Investigational New Drugs最新文献

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.

Lynch syndrome (LS) is an autosomal autosomal dominant inherited disease characterized by impaired DNA mismatch repair (dMMR), resulting in an elevated susceptibility to various types of cancer. The incidence of brain cancers in individuals with LS ranges from 2 to 8%, with the highest risk observed for glioblastoma, astrocytoma, and oligodendroglioma. Medulloblastoma (MB) with Lynch syndrome, a common malignant brain tumor in children, is exceedingly rare. In this case, we present a case of a pediatric patient diagnosed with MB based on clinical and pathological findings, which was further characterized as an TP53-mutant, SHH-activated MB through next-generation sequencing (NGS), and methylation profiling. His tumor was found to harbor a somatic MSH2 mutation and a suspected pathogenic germline MLH1 heterozygous variant. Simultaneously, the tumor exhibited microsatellite instability-high (MSI-H) and an exceptionally elevated tumor mutation burden (TMB = 297.17 Mut/Mb). The presence of the MLH1 germline variant in the patient's mother and maternal grandmother was confirmed by sequencing, and the patient's maternal grandmother had a history of colorectal cancer. Ultimately, the patient was diagnosed with MB associated with LS. This case is the third case of LS with medulloblastoma, which contributes additional evidence to the cancer spectrum associated with LS and presents a novel avenue for patient treatment.

Interleukin (IL)-1 signaling has an essential role in tumor progression and immunosuppression and is linked to acquired resistance to anti-PD-1/PD-L1 treatment. Nadunolimab is an IL1RAP (IL-1 receptor accessory protein)-targeting antibody that blocks IL-1α/IL-1β signaling and has enhanced antibody-dependent cellular cytotoxicity. We investigated the safety and preliminary efficacy of nadunolimab with pembrolizumab in patients with metastatic solid tumors who had progressed on previous checkpoint inhibitor treatment, suggesting acquired checkpoint inhibitor resistance (NCT04452214). This phase 1b trial enrolled patients with metastatic disease who had exhausted or declined standard-of-care alternatives. Patients received nadunolimab (5 mg/kg) and standard-dose pembrolizumab. The primary objective was to assess safety. Secondary objectives were anti-tumor response as per iRECIST, pharmacokinetics, and changes in immune mediators. Fifteen patients with stage IV cancer (head and neck squamous cell carcinoma, non-small cell lung cancer, melanoma) entered the trial. Grade ≥ 3 adverse events were reported for 7 patients (47%). There was one dose-limiting toxicity of febrile neutropenia. The most frequent grade ≥ 3 adverse event was dysphagia (two patients). Seven patients (47%) had reductions in target lesion size. Median iPFS was 3.4 months (95% CI 1.4-8.6). Median OS was 19.7 months (95% CI 4.3-28.7) with 67% 1-year survival. Survival was significantly longer in patients with higher baseline tumor infiltration of CD163 + macrophages and natural killer cells and in patients with reduced on-treatment circulating IL-6 levels or neutrophil-to-lymphocyte ratio. Nadunolimab with pembrolizumab had an acceptable safety profile, and prolonged disease control was observed in a subset of patients. The results support further development of nadunolimab in combination with checkpoint inhibitors.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with poor prognosis and limited treatment options, particularly in advanced stages. Glypican-3 (GPC3) has emerged as a promising therapeutic target, but existing antibodies primarily bind its C-terminal region, where glycosylation can mask epitopes and compromise efficacy. To address this limitation, we focused on the GPC3 N-terminal region, which offers better accessibility and potential for tumor signaling regulation. We developed Pro-12, a high-affinity humanized IgG1 antibody targeting the 25-45 peptide of the GPC3 N-terminus, avoiding glycosylation interference while modulating tumor pathways. Building on Pro-12, we engineered a GPC3/CD3 bispecific antibody (BsAb) using CrossMab and Knob-into-Hole technologies. This BsAb demonstrated dual anti-tumor effects by activating immune cells and inhibiting both the Wnt/β-catenin and PI3K/AKT pathways, achieving outcomes typically requiring tri-specific antibodies. Our findings highlight the GPC3 N-terminal region as a novel therapeutic target and introduce a promising bispecific antibody approach for the treatment of GPC3-positive HCC.

Objective: Limited treatment options for primary central nervous system lymphoma (PCNSL) highlight the need for alternative therapies. This study evaluated orelabrutinib (O) and rituximab (R), plus high-dose methotrexate (M) (ORM), as a potential induction therapy for newly diagnosed PCNSL.

Methods: Patients received six cycles of 150 mg/day orelabrutinib, 375 mg/m² rituximab, plus 3.5 g/m² methotrexate every 3 weeks, followed by autologous hematopoietic stem cell transplantation and orelabrutinib maintenance. The primary endpoint was the overall response rate (ORR) at the end of induction therapy. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety.

Results: From October 21, 2020, to October 22, 2024, 28 patients were treated and evaluated for efficacy and safety analyses. At the end of induction therapy, the ORR was 71.4% (95% CI, 51.3-86.8), including 16 (57.1%) complete and 4 (14.3%) partial responses. At a median follow-up of 21.6 months, the median PFS was 35.3 months (95% CI, 8.4-not evaluable), and the median OS was not reached, with PFS and OS rates of 64.3% and 96.3% at 1 year, 64.3% and 90.9% at 2 years, and 45.9% and 82.7% at 3 years, respectively. All 28 (100%) patients experienced treatment-related adverse events (TRAEs) of any grade. Grade 3 TRAEs occurred in seven (25.0%) patients, including five (17.9%) leukopenia, one (3.6%) thrombocytopenia, and one (3.6%) diarrhea. No other Bruton's tyrosine kinase inhibitor-related off-target toxicities (e.g., atrial fibrillation/flutter) or TRAE-related deaths were observed.

Conclusion: The ORM induction regimen showed anti-tumor activity with a favorable safety profile, offering a potential therapeutic strategy for newly diagnosed PCNSL.

Clinical trial registration:  ClinicalTrials.gov: NCT05600660.

Diffuse large B cell lymphoma (DLBCL) presents a great challenge in the clinic due to its poor prognosis. Prior research has identified c-Myc as a promising therapeutic target in DLBCL; however, direct targeting of c-Myc protein has proven challenging. The bromodomain and extraterminal (BET) protein family, which acts as transcriptional and epigenetic regulators, plays a crucial role in super-enhancer organization and transcriptional regulation of oncogenic drivers like c-Myc, offering an alternative approach. Recently developed BET proteolysis targeting chimera (PROTAC) compounds can rapidly and effectively degrade BET proteins and potentially offer a more durable effect than traditional BET inhibitors. In this work, we compared the anti-tumor activity of a BET PROTAC, ARV-825, with a BET inhibitor, JQ1, in DLBCL. Cell proliferation was assessed by CCK-8 assay, apoptosis was evaluated by Annexin V/PI staining, and the cell cycle was analyzed by staining DNA with propidium iodide (PI). Western blotting was used to determine the expression levels of BET family proteins and its downstream regulatory gene c-Myc, and the in vivo SCID mouse model implanted with SU-DHL-4 cells was used to analyze the in vivo drug efficacy. Our results showed that ARV-825 was superior to JQ1 in inhibiting DLBCL cell proliferation, inducing apoptosis, promoting cell cycle arrest, and prolonging survival. Notably, ARV-825 was more effective at downregulating c-Myc and BET protein levels than JQ1 in both in vitro and in vivo experiments. These evidences suggest that BET-PROTACs may offer a promising novel strategy for the clinical treatment of DLBCL.

Cancer is a major cause of morbidity and mortality, making it one of the most debilitating diseases in our time. Despite advancements in therapeutic strategies, the development of chemoresistance and the occurrence of secondary tumours pose significant challenges. While several promising anti-tumour agents have been identified, their clinical utility is often limited due to toxicity and associated side effects. MicroRNAs (mi-RNAs) are critical regulators of gene expression, and their altered levels are closely linked to cancer development and progression. Although some microRNAs have shown potential as biomarkers for cancer detection, their integration into routine clinical practice has yet to be realized. Numerous candidate microRNAs exhibit therapeutic potential for cancer treatment; however, further research is needed to create efficient, patient-compliant, and customized drug delivery systems. In recent decades, various nanotechnology platforms have successfully transitioned to clinical trials, particularly in the field of RNA nanotechnology. Several RNA nanoparticles have been developed to address key challenges in vivo for targeting cancer, demonstrating favourable biodistribution characteristics. Studies have shown that RNA nanoparticles, characterized by precise stoichiometry and homogeneity, can effectively target tumour cells while avoiding aggregation in normal, healthy tissues following systemic injection. Animal models have demonstrated that RNA nanoparticles can deliver therapeutics such as siRNA and anti-microRNA, effectively inhibiting tumour growth. Using nanoparticles conjugated with antibodies and/or peptides enhances the targeted delivery and sustained release of microRNAs and anti-microRNAs, which may reduce the required therapeutic dosage and minimize systemic and cellular damage. This review focuses on developing microRNA nanoformulations to improve cellular uptake, bioavailability, and accumulation at tumour sites, assessing their potential anti-tumour efficacy against various types of malignancies. The significance of these advancements in clinical oncology cannot be overstated.

Olaparib is selected based on the presence of BRCA mutations in patient populations; however, further investigation is still required regarding its effect on restoring homologous recombination (HR) through the inactivation of non-homologous end joining (NHEJ). Therefore, identifying regulators of NHEJ could increase the sensitivity of cancer cells to Olaparib by inhibiting DNA damage repair is a major focus of current research. Loss of DNA-dependent protein kinase (DNA-PK), which is a major components of NHEJ, compromises DNA damage repair, and the resulting increase in DNA damage burden may heighten reliance on poly (ADP-ribose) polymerase (PARP)-dependent DNA repair in cancer cells, rendering them more susceptible to PARP inhibitor therapy. However, DNA-PK alone is not sufficient to enhance the effectiveness of Olaparib, so various adjuvant and combination therapies are being explored. We classified colorectal cancer (CRC) cells based on their sensitivity to Olaparib and found that they were categorized according to TP53 status. Here, we examine the role of DNA-PK in the response to Olaparib, emphasizing its relationship with TP53 status. Our findings indicate that the inhibition of DNA-PK enhances sensitivity to Olaparib and induces phosphorylation of p53 exclusively in cells with TP53 wild-type (WT). Furthermore, using CRC patient-derived cells (PDC) and patient-derived xenograft (PDX) model, we show that the sensitivity of Olaparib is determined TP53 and DNA-PK genotypes. These findings highlight TP53 and DNA-PK as potential predictive biomarkers for optimizing PARP inhibitor-based therapy in CRC.

Mitochondrial dysfunction is a key driver of cancer progression, with therapies increasingly targeting metabolic weaknesses. Peptide YY (PYY), a gastrointestinal hormone, regulates cellular activity, but its influence on mitochondrial health in lung cancer remains poorly understood. We explored how PYY1-36, a bioactive fragment of PYY, affects mitochondrial stability in NCI-H1581 lung cancer cells. Using dose-response experiments, we measured oxidative stress by tracking lactate dehydrogenase (LDH) release, mitochondrial ROS levels, and oxidative DNA damage (8-OHdG). Energy production was evaluated through ATP levels, oxygen consumption rates (OCR), and Complex I activity. We also analyzed mitochondrial biogenesis markers (NRF1, TFAM, PGC-1α) and the RNA-binding protein RBM43 via qPCR and immunoblotting. Dose-dependent tests showed that PYY1-36 triggers mitochondrial oxidative damage, marked by higher LDH release and ROS spikes. These changes aligned with sharp drops in ATP production and disrupted respiratory function. Notably, PYY1-36 reduced mitochondrial mass and biogenesis, supported by weaker MitoTracker Red signals and lower mtDNA/nDNA ratios. Key regulators NRF1 and TFAM were strongly suppressed, pointing to widespread mitochondrial failure. Intriguingly, PYY1-36 blocked PGC-1α protein synthesis without altering mRNA levels, suggesting a post-transcriptional control mechanism. PYY1-36 also boosted RBM43 levels. Knocking down RBM43 reversed PYY1-36's effects on PGC-1α and mitochondrial health. Our findings reveal RBM43 as a central player in PYY1-36-induced mitochondrial dysfunction through its suppression of PGC-1α translation. Targeting RBM43 could unlock new strategies to tackle metabolic chaos in lung cancer.