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Vascular-disrupting agents (VDA) kill tumor cells by selectively disrupting blood circulation in tumors. In vivo analysis of this intensely studied class of anticancer agents is invaluable for preclinical assessment of pharmacodynamic end points and effective therapeutic windows. In this review, we consider the role of intravital video microscopy in measuring tumor vascular response to VDAs, the potential of which lies in the opportunity to quantitate specific variables and to obtain real-time information on how VDAs affect tumor microcirculation. (Cancer Res 2006; 66(24): 11517-9)

Interstitial fluid pressure (IFP) is elevated in tumors due to abnormal vasculature, lack of lymphatic drainage, and alterations in the tumor interstitium. ZD6126 is a tubulin-binding agent that selectively disrupts tumor vasculature resulting in tumor necrosis. This study examined the effect of ZD6126 on tumor IFP and the response of tumors with different IFP levels to ZD6126. Pretreatment IFP was measured using the wick-in-needle method in tumors (murine KHT-C and human CaSki) growing i.m. in the hind legs of mice. Mice were treated i.p. with a single dose of ZD6126 (100 or 200 mg/kg) and posttreatment IFP measurements were made. Blood flow imaging was conducted using Doppler optical coherence tomography, whereas oxygen partial pressure was measured using a fiber optic probe. Clonogenic assays were done to determine tumor cell survival. In KHT-C tumors, IFP dropped significantly at 1 hour posttreatment, returned to pretreatment values at 3 hours, and then declined to ∼25% of the pretreatment values by 72 hours. In CaSki tumors, the IFP decreased progressively, beginning at 1 hour, to ∼30% of pretreatment values by 72 hours. Clonogenic cell survival data indicated that ZD6126 was less effective in tumors with high IFP values (>25 mm Hg). Vascular disrupting agents, such as ZD6126, can affect IFP levels and initial IFP levels may predict tumor response to these agents. The higher cell survival in high IFP tumors may reflect greater microregional blood flow limitations in these tumors and reduced access of the drug to the target endothelial cells. (Cancer Res 2006; 66(4): 2074-80)

Studies in cancer models with AGX51, a Direct Transcriptional RegulatorTM The inhibitors of differentiation (Id) proteins (Id1, Id2, Id3, and Id4) are negative regulators of differentiation that act by sequestering basic helix loop helix (bHLH, e.g. E47) transcription factors. Ids are highly expressed during embryonic development but in adult tissues their expression is rare to absent. However, Id proteins are required for tumor angiogenesis, highly expressed in many cancers and as shown in many clinical studies, associated with an aggressive phenotype and a poor clinical outcome As a proof of concept, decreased angiogenesis and tumor load as a result of blocking Id expression by antisense and siRNA molecules demonstrated that Id is a compelling anti-cancer target. Despite these findings, the Ids are a heretofore unexplored target for the treatment of cancer. While no anti-Id agent has been studied clinically or has undergone preclinical development, AGX recently discovered and patented the first unique and potent anti-Id agent, AGX51. This small molecule is an inhibitor of the Id1-E47 interaction and was discovered through a systematic research effort using x-ray crystallography, gel shift (EMSA) assays, Matrigel evaluations and xenograft studies. AGX51 is the founding member of a new class of therapeutics: Direct Transcriptional RegulatorsTM. In preclinical studies: (1) At a dose below 7 mg/kg, bid, AGX51 significantly blocked the growth of tumors in mice with implanted human breast cancer cells when treated briefly with a taxane like Taxol®, paclitaxel, or Taxotere®, docetaxel. This effect of AGX51 was expected based on the discovery that endothelial cell production in the bone marrow is responsible for the rapid repair to damaged vasculature after administration of paclitaxel or vascular disrupters such as ZD6126 or AVE8062, through mobilization of endothelial precursor cells (EPCs) followed by homing of the EPCs to the damaged vasculature; (2) At a dose below 20 nM, AGX51 restored cell cycle control in DU-145 human prostate cancer cells; (3) At low micromolar concentrations, AGX51 blocked migration of DU-145 cancer cells in “scratch” assays; (4) As a single agent, AGX51 completely blocked tumor associated angiogenesis in nude mice implanted with MDA-MB231 human breast cancer cells at a dose of 60 mg/kg, bid; (5) As expected, AGX51 restored levels of p21 and p27, two important mediators of cell cycle regulation in both PC3 and DU145 cancer cells; (6) AGX51 caused no toxicity in multiple day dosing based on weight, clinical chemistry or hematology measurements; (7) AGX51 has a terminal elimination half-life in mice of approximately 6 hours, which is suggestive of ultimate bid and perhaps even qd dosing in man. In summary, a specific inhibitor of Id-E47 interaction that has anti-tumor activity is described for the first time. This research was supported by AngioGenex, Inc. Citation Format: William Garland, Richard Salvador, Jaideep Chaudhary. Studies in cancer models with AGX51, a Direct Transcriptional RegulatorTM. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 758. doi:10.1158/1538-7445.AM2013-758

Neuroblastoma (NBL) is the most common extracranial solid tumor of childhood, accounting for between 7-10% of paediatric cancers. The proto-oncogene MYCN is amplified in 25% of NBL and is associated with high-risk disease, enhanced tumor angiogenesis and poor survival. A genetically-engineered mouse model for high risk, MYCN-amplified NBL has been generated by directing expression of MYCN to the peripheral neural crest of transgenic mice. As part of a multi-parametric MRI study, we have evaluated the native spin-lattice relaxation time T1, sensitive to the ratio of bound to free water in tissue, as a potential noninvasive biomarker of treatment response of TH-MYCN NBL to three different classes of anti-cancer agent. TH-MYCN mice with abdominal tumors were identified by palpation and imaged prior to and following treatment. Native T1 (ms) was quantified at 7T using an inversion recovery (IR)-trueFISP sequence. In control cohorts, tumor progression over 48 hours and 4 days was associated with no significant change in T1. A single 25mg/kg dose of cylophosphamide, the current standard of care for childhood NBL, caused a significant 54% reduction of tumor volume at 48 hours. Treatment of TH-MYCN NBL with CPM leads to extensive cell death, which occurs primarily through apoptosis, and this response was associated with a highly significant 15% reduction in native T1. Given the hypervascular nature of NBL, their response to anti-vascular therapies was also investigated. Treatment with the pan VEGF receptor inhibitor cediranib (6mg/kg daily over 2 days) resulted in significant 19% anti-tumor activity and 8% reduction in T1 at 48 hours. Furthermore, this response was associated with a significant reduction in uptake of the perfusion marker Hoechst 33342 compared to control, but no difference in necrosis. Treatment with a single 200mg/kg dose of the colchicine derivative ZD6126 resulted in significant and unprecedented 43% anti-tumor activity at 24 hours, and which was also associated with a significant 14% reduction in native T1. Histology revealed a significant reduction in Hoechst 33342 uptake and extensive tumor necrosis. Collectively, these data show a systematic reduction of native T1 in the TH-MYCN model with successful chemotherapy. The CPM and ZD6126-induced reduction in T1 is consistent with a histologically confirmed reduction in cell density and increased extravascular space following cytotoxic therapy. The reduction of T1 following treatment with cediranib may be attributable to the resolution of edema caused by reduced vascular permeability. Accurate quantification of T1 affords a generic noninvasive biomarker for chemotherapy-mediated cell death in the TH-MYCN model. The high sensitivity of T1 will accelerate the pre-clinical evaluation of novel therapeutics for childhood neuroblastoma in this model. Quantitation of native T1 could be easily incorporated into conventional imaging protocols used in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5290. doi:10.1158/1538-7445.AM2011-5290