Treatment Effect of a Vascular-Disrupting Agent Dynamically Monitored by DWI: An Animal Experimental Study

Objective. To investigate the treatment effect of a vascular-disrupting agent, M410, using diffusion-weighted imaging in a rabbit model of hepatic VX2 tumor. Methods. 28 New Zealand white rabbit models with VX2 liver tumors were established and were randomly divided into M410 (intravenous injection of M410 at a dose of 25 mg/kg every three days) and control (intravenous injection of saline every three days) groups. Conventional and diffusion-weighted imaging (DWI) were acquired on a 3.0 T MR unit at baseline, 4 h, d 1, d 4, d 7, and d 14 posttreatment. B-value with 700 (s/mm2) was chosen during DWI examinations. Tumor volume and apparent diffusion coefficient (ADC) values of the entire tumor and solid component of the tumor at every time point were measured. Two randomly chosen rabbits from each group were sacrificed for H&E staining and CD34 immunohistochemical assessments at each time point. An independent sample t-test was used to assess differences in tumor sizes and ADC values of the entire tumor and solid component of tumors between two groups, with P < 0.05 considered statistically significant. Result. There was no significant difference in tumor volume between the two groups at baseline, 4 h, and d 1. With time, the tumors in the control group grew significantly faster than those in the M410 group, and the average ADC values of the M410 group were lower than those of the control group at d 1 and higher than those of the control group at d 4; as such, there were statistical differences between the two groups at these two time points but not at the other four time points. The following pathological results reflected the underlying morphological changes and vascular alterations. Conclusions. M410 performed well in inhibiting the growth of the hepatic VX2 tumor which could be noninvasively monitored by DWI metrics.

The Proper Administration Sequence of Radiotherapy and Anti-Vascular Agent—DMXAA Is Essential to Inhibit the Growth of Melanoma Tumors

Vascular disrupting agents (VDAs), such as DMXAA, effectively destroy tumor blood vessels and cause the formation of large areas of necrosis in the central parts of the tumors. However, the use of VDAs is associated with hypoxia activation and residues of rim cells on the edge of the tumor that are responsible for tumor regrowth. The aim of the study was to combine DMXAA with radiotherapy (brachytherapy) and find the appropriate administration sequence to obtain the maximum synergistic therapeutic effect. We show that the combination in which tumors were irradiated prior to VDAs administration is more effective in murine melanoma growth inhibition than in either of the agents individually or in reverse combination. For the first time, the significance of immune cells’ activation in such a combination is demonstrated. The inhibition of tumor growth is linked to the reduction of tumor blood vessels, the increased infiltration of CD8+ cytotoxic T lymphocytes and NK cells and the polarization of macrophages to the cytotoxic M1 phenotype. The reverse combination of therapeutic agents showed no therapeutic effect and even abolished the effect of DMXAA. The combination of brachytherapy and vascular disrupting agent effectively inhibits the growth of melanoma tumors but requires careful planning of the sequence of administration of the agents.

The diagnostic efficiency of the perfusion-related parameters in assessing the vascular disrupting agent (CA4P) response in a rabbit VX2 liver tumor model

Background There are inconsistencies when concomitantly using dynamic contrast enhancement (DCE) and intravoxel incoherent motion (IVIM) to evaluate diagnostic efficiency. Purpose To evaluate the diagnostic efficiency of perfusion-related parameters in assessing the effect of Combretastatin-A4-phosphate (CA4P) in a rabbit VX2 liver tumor model using DCE and IVIM. Material and Methods Twenty rabbits implanted with VX2 tumors were included in the study. The perfusion-parameters of DCE ( Ktrans and iAUC60) and IVIM ( f and D*) were measured at baseline and 4 h after administration of CA4P. Subsequently, the rabbits were euthanized. Pre- and post-treatment perfusion parameters were analyzed using paired t-test. Correlation between the various perfusion parameters and correlation of perfusion parameters with microvascular density (MVD) were assessed using Pearson correlation analysis. The diagnostic efficiency was evaluated using receiver operating characteristic (ROC) curve analysis. Results All perfusion parameters ( Ktrans, iAUC60, f and D*) showed significant decrease after 4 h of CA4P administration (all P < 0.001). Post-treatment perfusion parameters showed a moderate correlation with MVD (r = 0.663, r = 0.567, r = 0.685, r = 0.618, respectively; all P < 0.05). At baseline and after treatment, Ktrans values and iAUC60 showed correlation with f and D* (all P < 0.05). Concomitant use of perfusion parameters of DCE and IVIM showed the best diagnostic performance, which was slightly greater than that observed with individual application of DCE or IVIM (AUC = 0.915, 0.880, and 0.895, respectively). Conclusion Although concomitant application of DCE and IVIM can slightly improve the diagnostic value in assessing the effect of CA4P, the values were relatively small.

Discovery of new vascular disrupting agents based on evolutionarily conserved drug action, pesticide resistance mutations, and humanized yeast

Thiabendazole (TBZ) is an FDA-approved benzimidazole widely used for its antifungal and antihelminthic properties. We showed previously that TBZ is also a potent vascular disrupting agent and inhibits angiogenesis at the tissue level by dissociating vascular endothelial cells in newly formed blood vessels. Here, we uncover TBZ’s molecular target and mechanism of action. Using human cell culture, molecular modeling, and humanized yeast, we find that TBZ selectively targets only 1 of 9 human β-tubulin isotypes (TUBB8) to specifically disrupt endothelial cell microtubules. By leveraging epidemiological pesticide resistance data and mining chemical features of commercially used benzimidazoles, we discover that a broader class of benzimidazole compounds, in extensive use for 50 years, also potently disrupt immature blood vessels and inhibit angiogenesis. Thus, besides identifying the molecular mechanism of benzimidazole-mediated vascular disruption, this study presents evidence relevant to the widespread use of these compounds while offering potential new clinical applications.

A phase I trial of plinabulin in combination with nivolumab and ipilimumab in patients with relapsed small cell lung cancer (SCLC): Big Ten Cancer Research Consortium (BTCRC-LUN17-127) study.

8570 Background: Plinabulin (BPI-2358) is a vascular disrupting agent with immune-enhancing function by inducing dendritic cell maturation and decreasing regulatory T cells. Preclinical studies report that plinabulin potentiates the cytotoxicity of dual checkpoint inhibition (CPI) with nivolumab and ipilimumab. Plinabulin may also reduce immune-related AEs from CPI through its phosphodiesterase-4 (PDE4) inhibitory activity which is associated with anti-inflammatory effects. We report initial results from a Phase I study assessing plinabulin in combination with nivolumab and ipilimumab. Methods: In this dose-escalation phase I study, patients with extensive-stage SCLC who had progressed on or after prior platinum-based chemotherapy (±CPI) were enrolled using a 3+3 design. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D). Patients received nivolumab (1 mg/kg), ipilimumab (3 mg/kg) and plinabulin (as per dose escalation schema) IV on day 1 of each 21 day cycles. After completion of 4 cycles, patients continued therapy with nivolumab (240 mg) and plinabulin every 2 weeks till progression or intolerable toxicity. Patients were evaluable for DLT if they received at least 2 cycles of therapy; DLT period was defined as the first 6 weeks from C1D1. Secondary endpoints were ORR, PFS and frequency of irAEs. Correlative analysis included inflammatory biomarkers: hsCRP, ESR, SAA and haptoglobin. Results: Between 9/2018 and 11/2020, 17 patients were enrolled (1 patient withdrew consent before treatment, 16 were evaluable for safety). Median age was 59 years (range 43 to 78); 9 patients were male and 10 had received prior CPI. Eight patients were treated at dose-level 1 of plinabulin (20 mg/m2) and 8 patients at 30 mg/m2 of plinabulin (level 2); dose-level 2 was determined to be RP2D. There were 2 DLTs; 1 at dose-level 1 (grade 3 altered mental status lasting < 24 hours) and 1 at dose-level 2 (grade 3 infusion reaction). The most common treatment-related AEs (all grades) were nausea (10; 63%), infusion reaction (8; 50%), vomiting (7; 44%), diarrhea (7; 44%) and fatigue (6, 32%). Seven patients (44%) had at least one grade 3 or higher treatment-related AE; there were no treatment-related deaths. Two patients (13%) had grade 3 or higher irAE requiring steroids (1 colitis, 1 transaminitis); both at dose-level 1. At data cutoff (12/30/20), there were 3 PRs in CPI naïve patients (3/6; 50%) and 2 PRs in evaluable CPI-resistant patients (2/7; 29%). In the two CPI-resistant patients with confirmed response, the tumor reduction was 68% and 52%. Conclusions: Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated. A phase 2 study in CPI-experienced patients with relapsed SCLC is planned to confirm the preliminary signals of clinical activity and reduced immune toxicity. Clinical trial information: NCT03575793.