Investigational New Drugs最新文献

Acute myeloid leukemia (AML) is a malignant clonal hematological tumor originating from immature myeloid cells and is the most prevalent type of leukemia in adults. Traditional chemotherapy regimens based on cytarabine and anthracycline agents are associated with a high relapse rate. Therefore, investigation of novel targeted therapies is crucial for improving AML treatment outcomes. In this study, we found that CTI-2, a novel inhibitor of perinucleolar compartment (PNC), has potential anti-AML activity with a favorable safety profile. CTI-2 induced a greater degree of apoptosis in FLT3-ITD mutant AML cells compared to AML cells with wild-type FLT3 mainly through the intrinsic apoptotic pathway. Furthermore, MK2 and Pim-1 were identified as potential targets of CTI-2 through molecular docking analysis. CTI-2 decreased both the overall expression level and the phosphorylation of c-Myc, which are regulated by MK2 and Pim-1, respectively. Notably, CTI-2 exhibited a more substantial inhibitory effect on c-Myc in FLT3-ITD mutant cells, which may contribute to the enhanced efficacy of CTI-2 in this specific subset of AML. In summary, we have conducted a preliminary investigation into the anti-AML activity and underlying mechanisms of CTI-2. These results provide clues for the targeting of PNC in the treatment of AML.

SL-279252 is a bifunctional hexameric fusion protein adjoining the extracellular domains of PD-1 and OX40L via an inert IgG4 derived Fc domain. A Phase 1 dose escalation study was conducted in patients (pts) with advanced solid tumors or lymphomas. SL-279252 was administered intravenously across 12 dose levels (range: 0.0001-24 mg/kg). Objectives included evaluation of safety, dose-limiting toxicity (DLT), recommended phase 2 dose, pharmacokinetic and pharmacodynamic (PD) parameters, and anti-tumor activity. Forty-nine pts (48 with solid tumor and 1 with lymphoma) were enrolled (median age 64 years; 53% male; median [range] of 3 [0-5] prior systemic therapies; 61% had been previously treated with PD-1/L1 inhibitors). Most common treatment-related adverse events (AEs) were infusion-related reaction (16%), maculopapular rash (10%), fatigue (6%), and neutropenia (6%). Treatment-related Grade (G) 3 AE was neutropenia (4%). There were no G4 or G5 AEs or DLTs. SL-279252 Cmax and area under the curve (AUC) increased proportionally with dose. T½ was ~ 20 h. Baseline anti-drug antibodies (ADA) were observed in 11/42 pts who had received a PD-1 inhibitor within 250 days. 7/31 pts had a persistent SL-279252 induced ADA response. PD effects consistent with OX40 engagement included dose dependent egress of CD4 + OX40 + cells and increases in Ki67 + CD4 and CD8 central and effector memory cells in the blood. Best response by iRECIST [1] in 46 response evaluable subjects was 1 iPR and 15 iSD. SL-279252 was well tolerated. PD effects consistent with OX40 activation were observed, however, efficacy was limited which may have been due to the disease characteristics, prior treatment with PD-1/L1 inhibitors, neutralization of the PD-1 domain of SL-279252 by circulating PD-1 inhibitors, limited SL-279252 penetration into tumors or other variables. Trial register number NCT03894618. Trial registration date 28-March-2019.

HER2 and EGFR are frequently co-expressed in various tumors. While antibody-drug conjugates (ADCs) targeting HER2, such as T-DM1 and T-Dxd, have shown remarkable antitumor effects in clinical responses, their effectiveness is constrained by drug resistance. EGFR amplification or high expression is one of the factors that lead to resistance against HER2-targeted ADCs. Likewise, the amplification of HER2 may lead to the development of resistance to EGFR-targeted therapies. To overcome these challenges, we, therefore, developed a bispecific antibody (B2C4) that targets HER2 and EGFR. B2C4 exhibited strong binding affinity and internalization activity in tumor cells with high expression of HER2 and EGFR, as well as in those with high expression of either target. B2C4 was then conjugated with vc-MMAE to create a bispecific ADC (B2C4-MMAE) with an average DAR of 4.05. By effectively engaging both arms of the bispecific ADC, B2C4-MMAE demonstrated significant antitumor activity in tumor cells and animal models that were unresponsive HER2- or EGFR-targeted ADCs. B2C4-MMAE could serve as an alternative therapeutic option for tumors that are resistant to single-target treatments. Additionally, B2C4-MMAE exhibited potential in treating tumors resistant to T-Dxd, underscoring its promise as a treatment for challenging cases.

To study the clinical features of nivolumab-induced immune-related pancreatitis and to provide evidence for its recognition and treatment. Cases of nivolumab-induced pancreatitis were collected by searching Chinese and English databases until November 30, 2024. Forty-three patients were included, with a median age of 61 years (range 23, 79). The median time to onset of pancreatitis was 120 days (range 1, 990) after initial administration. The main symptoms of the patients were abdominal pain (55.8%), nausea (14.0%), vomiting (11.6%), fever (9.3%), anorexia (9.3%), and asymptomatic (7.0%). Laboratory tests showed elevated lipase and amylase levels, with median values of 391.5 IU/L (range 136, 4050) and 1588 IU/L (range 248, 8788), respectively. Pancreatic biopsy showed inflammatory cell infiltration (18.6%), fibrosis (7.0%), and acinar damage and dropout (4.7%). The main imaging findings were focal or diffuse enlargement of the pancreas and fat stranding. After discontinuation of nivolumab and receiving steroid and immunosuppressive therapy (88.4%), patients' symptoms improved at a median time of 42 days (range 7, 192), and 11.6% of patients died. Immune-related pancreatitis should be alert during nivolumab administration. The lack of specificity of clinical symptoms and laboratory tests confuses the diagnosis of pancreatitis. The diagnosis of immune-associated pancreatitis should be treated promptly.

Poly(ADP-ribose) polymerase (PARP) inhibitors may have cardioprotective properties. This study aimed to evaluate the potential cardioprotective effects of PARP inhibitors in patients with epithelial ovarian cancer treated with platinum-based chemotherapeutic agents. A retrospective cohort study was conducted using the Health Insurance Review & Assessment Service claims database from January 2007 to July 2022. Eligible patients were those diagnosed with ovarian, primary peritoneal, or fallopian tube cancer who received platinum-based chemotherapy after 2017. Propensity score matching was employed to adjust for potential confounders, and logistic regression and Cox proportional hazards regression analyses were utilized to estimate the odds ratios, hazard ratios, and 95% confidence intervals (CIs) for the occurrence of cardiac adverse events, including myocardial infarction, cardiomyopathy, and heart failure. A total of 7,253 eligible patients were included in the study, of which 233 (3.2%) used PARP inhibitors. After propensity score matching, no significant cardioprotective effect was observed in the PARP inhibitor-exposed group compared to the non-exposed group (adjusted odds ratio, 0.753; 95% CI 0.275-2.059; adjusted hazard ratio, 0.601; 95% CI 0.228-1.584). Although no statistically significant cardioprotective effect of PARP inhibitors was found in this study, there was a directional trend suggesting that patients with gynecologic malignancies treated with platinum-based chemotherapy could potentially benefit from PARP inhibitors. Further research with larger sample sizes and longer follow-up periods is warranted to elucidate the role of PARP inhibitors in mitigating cardiac adverse events in this patient population.

Over the past decade, Bruton's tyrosine kinase (BTK) has emerged as a pivotal therapeutic target for B-cell malignancies and autoimmune diseases, given its essential role in B-cell development and function. Dysregulation of BTK signalling is implicated in a range of hematologic cancers, including Waldenström's macroglobulinaemia (WM), mantle cell lymphoma (MCL), and chronic lymphocytic leukaemia (CLL). The development of BTK inhibitors (BTKIs), starting with ibrutinib, has revolutionized the treatment of these malignancies by inhibiting B-cell receptor (BCR) signalling and inducing apoptosis in malignant B-cells. Despite the impressive clinical efficacy of ibrutinib, challenges such as resistance mutations and off-target effects remain. To address these issues, next-generation BTKIs, including acalabrutinib, orelabrutinib, zanubrutinib, and pirtobrutinib, have been developed, offering improved specificity and reduced toxicity profiles. This review highlights the therapeutic potential of BTK-targeted therapies in treating B-cell malignancies, discusses recent advancements with FDA-approved BTKIs, and explores the latest clinical outcomes from ongoing trials of novel inhibitors.

This study investigates the function of Ubiquitin-specific protease 46 (USP46), a deubiquitinase, in the context of lung cancer, particularly its role in regulating cell proliferation via the ubiquitination of TRAF6. In A549 lung cancer cells, analysis revealed a significant downregulation of USP46 expression, while TRAF6 levels were notably elevated. These findings were corroborated by Western blotting, which confirmed the altered expression patterns. To further assess the implications of these changes, several experimental assays, including the Cell Counting Kit-8, transwell migration assays, and flow cytometry, were conducted to evaluate cell viability and apoptosis rates. Co-immunoprecipitation experiments demonstrated a direct interaction between USP46 and TRAF6, implicating USP46 in the modulation of TRAF6 ubiquitination, a process that is fundamental to tumor physiology. The results indicated that decreased USP46 expression led to an increase in the levels of the anti-apoptotic protein Bcl-2, while there was a corresponding decrease in key pro-apoptotic proteins such as caspase-3, caspase-9, and Bax. Additionally, the study found elevated levels of phosphorylated AKT and mTOR, which suggest the activation of survival signaling pathways in the cancer cells. These findings collectively suggest that the up-regulated USP46 promotes apoptosis in lung cancer cells through the regulation of TRAF6. Therefore, targeting the USP46/TRAF6 signaling pathway presents a promising therapeutic strategy for lung cancer treatment, potentially offering new avenues for intervention in cancer progression and cell survival mechanisms.

De novo or acquired resistance to chemotherapy is ubiquitous in pancreatic ductal adenocarcinoma (PDAC). SCO-101 is an oral compound that may counteract chemo-resistance by interacting with SRPK1, ABCG2 drug transporter, and liver enzyme UGT1A1. We first conducted preclinical experiments in paclitaxel-resistant PDAC cells to access the tumoricidal effects of SCO-101 or SRPK1-inhibitor alone or in combination with paclitaxel. Second, we enrolled 22 patients with non-resectable PDAC in a phase Ib trial to investigate safety and pharmaco-kinetics, and to establish maximum tolerated dose (MTD) by evaluation of dose-limiting toxicities (DLTs) during the first cycle of 80% dose gemcitabine (Gem) and nab-paclitaxel (Nab) together with increasing doses of SCO-101. In paclitaxel-resistant PDAC cells in vitro, a synergistic effect between SCO-101 and paclitaxel was demonstrated. In patients, daily doses for 6 days of SCO-101 resulted in a two- to threefold drug accumulation, and drug exposure was dose proportional. Treatment was well tolerated. Transiently increased blood bilirubin attributable to SCO-101 was observed in 12 cases (55%) and associated with jaundice in three patients. One and two DLTs, respectively, were observed at 150 and 250mg dosing-levels of SCO-101, and the MTD was determined to be 200 mg of SCO-101 daily for 6 days on a bi-weekly schedule together with 80% dose of Gem and Nab. Median progression-free and overall survival was 3.3 and 9.5 months, respectively. In PDAC, SCO-101 can be added to Gem and Nab with little and manageable toxicity. However, no clear added efficacy signal was observed of the combination. Trial registration number: NCT04652205 (Nov 29, 2020).

EGFR exon 19 deletions and exon 21 point mutations are the most common mutations in lung adenocarcinoma, with patients deriving significant clinical benefits from EGFR tyrosine kinase inhibitors (TKIs). However, the efficacy of TKIs in rare compound EGFR mutations remains uncertain. We report a case of lung adenocarcinoma with concurrent EGFR exon 18 G719A and exon 21 L833V mutations, showing a favorable response to third-generation TKI treatment. We reported a case of a 63-year-old female patient with brain, bone, and adrenal metastases from lung adenocarcinoma. Next-generation sequencing analysis identified a rare EGFR exon 18 G719A mutation in combination with an EGFR exon 21 L833V mutation. The patient received furmonertinib as first-line treatment and achieved a sustained response lasting over 12 months. This is the first reported case highlighting the efficacy of a third-generation TKI in treating lung adenocarcinoma with this rare compound mutation. Our findings suggest that third-generation TKIs may be a viable therapeutic option for prolonging progression-free survival in this patient subset.