Emerging Mechanism of Action

Emerging Mechanisms of Action for Solid Tumors

Recent publications highlight several innovative mechanisms of action emerging for solid tumor treatment:

Molecular Targeting Approaches

Epigenetic modifications are gaining prominence, with N6-methyladenosine (m6A) being the most abundant RNA modification playing important roles in various cancers. Histone methylation is another important target, with lysine demethylases influencing oncogenic pathways and drug resistance by modulating cancer cell metabolism.

RET inhibitors represent a major therapeutic target as RET alterations occur in nearly 2% of all cancers. Six inhibitors have been approved, with recent approvals focusing on selective RET inhibitors rather than multikinase inhibitors.

Mitochondrial-Based Strategies

Mitochondrial inhibition is emerging as a viable strategy for eradicating cancer stem cells, which show high chemo- and radioresistance. Recent approaches include: - Dextran-based nano-assemblies that target mitochondria and deplete glutathione (GSH) to enhance photodynamic therapy - "Vehicles" capable of transporting pharmacophores to mitochondrial tumor cells - Combined approaches targeting mitophagy, fusion, and fission of mitochondria

Novel Therapeutic Modalities

Metallodrugs show promise as alternatives to platinum-based medicines, including ruthenium, gold, copper, iridium, and osmium complexes effective against many cancer cell lines with less toxicity.

Photodynamic therapy (PDT) offers promising treatment against glioblastoma multiforme (GBM) cells, with β-galactosidase (β-gal) activatable phototheranostic agents being developed.

Gold nanoparticles (AuNPs) with photothermal properties are being developed for thermal ablation of tumors, showing significant inhibition effects both in vitro and in vivo.

Targeting Tumor Microenvironment

Tumor-associated macrophages (TAMs) are being targeted through three main approaches: - Reprogramming TAMs toward anti-tumor function - Blockade of recruitment - Reduction/ablation of TAMs

Imaging mass cytometry (IMC) with a panel of 31 markers enables spatially resolved analyses of intra-tumor heterogeneity at the single-cell level.

Cell Death Pathways

Pyroptosis-related genes (PRGs) are being studied as potential targets in skin cutaneous melanoma, with eight specific PRGs identified: AIM2, CASP3, GSDMA, GSDMC, GSDMD, IL18, NLRP3, and NOD2.

Autophagy modulation shows promise, with inhibitors like UAMC-2526 demonstrating beneficial effects when combined with gemcitabine in pancreatic ductal adenocarcinoma. Conversely, core-shell nanoinducers that trigger excessive autophagy using near-infrared light have shown remarkable efficacy in inhibiting tumor growth.

Drug Repurposing

Anthelmintic benzimidazoles (albendazole, mebendazole, flubendazole) are being repurposed for their anticancer potential due to their effects on microtubules and oncogenic signaling pathways.

Calycosin, a phytoestrogen from traditional Chinese medicine, has demonstrated inhibitory effects against various cancers by reducing tumor cell proliferation, inducing apoptosis, and suppressing migration and invasion.

Emerging End Points

Drugs with the Same Mechanism of Action as Nivolumab

Based on the provided context, there are several immune checkpoint inhibitors that share the same mechanism of action as Nivolumab, which is a fully human monoclonal antibody against programmed death receptor-1 (PD-1). However, there is no information available about Visugromab in the context, making it impossible to identify drugs that share mechanisms with both Visugromab and Nivolumab.

Other PD-1/PD-L1 Inhibitors

The following drugs share the same or similar mechanism of action as Nivolumab:

• PD-1 Inhibitors:

• Pembrolizumab - Used for treatment of cisplatin-ineligible patients with transitional cell cancer

• Cemiplimab - Mentioned in ocular adverse events study

• Sintilimab - Studied in esophageal squamous cell carcinoma

• Camrelizumab - Studied in esophageal squamous cell carcinoma

• Toripalimab - Studied in esophageal squamous cell carcinoma

• PD-L1 Inhibitors (related but slightly different target):

• Atezolizumab - Approved for cisplatin-ineligible patients with transitional cell cancer

• Avelumab - Mentioned in ocular adverse events study

• Durvalumab - Mentioned in ocular adverse events study

Intervention Models for Clinical Trials

These immune checkpoint inhibitors are being studied using various intervention models:

• Randomized, double-blind, phase 3 trials - Such as CheckMate 238 comparing nivolumab versus ipilimumab
• Non-comparative, open-label, phase II trials - Used for nivolumab in Japanese patients with melanoma

• Combination therapy models including:

• Nivolumab plus ipilimumab (anti-CTLA-4)

• Nivolumab plus cabozantinib (a multikinase blocker)

• Pembrolizumab plus axitinib (VEGFR and PDGFR blocker)

• Pembrolizumab plus lenvatinib (multikinase inhibitor)

• Nivolumab plus sitravatinib

• Atezolizumab plus bevacizumab

• Azacitidine plus nivolumab (for AML)

• Monotherapy models - Single-agent trials of various checkpoint inhibitors
• Multicenter phase II studies - Used for nivolumab in cancer of unknown primary
• Bayesian approach trials - Used in nivolumab study for glioblastoma

These drugs are being investigated for multiple indications including melanoma, renal cell carcinoma, urothelial carcinoma, glioblastoma, cancer of unknown primary, esophageal squamous cell carcinoma, and pituitary tumors.

Clinical trials for these PD-1/PD-L1 inhibitors include phase 1, phase 2, and phase 3 trials, with many studies comparing monotherapy versus combination therapy approaches to determine optimal treatment strategies.