In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 2600-2600
Abstract:
Angiogenesis, the process of new blood vessels formation, is essential for tumor growth and metastasis. Since tumors are unable to grow beyond a millimeter diameter in the absence of angiogenic factors, it was postulated that blocking of angiogenic factors could provide a new strategy to inhibit tumor leading to a potential novel anticancer therapy. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) was considered as a promising anticancer agent due its remarkable ability to induce apoptosis in cancer cells without harming normal cells. However, in clinical practice TRAIL efficacy was too low to become the effective single therapy agent. Here we present a novel fusion protein based on TRAIL/Apo2L and equipped with an antiangiogenic effector peptide originating from VEGF exon 6 that binds to natural VEGF receptors and competes with their natural ligand. The proposed fusion protein, AD-O51.4, consists of extracellular soluble portion of TRAIL linked to two tandemly arranged copies of the effector peptide, separated by a sequence that contains the motif recognized by tumor-specific proteases (MMP's, uPa). The AD-O51.4 fusion molecule exerts its dual cytotoxic and antiangiogenic activity upon interaction with cellular death and VEGF receptors on cancer endothelial cells. In consequence, the peptide blocks the binding of VEGF to its receptors, preventing new vessels formation. In addition, due to the presence of VEGF receptors on cancer cells, they can be also targeted by VEGF receptors-binding domain of AD-O51.4 making them susceptible for TRAIL-induced apoptosis. Indeed, an extensive panel of discovery-stage studies of AD-O51.4 showed broad cytotoxic activity on primary cancer cell lines but no toxic effects on normal cells and strong antitumor activity on subcutaneous and orthotropic xenograft models with complete tumor remission. Based on these data, early preclinical part of the program was initiated. An LC\MS-based method, specific for the intact molecule, was set up as the detection and quantification tool, enabling detection of AD-O51.4 in different biological matrices. Safety of the molecule was evaluated using healthy hepatocytes form humans and cynomolgus monkeys. To verify tumor targeting capacity of the molecule, tumor-specific accumulation in subcutaneous xenograft model of human colorectal cancer as a function of time was assessed using imaging techniques. Tumor specific accumulation was also confirmed using LC\MS method even after single administration. To analyse the pharmacological properties of the AD-O51.4, PK profiles were evaluated in Wistar rats and cynomoglus monkeys. Finally, strong antitumor activity was confirmed using PDX models of human lung, colon, rectal and pancreatic cancer. Currently the molecule is approaching formal ADME\Tox panel. Citation Format: Jerzy S. Pieczykolan, Anna Pieczykolan, Piotr Rozga, Sebastian Pawlak, Bartlomiej Zerek, Malgorzata Teska - Kaminska, Szymanik Michal, Albert Jaworski, Karl R. Erlemann, Jacek Capala. Preclinical evaluation of the novel fusion molecule with high dual antiangiogenic and anticancer potential. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2600. doi:10.1158/1538-7445.AM2014-2600
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-2600
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
Bookmarklink
