Co-Administration of Vadimezan and Recombinant Coagulase-NGR Inhibits Growth of Melanoma Tumor in Mice

Abstract

Purpose: Tumor vascular targeting appeared as an appealing approach to fight cancer, though, the results from the clinical trials and drugs in the market were proved otherwise. The promise of anti-angiogenic therapy as the leading tumor vascular targeting strategy was negatively affected with the discovery that tumor vascularization can occur non-angiogenic mechanisms such as co-option. An additional strategy is induction of tumor vascular infarction and ischemia. Methods: Such that we used truncated coagulase (tCoa) coupled to tumor endothelial targeting moieties to produce tCoa-NGR fusion proteins. We showed that tCoa-NGR can bypass coagulation cascade to induce selective vascular thrombosis and infarction of mild and highly proliferative solid tumors in mice. Moreover, combination therapy can be used to improve the potential of cancer vascular targeting modalities. Herein, we report combination of tCoa-NGR with vascular disrupting agent (VDA), vadimezan. Results: Our results show that synergistic work of these two agents can significantly suppress growth of B16-F10 melanoma tumors in C57/BL6 mice. Conclusion: For the first time, we used the simultaneous benefits of two strategies for inducing thrombosis and destruction of tumor vasculature as spatial co-operation. The tCoa-NGR induce thrombosis which reduces blood flow in the peripheral tumor region. And combined with the action of DMXAA, which target inner tumor mass, growth and proliferation of melanoma tumors can be significantly suppressed.

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

“…For many tumors, STING agonists are the prime candidates for precision oncotherapy. In many mouse models, stimulating STING with small molecules has yielded promising outcomes [134,[166][167][168]. This activation leads to a decrease in tumor size, primarily due to increased T-cell infiltration, tumor vesicle disruption, and heightened apoptosis.…”

“…There are other crucial points to consider, starting from the vast inter-species differences. For instance, 5,6-dimethylxanthenone 4-acetic acid (DMXAA) binds efficiently to mouse STING but not to human STING, leading to stark differences between preclinical [166][167][168] and clinical results [185] (few of them were published; reviewed in [19,186]). Desired effects might also be muted due to interference from other pathways.…”

Biomaterials-Mediated Tumor Infarction Therapy

“…However, due to the existence of the edge effect ( Dienst et al, 2005 ), the remaining tumor cells continued to grow through blood vessels of the surrounding normal tissue and accelerated the metastasis of the cells. To solve this problem, Adli et al combined the administration of vadimezan and recombinant coagulase-NGR to kill tumor cells ( Daei Farshchi Adli et al, 2021 ). The volume of the tumor in mice in the melanoma model treated by the combined administration group was 73.12%, smaller than that of the control tumor.…”

“…Second, we consider the activation of the fibrin pathway. In contrast to the pathway for exogenous coagulation, fibrinogen can be directly converted into fibrin to avoid the cascade reaction caused by the activation of a large number of coagulation-related factors ( Jahanban-Esfahlan et al, 2017 ; Seidi et al, 2018 ; Daei Farshchi Adli et al, 2021 ). An abnormally large number of coagulation-related factors are likely to cause secondary harm to the patient.…”