LECs) and the effects of rapamycin on this interaction, which may help to identify new targets for LAM treatment. This study used direct and indirect cocultures of TSC2-null cells and LECs. The xenograft model was applied to explore the therapeutic feasibility. Single-cell sequencing revealed increased LECs in the lungs of LAM patients through activation of pathways involved in lymphangiogenesis. TSC2-null cells attracted LECs and promoted tube formation. VEGF-D/VEGFR3 was a key mediator of the above interaction. Rapamycin can directly inhibit recruitment but not the tube formation of LECs in vitro. The combination of rapamycin with VEGFR3 inhibitors not only enhanced the effect of rapamycin but also inhibited lymphatic related manifestations including the tube formation and the lymphatic metastasis. Our findings demonstrated that LAM cells recruit LECs and promote tube formation via VEGF-D/VEGFR3. Rapamycin only partially blocked this interaction. The synergistic effects of rapamycin and VEGFR3 inhibitors suggest a novel strategy for the treatment of LAM and other TSC2-mutated diseases.