Tumor Growth Inhibition Research Articles

Poly (ADP-ribose) polymerase 1 (PARP1) is an important enzyme that plays a central role in the DNA damage response, facilitating repair of single-stranded DNA breaks via the base excision repair (BER) pathway and thus genomic integrity. Its therapeutic relevance is compounded in breast cancer, particularly in BRCA1 or BRCA2 mutant cancers, where compromised homologous recombination repair (HRR) leaves a synthetic lethal dependency on PARP1-mediated repair. This review comprehensively discusses the recent advances in computational chemistry for the discovery of PARP1 inhibitors, focusing on their application in breast cancer therapy. Techniques such as molecular docking, molecular dynamics (MD) simulations, quantitative structure–activity relationship (QSAR) modeling, density functional theory (DFT), time-dependent DFT (TD-DFT), and machine learning (ML)-aided virtual screening have revolutionized the discovery of inhibitors. Some of the most prominent examples are Olaparib (IC50 = 5 nM), Rucaparib (IC50 = 7 nM), and Talazoparib (IC50 = 1 nM), which were optimized with docking scores between −9.0 to −9.3 kcal/mol and validated by in vitro and in vivo assays, achieving 60–80% inhibition of tumor growth in BRCA-mutated models and achieving up to 21-month improvement in progression-free survival in clinical trials of BRCA-mutated breast and ovarian cancer patients. These strategies enable site-specific hopping into the PARP1 nicotinamide-binding pocket to enhance inhibitor affinity and specificity and reduce off-target activity. Employing computation and experimental verification in a hybrid strategy have brought next-generation inhibitors to the clinic with accelerated development, higher efficacy, and personalized treatment for breast cancer patients. Future approaches, including AI-aided generative models and multi-omics integration, have the promise to further refine inhibitor design, paving the way for precision oncology.

Immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with non-small-cell lung cancer (NSCLC), but the cure rate remains low because tolerant persister cancer cells can survive within the tumor during ICI treatment. We have previously reported that plasminogen activator inhibitor-1 (PAI-1) is involved in tolerance acquisition to osimertinib in epidermal growth factor receptor-mutated NSCLC. This study aimed to examine the role of PAI-1 in ICI tolerance and whether PAI-1 may be a therapeutic target to overcome this tolerance. In a mouse subcutaneous tumor model using Lewis lung carcinoma or KLN205 cells, cancer cells surviving within the tumor 7 days after anti-programmed death-1 (aPD-1) antibody treatment were defined as aPD-1 antibody-tolerant persister cells (aPD-1-TPs). PAI-1 and mesenchymal gene expression levels were higher in aPD-1-TPs than in control cells. Immunohistochemical analyses showed higher numbers of tumor-associated macrophages (TAMs), expression of programmed death-ligand 1 (PD-L1) in cancer cells, and degree of angiogenesis. In contrast, the number of tumor-infiltrating lymphocytes (TILs) was lower in aPD-1 antibody-tolerant tumors than in control tumors. Combination treatment with an aPD-1 antibody and the PAI-1 inhibitor TM5614 decreased mesenchymal gene expression, PD-L1 expression, TAM numbers, and angiogenesis and increased TIL counts in tolerant tumors. Furthermore, it resulted in prolonged inhibition of tumor growth. In conclusion, this study underscores the involvement of PAI-1 in the survival of aPD-1-TPs via epithelial-mesenchymal transition and alteration of the tumor microenvironment. Combination treatment with an aPD-1 antibody and TM5614 can be a new therapeutic strategy for NSCLC.

Pifithrin-[Formula: see text], a potent dual-pathway inhibitor of p53 and HSP70, suffers from poor aqueous solubility and dose-limiting systemic toxicity, which severely hinder its anticancer efficacy. To overcome these limitations, we developed melanin-based nanospheres (MNSs) through alkaline-driven self-polymerization of dopamine. Capitalizing on [Formula: see text]–[Formula: see text] stacking interactions, we achieved efficient surface loading of pifithrin-[Formula: see text] (forming MNS-[Formula: see text] with a high drug-loading capacity of 40%. The resulting MNS-[Formula: see text] platform exhibited excellent colloidal stability under simulated physiological conditions and displayed sustained, thermoresponsive drug release kinetics, retaining [Formula: see text] of the payload at physiological temperature while triggering rapid release at [Formula: see text]C. Flow cytometry and confocal microscopy analyzes confirmed enhanced cellular internalization of MNS-[Formula: see text] in HepG2 cells. Upon laser irradiation, MNS-[Formula: see text] mediated localized photothermal effects, enabling spatiotemporally controlled drug release and significant cytotoxicity, reducing HepG2 cell viability to 35% at 200[Formula: see text][Formula: see text]g/mL. In contrast, PEGylated MNS (MNS-PEG) controls showed negligible photothermal toxicity. In a HepG2 xenograft mouse model, the combination of MNS-[Formula: see text] and near-infrared (NIR) irradiation achieved superior tumor growth inhibition ([Formula: see text] reduction in tumor volume) compared to free pifithrin-[Formula: see text] monotherapy, attributable to enhanced tumor accumulation and on-demand drug release. Histopathological examination revealed extensive tumor necrosis in the combination group without observed systemic toxicity. This study highlights MNSs as a versatile and biocompatible nanoplatform for enhancing the therapeutic index of hydrophobic agents via photothermally augmented targeting and stimuli-responsive delivery.

Despite recent advances in the treatment of fibroblast growth factor receptor 3 (FGFR3)-altered metastatic urothelial carcinoma, there is no approved precision therapy that selectively targets FGFR3 while sparing other FGFR isoforms. Dabogratinib (TYRA-300)-a rationally designed selective FGFR3 inhibitor-was evaluated in vitro and in vivo. We also report three patient cases from the ongoing first-in-human, phase I/II SURF301 study (NCT05544552). Dabogratinib elicited a dose-dependent reduction in downstream signaling across three bladder cancer cell lines harboring an FGFR3 fusion, mutation, or gatekeeper resistance mutation. In a xenograft model driven by an FGFR3S249C-activating mutation, dabogratinib treatment resulted in dose-dependent tumor growth inhibition with tumor regression observed at the highest doses. These preclinical findings are supported by the three case reports from the SURF301 study, which demonstrate early clinical activity in patients with advanced metastatic urothelial carcinoma with an FGFR3 fusion or activating mutation.

Newcastle disease virus (NDV) is a promising oncolytic virus, yet requires further optimization. In this study, we engineered an F-gene-chimeric NDV expressing human Interleukin 2 (hIL-2) to enhance the oncolytic efficacy of the NDV Clone30 strain. This recombinant virus, designated ovNDV-28, was then produced in suspension-cultured HEK293 cells. The therapeutic potential of ovNDV-28 was evaluated across multiple cancer cell lines, as well as in the HuH-7 xenograft and B16-F0 syngeneic models. Both in vitro and in vivo results demonstrated that ovNDV-28 significantly improved tumor growth suppression compared to the wild-type NDV. Flow cytometry revealed notable increases in tumor-infiltrating CD3⁺CD4⁺ T cells, CD3⁺CD8⁺ T cells, and CD3⁻CD49b⁺ cells, along with elevated expression levels of IFN-γ, TNF-α, perforin, and Granzyme B within tumor tissue. Comprehensive toxicological assessments conducted on B16-F0 tumor-bearing mice involved intratumoral administration of ovNDV-28 at doses of 1.12 × 10⁶ or 1.46 × 10⁷ PFU/mouse every other day for 14 days. No ovNDV-28-related biochemical, hematological, or histopathological abnormalities were observed. The virus was detected in tumor tissue, mesenteric lymph nodes, abdominal adipose tissue, brain, and biceps femoris, without evidence of blood circulation or viral shedding. This study systematically demonstrates the efficacy, safety, and pharmacokinetics of ovNDV-28, supporting its potential for clinical translation.

Targeted mitochondrial-based therapeutic strategies for tumors have emerged as a significant research focus in the field of cancer treatment in recent years. Mitochondria, often referred to as the "energy factory" of cells, play a crucial role in the metabolic reprogramming of tumor cells, as well as in oxidative stress and immune evasion. In this study, we utilized a mitochondria-targeted photosensitizer, IR780, to engineer Celastrol (Cela)-loaded lipid nanoparticles, designed as Cela@Lip-IRH, for the synergistic therapy of chemotherapy and photodynamic therapy (PDT) against glioma. Cela@Lip-IRH could respond to the weakly alkaline environment of tumor cell mitochondria for rapid Cela release. Leveraging the mitochondrial targeting capacity and PDT property of IR780, Cela@Lip-IRH nanoparticles showed enhanced cellular uptake and mitochondria targeting distribution in vitro, as well as obvious tumor accumulation in vivo. Cela@Lip-IRH nanoparticles exhibited prominent intracellular reactive oxygen species (ROS) generation upon NIR laser irradiation, which was accompanied by pronounced photocytotoxicity and cell apoptosis, finally producing remarkable tumor growth suppression efficacy in vivo. We further verified that the potential antitumor molecular mechanism was triggered by the release of Cytochrome C, leading to an activated mitochondrial apoptosis pathway, alongside an immune response characterized by enhanced recruitment of CD4+ T cells and CD8+ T cells in tumor tissues. Currently, this mitochondria-targeted nanoplatform presents an ideal method to enhance the synergistic performance of chemotherapy and PDT in glioma, and it is anticipated that such a strategy will provide a promising alternative to optimize the tumor-targeted therapies.

Improved peptide pharmacokinetics are needed to enhance the therapeutic effects of peptide-based radionuclide therapy. Conjugation of albumin binders, such as fatty acids, to tumor-targeting peptides slows blood clearance, resulting in higher tumor uptake. In this study, we synthesized PD-conjugated monomeric and dimeric RGD peptides, PD-K-(111In-DOTA)-c(RGDfK) and PD-K(111In-DOTA)-E[c(RGDfK)]2, and evaluated their albumin binding. We compared pharmacokinetics with and without PD in tumor-bearing mice. The therapeutic effects of PD-K(177Lu-DOTA)-c(RGDfK) (7.5, 15, and 30 MBq) and PD-K(225Ac-DOTA)-c(RGDfK) (20 and 40 kBq) were investigated in tumor-bearing mice. 177Lu-DOTA-c(RGDfK) (30 MBq) was used as a control to evaluate the therapeutic effects of PD conjugation in comparison with PD-K(177Lu-DOTA)-c(RGDfK). An invitro binding study using HSA showed that the conjugation of PD significantly enhanced the albumin-binding ability. The albumin-binding percentages of 111In-DOTA-c(RGDfK) and 111In-DOTA-E[c(RGDfK)]2 were less than 1%, while their PD conjugates were 50.93 ± 1.87 and 29.96 ± 1.60, respectively. A biodistribution study revealed that PD conjugates significantly prolonged blood clearance and increased tumor uptake. Unexpectedly, the tumor uptake of PD-K-(111In-DOTA)-c(RGDfK) was more sustained than that of PD-K(111In-DOTA)-E[c(RGDfK)]2, corresponding to their albumin-binding ability. In the therapeutic experiments with PD-K(177Lu-DOTA)-c(RGDfK), only 30 MBq suppressed tumor growth. PD-K(225Ac-DOTA)-c(RGDfK) significantly inhibited tumor growth; however, elevated ALT and AST levels were observed in mice treated with 40 kBq. Thus, PD conjugation successfully increased tumor uptake by prolonging blood clearance, leading to preferential therapeutic efficacy. This study demonstrated that PD-K(225Ac-DOTA)-c(RGDfK) enhanced the therapeutic effects of radionuclide therapy by sustaining high tumor uptake, which led to significant tumor growth inhibition and prolonged median survival time.

Lipid metabolism plays a pivotal role in tumor growth and survival, with altered lipid pathways being associated with cancer progression. Statins, well-known for their cholesterol-lowering properties, have emerged as potential anticancer agents by targeting lipid metabolism in tumors. However, their clinical use is limited due to low bioavailability and stability. Encapsulating statins in polymeric nanocapsules has been suggested to overcome these limitations and enhance therapeutic efficacy. Methods: This systematic review and meta-analysis compiled data from 22 preclinical studies involving 127 animals to evaluate the antitumor efficacy of statin-loaded polymeric nanocapsules. The meta-analysis assessed tumor growth inhibition, tumor weight reduction, and the overall effect size of these nanocapsules compared to non-encapsulated statins. Statistical methods were used to compute Standard Mean Differences (SMD) and evaluate heterogeneity. Results: The meta-analysis showed that statin-loaded polymeric nanocapsules significantly inhibited tumor growth (SMD −1.79; 95% CI −2.21 to −1.38; p < 0.00001) and reduced tumor weight (SMD –3.53; 95% CI −4.75 to −2.31; p < 0.0001) across various solid tumor models. Risk of bias assessments indicated moderate to high variability in the quality of the included studies. Conclusions: Statin-loaded polymeric nanocapsules significantly enhance the antitumor efficacy of statins by improving their bioavailability and stability. These findings highlight the potential of nanomedicine in cancer therapy, particularly for tumors dependent on lipid metabolism. Future clinical trials are needed to validate these preclinical results and further explore the clinical applicability of statin-loaded nanocapsules in cancer treatment. Implications for Clinical Practice and Future Research: The development of statin-loaded polymeric nanocapsules offers a promising strategy for enhancing the effectiveness of statins in cancer therapy. Future research should focus on optimizing nanocapsule formulations, conducting clinical trials to assess long-term safety and efficacy, and exploring combination therapies with other anticancer agents.

The programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, a pivotal immune checkpoint, enables tumor immune evasion, and its blockade is fundamental to cancer immunotherapy. The development of small-molecule agents targeting the PD-1/PD-L1 pathway offers a promising strategy for enhancing antitumor immunity. In this study, we screened an in-house compound library using RKO cells to discover novel PD-L1 downregulators. MS1-96 was identified as a potent PD-L1 degrader that promotes lysosome-dependent PD-L1 degradation. Furthermore, MS1-96 effectively reduced PD-L1 protein levels across multiple colorectal cancer (CRC) cell lines. By disrupting the PD-1/PD-L1 pathway, MS1-96 enhances CD8+ T cell-mediated killing of carcinoma cells and exerts dose-dependent antitumor effects in C57BL/6 mice bearing MC38 CRC xenografts, resulting in significant tumor growth inhibition after oral administration for 10 d (100, 200, or 400 mg·kg⁻¹·d⁻¹). Mechanistic studies revealed that Huntingtin interacting protein 1-related (HIP1R) plays an indispensable role in MS1-96-driven PD-L1 degradation, and HIP1R knockdown abolishes MS1-96's ability to degrade PD-L1. MS1-96 directly binds to PD-L1 with a KD of 2.58 μM and enhances the interaction between HIP1R and PD-L1, thereby altering the intracellular trafficking of PD-L1 within clathrin-coated vesicles. This leads to reduced transport of PD-L1 to recycling endosomes and increased delivery to late endosomes and lysosomes for degradation. Furthermore, MS1-96 induces abnormal N-glycosylation of PD-L1, destabilizing the protein and hastening its lysosome-mediated degradation. Moreover, MS1-96 effectively enhances the antitumor efficacy of PD-1 antibodies in MC38 CRC models. These findings indicate that MS1-96 offers a potential strategy for advancing tumor immunotherapy.

Novel β-carboline derivatives show promise as dual-target inhibitors of DNA and TOP2A for the treatment of triple negative breast cancer.

Prognostic implications of antitumour efficacy and adverse events of EGFR-TKIs in non-small cell lung cancer: an ambispective cohort study.

Astragaloside IV potentiates cisplatin sensitivity in triple-negative breast cancer via STING signaling pathway activation.

Multi-omics profiling reveals ortho-topolin riboside and protocatechualdehyde combination exhibits anti-proliferative activity by modulating metabolic pathways in in vitro and in vivo radio-resistant MDA-MB-231 cell models.

pH-triggered small molecule theranostic nanodrug mediates selective tumor CT imaging and chemotherapy.

An injectable nanosuspension based on orthoester and biomimetic carboxymethyl chitosan nanoparticles for chemo/thermo-synergistic tumor therapy.

Discovery of novel microtubule destabilizing agents via virtual screening methods and antitumor evaluation.

Multifunctional silver nanoclusters with hyaluronic acid for dual-targeted tumor imaging and ROS-mediated therapy.

Artesunate induces ferroptosis in gastric cancer by targeting the TFRC-HSPA9 axis for iron homeostasis regulation.

Synthesis and evaluation of lactam and maleimide derivatives of 16-hydroxycleroda-3, 13 (14) Z-dien-15, 16-olide from Polyalthia longifolia as potential anticancer agents.

Rational design of NAMPT-based dual inhibitors with improved drug-like and pharmacokinetic properties for cancer treatment.