Ceramide Ehux-C22 Targets the miR-199a-3p/mTOR Signaling Pathway to Regulate Melanosomal Autophagy in Mouse B16 Cells.

Melanosomes are specialized membrane-bound organelles where melanin is synthesized and stored. The levels of melanin can be effectively reduced by inhibiting melanin synthesis or promoting melanosome degradation via autophagy. Ceramide, a key component in the metabolism of sphingolipids, is crucial for preserving the skin barrier, keeping it hydrated, and warding off the signs of aging. Our preliminary study indicated that a long-chain C22-ceramide compound (Ehux-C22) isolated from the marine microalga Emiliania huxleyi, reduced melanin levels via melanosomal autophagy in B16 cells. Recently, microRNAs (miRNAs) were shown to act as melanogenesis-regulating molecules in melanocytes. However, whether the ceramide Ehux-C22 can induce melanosome autophagy at the post-transcriptional level, and which potential autophagy-dependent mechanisms are involved, remains unknown. Here, miR-199a-3p was screened and identified as a novel upregulated miRNA in Ehux-C22-treated B16 cells. An in vitro high melanin expression model in cultured mouse melanoma cells (B16 cells) was established by using 0.2 µM alpha-melanocyte-stimulating hormone(α-MSH) and used for subsequent analyses. miR-199a-3p overexpression significantly enhanced melanin degradation, as indicated by a reduction in the melanin level and an increase in melanosome autophagy. Further investigation demonstrated that in B16 cells, Ehux-C22 activated miR-199a-3p and inhibited mammalian target of rapamycin(mTOR) level, thus activating the mTOR-ULK1 signaling pathway by promoting the expression of unc-51-like autophagy activating kinase 1 (ULK1), B-cell lymphoma-2 (Bcl-2), Beclin-1, autophagy-related gene 5 (ATG5), and microtubule-associated protein light chain 3 (LC3-II) and degrading p62. Therefore, the roles of Ehux-C22-regulated miR-199a-3p and the mTOR pathway in melanosomal autophagy were elucidated. This research may provide novel perspectives on the post-translational regulation of melanin metabolism, which involves the coordinated control of melanosomes.

Bintrafusp Alfa for Recurrent or Metastatic Cervical Cancer After Platinum Failure: A Nonrandomized Controlled Trial.

Importance: Cervical cancer is a common and lethal cancer worldwide. Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of the human transforming growth factor ß receptor II (or transforming growth factor ß trap) fused via a flexible linker to the C-terminus of each heavy chain of an immunoglobulin G1 antibody blocking programmed cell death 1 ligand 1. Objective: To evaluate the safety and response rates of bintrafusp alfa in patients with recurrent or metastatic cervical cancer. Design, Setting, and Participants: This phase 2 nonrandomized controlled trial evaluated bintrafusp alfa monotherapy in patients with recurrent or metastatic cervical cancer with disease progression during or after platinum-based chemotherapy. Data were collected from March 2020 to February 2022. Intervention: Patients received bintrafusp alfa, 1200 mg, intravenously once every 2 weeks. Main Outcomes and Measures: The primary end point was confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. Results: At data cutoff, 146 of 203 screened patients received 1 or more doses of bintrafusp alfa; of these, the median (range) age was 53 (24-79) years. The study met its primary end point of a 95% CI above the objective response rate benchmark of 15%, with a confirmed objective response rate of 21.9% (95% CI, 15.5-29.5) per the independent review committee. Of these patients, 19 (59.4%) had a durable response of 6 months or more. At data cutoff, responses were ongoing in 13 of 32 responders (40.6%). The most common treatment-related adverse events were anemia (25 [17.1%]), rash (21 [14.4%]), hypothyroidism (15 [10.3%]), and pruritus (15 [10.3%]). Any-cause adverse events of special interest included anemia (82[56.2%]), bleeding events (81 [55.5%]), and immune-related adverse events (49 [33.6%]). Conclusions and Relevance: This phase 2 nonrandomized controlled trial of bintrafusp alfa met its primary end point, which may support the potential of a bispecific therapy targeting transforming growth factor ß and programmed cell death 1 ligand 1 in patients with recurrent or metastatic cervical cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT04246489.

Senaparib as first-line maintenance therapy in advanced ovarian cancer: a randomized phase 3 trial.

Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Synergistic induction of autophagy in gastric cancer by targeting CDK4/6 and MEK through AMPK/mTOR pathway.

KRAS is a commonly mutated oncogene in human gastric cancer and is often associated with drug resistance and poor prognosis. Co-clinical trial of combined MEK-CDK4/6 inhibition in KRAS mutated cancers demonstrated therapeutic efficacy in patient-derived xenografts and safety in patients. Here, present research focuses on targeting CDK4/6 and MEK synergistically block the proliferation of KRAS-mutated gastric cancer cells in vitro and in vivo and induced autophagy through the AMPK/mTOR pathway. Furthermore, autophagy inhibitor combined with targeting CDK4/6 and MEK therapy had significant antitumor effects on KRAS mutant gastric cancer cells. Clinical trials are needed to determine the mechanism behind this finding and its clinical utility. In conclusion, our results demonstrate autophagy inhibitor combined targeting MEK and CDK4/6 that concurrently block multiple metabolic processes may be an effective therapeutic approach for gastric cancer.

Biomarker-driven targeted therapy in patients with recurrent platinum-resistant epithelial ovarian cancer (BRIGHT): protocol for an open-label, multicenter, umbrella study.

BACKGROUND: Platinum-resistant, recurrent ovarian cancer has an abysmal prognosis with limited treatment options. Poly-(ADP-ribose)-polymerase (PARP), angiogenesis, and immune checkpoint inhibitors might improve the outcomes of platinum-resistant, recurrent ovarian cancer, but accurate patient selections for those therapies remain a significant clinical challenge. PRIMARY OBJECTIVE: To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. STUDY HYPOTHESIS: A precision medicine combination of PARP inhibitors, anti-angiogenic therapy, immunotherapy, and chemotherapy will improve disease outcomes of platinum-resistant, recurrent ovarian cancer by accounting for genomic and immunologic features. TRIAL DESIGN: The BRIGHT Trial is a prospective, open-label, multicenter, phase II, umbrella study planning to enroll 160 patients with serous, endometrioid, or clear cell platinum-resistant, recurrent ovarian cancer from 11 clinical centers in China. Patients are assigned to one of three experimental arms based on biomarkers. Patients with BRCA1/2 mutations will receive pamiparib plus bevacizumab (arm 1, n=40) regardless of CD8+ tumor-infiltrating lymphocytes count. Patients with wild-type BRCA1/2 (BRCAwt) and ≥3 CD8+ tumor-infiltrating lymphocytes count will receive the combination of tislelizumab, bevacizumab, and nab-paclitaxel (arm 2, n=50), while BRCAwt patients with <3 CD8+ tumor-infiltrating lymphocytes count will receive bevacizumab plus dose-dense nab-paclitaxel (arm 3, n=50). After completing patient enrollment in arm 2, another 20 BRCAwt patients with ≥3 CD8+ tumor-infiltrating lymphocytes count will be included as an arm 2 expansion. Treatment will continue until disease progression or intolerable toxicity, and all adverse events will be recorded. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients include those aged ≥18 with serous, endometrioid, or clear cell ovarian cancer, platinum-resistant recurrence, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. PRIMARY ENDPOINT: Objective response rate (ORR) assessed by the investigators by the RECIST 1.1 criteria. SAMPLE SIZE: 160 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Recruitment is estimated to be completed by 2024 and results may be published by 2027. TRIAL REGISTRATION: ClinicalTrials.gov: NCT05044871.

Combining cisplatin with Pinellia pedatisecta Schott lipid-soluble extract induces tumor immunogenic cell death in cervical cancer.

BACKGROUND: Pinellia pedatisecta Schott extract (PE) is extracted from Pinellia pedatisecta Schott (PPS), a traditional Chinese medicinal plant with the potential for direct anticancer effects or eliciting an anti-tumor response by activating the immune system. PURPOSE: To explore PE's ability and mechanism to reconstruct cisplatin's immunogenicity. METHODS: Cervical cancer cells were treated with cisplatin (CDDP) and/or PE. The exposure of calreticulin (CRT) on cell membrane was investigated by flow cytometry. The extracellular of ATP and HMGB1 was investigated by Western blot analysis, immunofluorescence and ELISA assay. Changes in immune profiles were using flow cytometry in vaccination and anti-tumor assays in vivo. Lastly, the mechanism of PE influenced the ROS/ERS pathway was examined by ROS assay kit, flow cytometry and Western blotting. RESULTS: PE treatment induced translocation of CRT from the endoplasmic reticulum to the cell membrane of tumor cells, concomitantly triggering immunogenic cell death (ICD). In terms of mechanisms, endoplasmic reticulum (ER) stress relievers could impede the ability of PE to induce immunogenicity. This indicates that PE is activated by ER stress, leading to subsequent induction of ICD. Upon analyzing RNA-seq data, it was observed that PE primarily induces programmed cell death in tumors by impeding upstream antioxidant mechanisms. Additionally, it transforms dying tumor cells into vaccines, activating a series of immune responses. CONCLUSIONS: This study observed for the first time that PE-induced CRT exposure on the membrane of cervical cancer cells compensates for the defect of nonimmunogenic cell death inducer CDDP thereby stimulating potent ICD. This ability restores the immunogenicity of CDDP through ER stress induced by the ROS signal. ROS played a role in PE's ability to induce ICD, leading to increased expression of ER stress-related proteins, including ATF3 and IRE-1α. PE exerted anti-cancer effects by increasing the ROS levels, and ROS/ERS signaling may be a potential avenue for cervical cancer treatment. Hence, the synergistic use of PE and CDDP holds potential for enhancing immunochemotherapy in cancer treatment.

Cadonilimab Combined with Chemotherapy with or without Bevacizumab as First-Line Treatment in Recurrent or Metastatic Cervical Cancer (COMPASSION-13): A Phase 2 Study.

PURPOSE: Immune checkpoint inhibitors (ICI) have been a potential treatment option for patients with cervical cancer in several clinical studies. We investigated the safety and efficacy of cadonilimab, a bispecific antibody targeting PD-1 and CTLA-4, plus standard therapy for the first-line treatment of R/M CC (recurrent and/or metastatic cervical cancer). PATIENTS AND METHODS: Eligible patients were assigned to 3 cohorts: cohort A-15 (cadonilimab 15 mg/kg every 3 weeks (Q3W) plus chemotherapy), cohort A-10 (cadonilimb 10 mg/kg Q3W plus chemotherapy), and cohort B-10 (cadonilimab 10 mg/kg Q3W plus chemotherapy and bevacizumab). They received the corresponding treatments until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision. The primary objective was safety; the secondary endpoints included objective overall response (ORR), duration of response, disease control rate, progression-free survival, and overall survival. This study is registered with ClinicalTrials.gov (NCT04868708). RESULTS: As of February 13, 2023, treatment-related adverse events (TRAE) occurred in 45 (100.0%) patients. Grade ≥3 TRAEs were reported in 33 (73.3%) patients. Immune-related adverse events (irAE) occurred in 29 (64.4%) patients and grade ≥3 irAEs were observed in 9 (20.0%) patients. Seven (15.6%) of 45 patients permanently discontinued cadonilimab treatment due to TRAEs. One death due to hemorrhagic shock occurred in cohort B-10. Among 44 patients who underwent at least one post-baseline tumor assessment, the ORR was 66.7% in cohort A-15, 68.8% in cohort A-10, 92.3% in cohort B-10, and 79.3% in cohorts A-10 and B-10 combined. CONCLUSIONS: Cadonilimab combined with standard therapy was acceptable, with encouraging antitumor activity in patients with R/M CC.

Comparison of Lipid Composition between Quasipaa spinosa Oil and Rana catesbeiana Oil and Its Effect on Lipid Accumulation in Caenorhabditis elegans.

Frog oil has been recognized for its nutritional and medicinal value. However, there is limited research on the role of frog oil in preventing obesity. In this study, we aimed to investigate the lipid composition of Quasipaa spinosa oil (QSO) and Rana catesbeiana oil (RCO) using lipidomics analysis. We compared the lipid accumulation effects of these two kinds of frog oils and soybean oil (SO) in Caenorhabditis elegans (C. elegans). Additionally, we determined the gene expression related to lipid metabolism and used the nhr-49 mutant (RB1716) and sir-2.1 mutant (VC199) for validation experiments. The results showed that the lipid composition of QSO and RCO was significantly different (p < 0.05), and QSO was rich in more polyunsaturated fatty acids (PUFAs). After feeding C. elegans, the lipid accumulation of the QSO group was the lowest among the three dietary oil groups. In addition, compared with RCO and SO, QSO significantly inhibited the production of malondialdehyde (MDA) and increased the activity of superoxide dismutase (SOD). The effects of three kinds of dietary oils on the fatty acid composition of C. elegans were significantly different. Compared with SO and RCO, QSO significantly up-regulated (p < 0.05) the expression of sir-2.1 and ech-1 genes. The results showed that QSO might reduce lipid accumulation through the SIRT1 and nuclear hormone signaling pathways. Such a situation was verified experimentally by the nhr-49 mutant (RB1716) and sir-2.1 mutant (VC199). This study proposed a new functional oil, laying the groundwork for developing functional foods from Quasipaa spinosa.

Preparation and identification of antioxidant peptides from Quasipaa spinosa skin through two-step enzymatic hydrolysis and molecular simulation.

Frog skin, a by-product of Quasipaa Spinosa farming, is rich in protein and potentially a valuable raw material for obtaining antioxidant peptides. This study used papain combined with acid protease to digest frog skin in a two-step enzymatic hydrolysis method. Based on a single factor and response surface experiments, experimental conditions were optimized, and the degree of hydrolysis was 30 %. A frog skin hydrolysate (QSPH-Ⅰ-3) was obtained following ultrafiltration and gel filtration chromatography. IC50 for DPPH, ABTS, and hydroxyl radical scavenging capacities were 1.68 ± 0.05, 1.20 ± 0.14 and 1.55 ± 0.11 mg/mL, respectively. Peptide sequences (17) were analyzed and, through molecular docking, peptides with low binding energies for KEAP1 were identified, which might affect the NRF2-KEAP1 pathway. These findings suggest protein hydrolysates and antioxidant peptide derivatives might be used in functional foods.

Targeted Imaging of Endometriosis and Image-Guided Resection of Lesions Using Gonadotropin-Releasing Hormone Analogue-Modified Indocyanine Green.

Objective: In this study, we utilized gonadotropin-releasing hormone analogue-modified indocyanine green (GnRHa-ICG) to improve the accuracy of intraoperative recognition and resection of endometriotic lesions. Methods: Gonadotropin-releasing hormone receptor (GnRHR) expression was detected in endometriosis tissues and cell lines via immunohistochemistry and western blotting. The in vitro binding capacities of GnRHa, GnRHa-ICG, and ICG were determined using fluorescence microscopy and flow cytometry. In vivo imaging was performed in mouse models of endometriosis using a near-infrared fluorescence (NIRF) imaging system and fluorescence navigation system. The ex vivo binding capacity was determined using confocal fluorescence microscopy. Results: GnRHa-ICG exhibited a significantly stronger binding capacity to endometriotic cells and tissues than ICG. In mice with endometriosis, GnRHa-ICG specifically imaged endometriotic tissues (EMTs) after intraperitoneal administration, whereas ICG exhibited signals in the intestine. GnRHa-ICG showed the highest fluorescence signals in the EMTs at 2 h and a good signal-to-noise ratio at 48 h postadministration. Compared with traditional surgery under white light, targeted NIRF imaging-guided surgery completely resected endometriotic lesions with a sensitivity of 97.3% and specificity of 77.8%. No obvious toxicity was observed in routine blood tests, serum biochemicals, or histopathology in mice. Conclusions: GnRHa-ICG specifically recognized and localized endometriotic lesions and guided complete resection of lesions with high accuracy.

Favorable response to surufatinib in a patient with necrolytic migratory erythema: A case report.

Necrolytic migratory erythema (NME) is usually associated with paraneoplastic syndrome caused by functional pancreatic neuroendocrine tumor (PNET). Accurate diagnosis and effective treatment of NET-related NME is challenging due to its rarity and lack of typical clinical symptoms and specific pathological manifestations. Here we report a rare case of PNET with NME as the initial manifestation. 68Ga-DOTA-TATE PET/MR was used to detect the primary pancreatic and metastatic liver tumors. Finally, the patient was diagnosed as PNET via liver biopsy. After four cycles of standard capecitabine plus temozolomide chemotherapy combined with long-acting octreotide, the patient's skin lesions on both lower extremities improved only slightly, while tumors remained stable and unchanged in size. Then the patient was treated with surufatinib. Two months later, the skin lesions healed completely, and tumors responded significantly. This rare case suggests that surufatinib may be a promising therapy for patients with PNET-associated NME.

Safety and antitumour activity of cadonilimab, an anti-PD-1/CTLA-4 bispecific antibody, for patients with advanced solid tumours (COMPASSION-03): a multicentre, open-label, phase 1b/2 trial.

BACKGROUND: Immune checkpoint inhibitors targeting PD-1 or CTLA-4 individually have shown substantial clinical benefits in the treatment of malignancies. We aimed to assess the safety and antitumour activity of cadonilimab monotherapy, a bispecific PD-1/CTLA-4 antibody, in patients with advanced solid tumours. METHODS: This multicentre, open-label, phase 1b/2 trial was conducted across 30 hospitals in China. Patients aged 18 years or older with histologically or cytologically confirmed, unresectable advanced solid tumours, unsuccessful completion of at least one previous systemic therapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible for inclusion. Patients who had previously received anti-PD-1, anti-PD-L1, or anti-CTLA-4 treatment were not eligible for inclusion. In the dose escalation phase of phase 1b, patients received intravenous cadonilimab at 6 mg/kg and 10 mg/kg every 2 weeks. In the dose expansion phase of phase 1b, cadonilimab at 6 mg/kg and a fixed dose of 450 mg were given intravenously every 2 weeks. In phase 2, cadonilimab at 6 mg/kg was administered intravenously every 2 weeks in three cohorts: patients with cervical cancer, oesophageal squamous cell carcinoma, and hepatocellular carcinoma. The primary endpoints were the safety of cadonilimab in phase 1b and objective response rate in phase 2, based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The safety analysis was done in all patients who received at least one dose of cadonilimab. Antitumour activity was assessed in the full analysis set for the cervical cancer cohort, and in all patients with measurable disease at baseline and who received at least one dose of cadonilimab in the oesophageal squamous cell carcinoma and hepatocellular carcinoma cohorts. The study is registered on ClinicalTrial.gov, NCT03852251, and closed to new participants; follow-up has been completed. FINDINGS: Between Jan 18, 2019, and Jan 8, 2021, 240 patients (83 [43 male and 40 female] in phase 1b and 157 in phase 2) were enrolled. Phase 2 enrolled 111 female patients with cervical cancer, 22 patients with oesophageal squamous cell carcinoma (15 male and seven female), and 24 patients with hepatocellular carcinoma (17 male and seven female). During dose escalation, no dose-limiting toxicities occurred. Grade 3-4 treatment-related adverse events occurred in 67 (28%) of 240 patients; the most frequent grade 3 or worse treatment-related adverse events were anaemia (seven [3%]), increased lipase (four [2%]), decreased bodyweight (three [1%]), decreased appetite (four [2%]), decreased neutrophil count (three [1%]), and infusion-related reaction (two [1%]). 17 (7%) patients discontinued treatment due to treatment-related adverse events. 54 (23%) of 240 patients reported serious treatment-related adverse events, including five patients who died (one due to myocardial infarction; cause unknown for four). In phase 2, in the cervical cancer cohort, with a median follow-up of 14·6 months (IQR 13·1-17·5), the objective response rate was 32·3% (32 of 99; 95% CI 23·3-42·5). In the oesophageal squamous cell carcinoma cohort, with a median follow-up of 17·9 months (IQR 4·0-15·1), the objective response rate was 18·2% (four of 22; 95% CI 5·2-40·3). In the hepatocellular carcinoma cohort, with a median follow-up of 19·6 months (IQR 8·7-19·8), the objective response rate was 16·7% (four of 24; 95% CI 4·7-37·4). INTERPRETATION: Cadonilimab showed an encouraging tumour response rate, with a manageable safety profile, suggesting the potential of cadonilimab for the treatment of advanced solid tumours. FUNDING: Akeso Biopharma. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Nuclear PARP1-Targeted Photosensitizer as a Dual-Mode DNA-Damaging Agent and Immune Activator for Tumor Ablation.

Photodynamic therapy is a promising cancer therapeutic method that can damage DNA via photoinduced reactive oxygen species production. However, tumor cells can initiate DNA repair pathways to resist oxidative damage. In this study, a nuclear-targeted photosensitizer PARP-PS with a poly (ADP-ribose) polymerase 1 (PARP1) inhibitory effect is developed based on the reported PARP1 inhibitor, rucaparib. As a dual-mode DNA-damaging agent, PARP-PS damages DNA upon photoirradiation and enhances oxidative DNA damage by blocking the DNA repair pathway via PARP1 inhibition and degradation. Both in vitro and in vivo investigations demonstrate that PARP-PS exhibits high antitumor activity with few side effects in breast cancer. In addition, PARP-PS can act as an immunogenic cell death inducer to activate immune responses characterized by the promotion of cytotoxic T lymphocyte activation and tumor infiltration. Therefore, PARP-PS is a potential multimodal antitumor agent with synergistic phototherapeutic, chemotherapeutic, and immunotherapeutic effects.

A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis.

BACKGROUND: The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC). METHODS: This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCAmut). RESULTS: Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6-51.0) and 65.4% (95% CI 50.9-78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7-84.3); this dose was determined to be the RP2D. Patients with gBRCAmut had higher ORR and longer median progression-free survival (PFS) than those with gBRCAwt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg. CONCLUSIONS: Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).

ROS impairs tumor vasculature normalization through an endocytosis effect of caveolae on extracellular SPARC.

BACKGROUND: The accumulation of reactive oxygen species (ROS) in tumor microenvironment (TME) is an important player for tumorigenesis and progression. We aimed to explore the outcomes of ROS on tumor vessels and the potential regulated mechanisms. METHODS: Exogenous H2O2 was adopted to simulate the ROS setting. Immunofluorescence staining and ultrasonography were used to assess the vascular endothelial coverage and perfusions in the tumors inoculated with Lewis lung cancer (LLC) and melanoma (B16F10) cells of C57BL/6 mice, respectively. ELISA and western-blot were used to detect the expression of secreted acidic and cysteine-rich protein (SPARC) and Caveale-1 in human umbilical vein endothelial cells (HUVEC) extra- and intracellularly. Intracellular translocation of SPARC was observed using electron microscopy and immunofluorescence approaches. RESULT: Under the context of oxidative stress, the pericyte recruitment of neovascularization in mouse lung cancer and melanoma tissues would be aberrated, which subsequently led to the disruption of the tumor vascular architecture and perfusion dysfunction. In vitro, HUVEC extracellularly SPARC was down-regulated, whereas intracellularly it was up-regulated. By electron microscopy and immunofluorescence staining, we observed that SPARC might undergo transmembrane transport via caveale-1-mediated endocytosis. Finally, the binding of SPARC to phosphorylated-caveale-1 was also detected in B16F10 tissues. CONCLUSION: In the oxidative stress environment, neovascularization within the tumor occurs structural deterioration and decreased perfusion capacity. One of the main regulatory mechanisms is the migration of extracellular SPARC from the endothelium to intracellular compartments via Caveolin-1 carriers.

Ligand-Directed Photodegradation of Interacting Proteins: Oxidative HER2/HER3 Heterodimer Degradation with a Lapatinib-Derived Photosensitizer.

In this work, we described a photocatalytic approach, termed ligand-directed photodegradation of interacting proteins (LDPIP), for efficient protein-protein heterodimer degradation. This LDPIP approach utilizes a combination of a photosensitizing protein ligand and appropriate light and molecular oxygen to induce oxidative damage to the ligand-binding protein as well as its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was rationally designed based on the FDA-approved HER2 inhibitor lapatinib to efficiently degrade HER2 together with its interacting protein partner HER3, which is thought to induce HER2-targeted therapy resistance and difficult to target by small molecules. HER-PS-I exhibited excellent anticancer activity against drug-resistant MDA-MB-453 cells and its three-dimensional multicellular spheroids. We hope that this LDPIP approach would find more applications in degrading proteins that are thought undruggable or difficult to drug.

Treatment With Niraparib Maintenance Therapy in Patients With Newly Diagnosed Advanced Ovarian Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The efficacy of niraparib maintenance therapy with an individualized starting dose (ISD) warrants further investigation in a broad population with newly diagnosed advanced ovarian cancer (aOC), including patients without postoperative residual disease. Objective: To evaluate the efficacy and safety of niraparib with an ISD in a broad population with newly diagnosed aOC (R0 resection permitted). Design, Setting, and Participants: This multicenter, randomized, double-blind, placebo-controlled, phase 3 study was conducted in China and enrolled 384 patients with newly diagnosed aOC who received primary or interval debulking surgery and responded to treatment with first-line platinum-based chemotherapy. By data cutoff (September 30, 2021), median follow-up for progression-free survival (PFS) was 27.5 (IQR, 24.7-30.4) months. Interventions: Patients were randomized 2:1 to receive niraparib or placebo with ISD (200 mg/d for those with a body weight of <77 kg and/or platelet count of <150 ×103/µL [to convert to ×109/µL, multiply by 1] at baseline; 300 mg/d otherwise) stratified by germline BRCA variant status, tumor homologous recombination deficiency status, neoadjuvant chemotherapy, and response to first-line platinum-based chemotherapy. Main Outcomes and Measurements: The primary end point was blinded, independent central review-assessed PFS in the intention-to-treat population. Results: A total of 384 patients were randomized (255 niraparib [66.4%]; median [range] age, 53 [32-77] years; 129 placebo [33.6%]; median [range] age, 54 [33-77] years), and 375 (247 niraparib [65.9%], 128 placebo [34.1%]) received treatment at a dose of 200 mg per day. Median PFS with niraparib vs placebo was 24.8 vs 8.3 months (hazard ratio [HR], 0.45; 95% CI, 0.34-0.60; P < .001) in the intention-to-treat population; not reached vs 10.8 months (HR, 0.40; 95% CI, 0.23-0.68) and 19.3 vs 8.3 months (HR, 0.48; 95% CI, 0.34-0.67) in patients with and without germline BRCA variants, respectively; not reached vs 11.0 months (HR, 0.48; 95% CI, 0.34-0.68) and 16.6 vs 5.5 months (HR, 0.41; 95% CI, 0.22-0.75) in homologous recombination deficient and proficient patients, respectively; and 24.8 vs 8.3 months (HR, 0.44; 95% CI, 0.32-0.61) and 16.5 vs 8.3 months (HR, 0.27; 95% CI, 0.10-0.72) in those with optimal and suboptimal debulking, respectively. Similar proportions of niraparib-treated and placebo-treated patients (6.7% vs 5.4%) discontinued treatment due to treatment-emergent adverse events. Conclusion and Relevance: This randomized clinical trial found that niraparib maintenance therapy prolonged PFS in patients with newly diagnosed aOC regardless of postoperative residual disease or biomarker status. The ISD was effective and safe in the first-line maintenance setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03709316.