Investigational New Drugs最新文献

Our study aims to target Met and EpCAM to inhibit angiogenesis in breast cancer, particularly triple-negative breast cancer (TNBC). We have developed a new bispecific antibody that targets both MET and EpCAM, which are commonly overexpressed in tumor cells. This antibody aims to reduce tumor cell proliferation and spread. After cloning and expressing the anti-Met/EPCAM sequence in Escherichia coli, we confirmed its accuracy through Western blot analysis. Flow cytometry indicated its binding activities to MET and EPCAM on MDA-MB-231 and MCF-7 cell lines. Our antibody showed anti-proliferative potential as indicated by apoptosis and MTT assay, leading to the inhibition of migration and invasion in breast cancer cell lines. After conducting a thorough analysis of cytokine production, we discovered that our bispecific antibody effectively influenced the levels of IL-8 and IL-6. These cytokines play crucial roles in angiogenesis and the progression of breast cancer. These findings indicate that our bispecific antibody holds promise as a potential therapy for triple-negative breast cancer. It has the potential to impede the formation of new blood vessels in tumors, thus restraining their growth and spread.

The concept of differentiation therapy emerged from the fact that hormones or cytokines may promote differentiation ex vivo, thereby irreversibly changing the phenotype of cancer cells. Its hallmark success has been the treatment of acute promyelocytic leukemia (APL), a condition that is now highly curable by the combination of retinoic acid (RA) and arsenic. Differentiation syndrome (DS) is a common and potentially life-threatening condition that was initially described with the induction therapy of targeted agents in acute promyelocytic leukemia (APL). DS is typically marked by symptoms such as fever, difficulty breathing, low blood pressure, weight gain, fluid buildup in the pleural or pericardial cavities, and acute kidney failure. The incidence of DS in APL patients varies from 2 to 27% reflecting the discrepancies in diagnostic criteria, in various treatment protocols, and sometimes the use of preventive treatments. Corticosteroids, with or without cytoreductive therapy, should be initiated immediately upon suspicion of DS to mitigate related morbidity and mortality. In cases of severe DS, targeted anti-leukemic therapy should be halted. This review will cover the pathogenesis of DS, its clinical presentations, diagnostic criteria, management approaches, and the importance of implementing prospective tracking in clinical trials.

The expanding clinical application of immune checkpoint inhibitors (ICIs) has led to increasing recognition of neurological immune-related adverse events, among which myelitis represents a rare but clinically significant complication. Currently, most available data come from case reports or small case series, highlighting the need for comprehensive characterization. Our study systematically analyzed the clinical features of ICI-induced myelitis to improve diagnostic and therapeutic approaches. Through a comprehensive literature review up to February 28, 2025, we identified and analyzed 36 cases of ICI-associated myelitis from 27 publications. The study cohort had a median age of 58 years (range 16-81) with male predominance (58.3%). Clinical presentations included isolated myelitis (63.9%) and multifocal neurological involvement (36.1%), most commonly manifesting meningoencephalomyelitis/encephalomyelitis. The median time to symptom onset was 2 months (range 0.3-8) after treatment initiation, with a median of 4 treatment cycles (range 1-51). The most frequently associated malignancies were melanoma and lung cancer, with programmed cell death protein-1 inhibitor being the most commonly used regimen (69.4%). Diagnostic evaluation revealed longitudinally extensive spinal cord lesions (≥ 3 vertebral segments) in 75.0% of patients, along with frequent inflammatory cerebrospinal fluid abnormalities. Neural autoantibodies were detected in 33.3% of cases. Treatment strategies predominantly involved corticosteroids (97.2%) and ICI discontinuation (91.7%). While most patients (72.2%) showed improvement, relapses occurred in 30.6% of cases. These findings emphasize the importance of early recognition and prompt immunosuppressive therapy for ICI-induced myelitis.

Pleural mesothelioma (PM) is a rare cancer affecting the pleural layer on the body's serosal surfaces. Exposure to asbestos fibers, a naturally occurring fibrous material with insulating characteristics, contributes to PM's prevalence. PM has a long latency period, making major surgery ineffective and necessitating systemic treatment. Despite the progress of mesothelioma treatment, the median survival is very poor; so, there is a strong need to explore new therapeutic approaches. This study explores the use of BOLD-100, a novel therapeutic drug that targets GRP78, a protein overexpressed in PM cells. BOLD-100, a ruthenium-based small molecule therapeutic drug, is being investigated for the treatment of advanced gastrointestinal malignancies in conjunction with chemotherapy. Our aim is to investigate cellular responses of several PM cell lines to a regimen that includes BOLD-100 in addition to other commonly used treatments. BOLD-100 is a ruthenium-based anticancer therapeutic.

The dysregulation of cellular epigenetic machinery has been established as a fundamental driver of oncogenesis. This recognition has propelled cancer epigenetics to the forefront of biomedical research, particularly regarding the mechanistic characterization of epigenetic switching events. These molecular switches represent critical regulatory nodes in the malignant transformation. The epigenetic switch is a complex structure formed through interactions between nucleic acid-protein complexes or protein-protein interaction complexes and specific DNA fragments. Triggered by a priming event, this molecular apparatus can reversibly activate or repress the transcription of multiple downstream genes. The inherent reversibility of these epigenetic switches presents novel therapeutic opportunities for targeted cancer intervention. Consequently, this review provides a systematic analysis of cancer-associated epigenetic switches identified in the past decade.

Onivyde, a liposome-encapsulated irinotecan, is used for advanced pancreatic, while TAS-102 (trifluridine/tipiracil) is indicated for metastatic colorectal and gastric cancers. This study aims to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profiles of liposomal irinotecan combined with TAS-102. This multicenter, phase I study utilized a 3 + 3 dose-escalation design. Patients with treatment-refractory solid malignancies received free base liposomal irinotecan at 50-70 mg/m² on Day 1 and TAS-102 at 25-35 mg/m² twice daily on Days 1-5 of a 14-day cycle. Patients homozygous for UGT1A1*28 (TA7/TA7), UGT1A1*6 (A/A), or double heterozygous (TA6/TA7 and G/A) alleles were excluded. Prophylactic G-CSF was allowed. Twenty-six evaluable patients were enrolled across seven dose levels of liposomal irinotecan (free-base)/TAS-102 combination: 3 patients each at level 1 (50/25 mg/m²), level 2A (60/25 mg/m²), level 2B (50/30 mg/m²), and level 3 (60/30 mg/m²); 6 at level 4A (70/30 mg/m²); 3 at level 4B (60/35 mg/m²); and 5 at level 5 (70/35 mg/m²). An additional 15 patients were enrolled in the expansion cohort at the MTD of 70/30 mg/m² (level 4A), designated as the RP2D. Overall grade 3-4 treatment-related adverse events occurred in 44.2% of 43 all treated patients, with neutropenia (16.3%), diarrhea (14%), and fatigue (11.6%). Partial responses were observed in 18.4% of patients, predominantly in neuroendocrine tumor, gastric and esophageal carcinomas. The combination of liposomal irinotecan and TAS-102 at the RP2D of 70/30 mg/m² demonstrated acceptable safety and promising efficacy in refractory solid tumors, warranting further investigation.

Central nervous system lymphoma (CNSL) are mainly diffuse large B-cell lymphomas (DLBCLs). Orelabrutinib is a second-generation Bruton's tyrosine kinase (BTK) inhibitor and has shown single-agent activity in CNSL. This study aims to evaluate the efficacy and safety of orelabrutinib combined with rituximab and high dose methotrexate (ORM) regimen in the treatment of patients with CNSL. We retrospectively analyzed data from CNSL patients treated with ORM regimen at Jiangsu Province Hospital, the First Affiliated Hospital of Nanjing Medical University from April 2021 to October 2023. Patients receiving rituximab plus high-dose methotrexate (RM regimen) from June 2017 to January 2024 were identified as the control group. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A total of 32 patients were identified: 14 patients in the ORM group and 18 in the RM group. CR rates were 84.6% in the ORM group and 44.4% in the RM group (P = 0.032). Median PFS was 18.6 months in the RM group and 26.3 months in the ORM group (P = 0.133). Median OS was 34.1 months in the RM group and has not yet been reached in the ORM group (P = 0.041). Patients in the ORM group showed a higher 2-year OS rate than those in the RM group (82.1% vs. 57.5%). No grade 5 AE was reported in both groups. The incidence of grade 3-4 AE was comparable between the two treatment groups. ORM regimen was effective and well-tolerated in patients with CNSL. This combination therapy provides a new potential therapeutic strategy for patients with CNSL.

In Japan, atezolizumab is indicated for several cancers at a dose of 1200 mg every 3 weeks or 840 mg every 2 weeks. This open-label study (jRCT2031220151) aimed to assess an atezolizumab monotherapy dose of 1680 mg every 4 weeks (Q4W) in Japanese patients ≥ 18 years of age with advanced or recurrent solid tumors that were not responsive to standard treatment. The primary endpoints were tolerability, safety, and pharmacokinetics (PK). Secondary endpoints included overall response rate and progression-free survival. Overall, 21 patients were enrolled in the study. The median age for males (42.9%) and females (57.1%) was 61 years, and the median (range) treatment duration was 29.0 (1-224) days. During the dose-limiting toxicity (DLT) evaluation period, 3 out of 6 (50.0%) patients experienced at least 1 adverse event, although no DLTs or deaths were experienced. The PK profile of atezolizumab 1680 mg Q4W monotherapy in cycle 1 after 30 min of administration had an arithmetic mean maximum concentration (standard deviation [SD]) of 699 (146) µl/mL and a mean minimum concentration (SD) 133 (46.0) µl/mL, The mean (SD) area under the curve was 7180 (1340) days‧µg/mL. These data show that atezolizumab 1680 mg Q4W monotherapy was well tolerated in Japanese patients with no new safety concerns, suggesting that this less frequent dosing regimen could have the potential to offer greater flexibility and convenience for patients and caregivers.

Background: Despite advances in cancer treatment, chemotherapy remains a cornerstone of clinical practice. However, its efficacy is often compromised by dose-limiting haematologic toxicities. Recent strategies aim to enhance chemotherapy tolerability while preserving its effectiveness. One emerging approach involves selective CDK4 inhibitors to serve as myeloid-protective agents in retinoblastoma (RB)-negative tumours, such as triple-negative breast cancer (TNBC). Because bone marrow (BM) cells rely on RB for proliferation, CDK4 inhibitors may protect these cells while sparing RB-deficient tumour cells. The present study investigated the potential of AU2-94, a first-in-class CDK4 inhibitor, to protect BM cells during myelosuppressive chemotherapy in TNBC, beyond its established application in RB-positive cancers.

Methods: This study employed in vitro, ex vivo, and in vivo experiments to evaluate the myeloid-protective effects of AU2-94 against chemotherapy-induced damage.

Results: AU2-94 induced a transient G1 arrest that protects BM cells from chemotherapy-induced apoptosis by preventing DNA double-strand breaks. Pre-treatment with AU2-94 prior to 5-fluorouracil (5-FU) administration reduced BM cells apoptosis, preserved Ki67-positive cells, and mitigated declines in red blood cells and neutrophils. Similarly, AU2-94 pre-treatment before cisplatin administration reduced cisplatin-induced haematologic toxicity in RB-deficient TNBC bearing mice without compromising the efficacy of chemotherapy.

Conclusion: These findings support the repurposing of AU2-94 as a myeloprotective agent, highlighting its therapeutic potential in RB-deficient tumours. With AU2-94 advancing to clinical trials, these results underscore its broader therapeutic promise, extending to both RB-positive and RB-negative cancer treatment.

Acute myeloid leukemia (AML) is a relapsing and drug-resistant hematologic malignancy. We report AB138, a novel molecular glue degrader that recruits G1-to-S phase transition protein 1 (GSPT1) to cereblon (CRBN). In AML cell lines, AB138 induces rapid, sustained GSPT1 degradation. qPCR and immunoblotting revealed activation of the integrated stress response, as evidenced by eIF2α phosphorylation and the upregulation of ATF3 and CHOP. The subsequent depletion of the oncoproteins MCL1 and c-Myc coincides with the accumulation of cleaved caspase-3 and cleaved PARP and marked apoptosis. Flow cytometric analysis confirmed pronounced S-phase arrest together with an increase in the number of Annexin V-positive cells. Oral administration of AB138 significantly reduces the tumor burden in an MV-4-11-Luc xenograft model without overt toxicity. These findings demonstrate that efficient GSPT1 degradation by AB138 promtoes integrated stress signaling and downregulates the survival-promoting BCL-2 family member MCL1 and the oncogenic driver c-Myc, leading to potent antileukemic activity in vitro and in vivo and supporting further development of AB138 for AML therapy.