A Phase 1/2 Multi-Center, Safety and Efficacy Study Evaluating Intravenously Administered 131I-TM601 in Patients With Progressive and/or Recurrent Malignant Glioma

The purpose of this study is to evaluate the safety and effectiveness of 131I-TM601 in the treatment of adult patients with progressive or recurrent malignant gliomas.

Start Date01 Aug 2008

Sponsor / Collaborator

TransMolecular, Inc.

NCT00591058 / Unknown statusPhase 1

A Phase I Dose Escalation Study Evaluating the Safety and Biologically Active Dose of TM-601 Based on Perfusion MRI Imaging Criteria in Patients With Progressive and/or Recurrent Malignant Glioma

The purpose of this study is to evaluate the safety and biologically active dose of TM-601 in adult patients with recurrent malignant glioma.

Start Date01 Feb 2008

Sponsor / Collaborator

TransMolecular, Inc.

NCT00379132 / CompletedPhase 1

A Phase I Imaging and Safety Study of Intravenous 131-I-TM-601 Labeled Chlorotoxin in Patients With Recurrent or Refractory Somatic and/or Cerebral Metastatic Solid Tumors

This study is designed to evaluate the ability of intravenously (IV)administered 131-I-labeled TM-601 (chlorotoxin) to provide tumor-specific localization(via radiographic imaging) in patients with recurrent or refractory primary solid tumors with evidence of metastatic involvement. (Refractory tumors are non-responsive to standard treatment.) The safety and tolerability of IV administered 131-I-TM-601 in this patient population will be evaluated as part of this study.

Start Date01 Aug 2006

Sponsor / Collaborator

TransMolecular, Inc.

100 Clinical Results associated with TransMolecular, Inc.

0 Patents (Medical) associated with TransMolecular, Inc.

Literatures (Medical) associated with TransMolecular, Inc.

15 Apr 2010·Cancer Research

Abstract 4510: Similarities in trans-Golgi localization of chlorotoxin in tumor and in normal vascular endothelial cells

Author: Wiranowska, Marzenna ; Jacoby, Douglas B. ; Colina, Lucrecia O. ; Johnson, Joseph O. ; Thomas, Charles E.

AbstractIntroduction: Chlorotoxin (TM601), a scorpion derived 36-amino acid peptide is a new experimental drug currently in Phase II clinical trials for adult recurrent glioma. Despite its known specificity for tumor cells, its exact mode of action is not known but anti-angiogenic effects have been observed. Here we provide evidence that TM601 localizes near the Golgi complex in human glioma (U373, U87), lung carcinoma (A549), and in normal human vascular endothelial cells (HUVEC) but not in normal human dermal fibroblasts (HDF) and astrocytes (NHA). TM601 enters glioma cells via clathrin-mediated transport and affects level of several Golgi associated peptides. Methods: Cells were treated with or without 10 µM TM601 or fluorescent TM601 for 1 or 24 hours. We evaluated: 1) TM601 cellular localization in relation to the Golgi (antibodies to TM601 and Golgin97 marker) and lysosomes (fluorescent trackers) using immunocytochemistry or direct immunofluorescence visually and quantitatively by confocal microscopy; 2) TM601 cellular entry in U373 and HDF cells using an inhibitor of clathrin-dependent endocytosis (chlorpromazine 10 µg/ml) or inhibitor of macropinocytosis (amiloride 300 µM). Cell lysates were prepared and proteins evaluated by Western blot; 3) TM601 effects on the U373 proteome in the sucrose fractionated Golgi-enriched fraction using liquid chromatography coupled to tandem mass spectrometry. Results: 1) In all tumor cells and HUVEC cells, TM601 was observed as an intense granular staining at the trans-Golgi. In normal fibroblasts and astrocytes it was found at a low level in the cytoplasm. In U373 glioma, but not in the normal HDF and NHA cells, TM601 showed a statistically significant colocalization with the LysoTracker (p=3.9E-05) that stained Golgi associated lysosomal vesicles. 2) A statistically significant effect on TM601 cellular level in U373 was observed after treatment with chlorpromazine and in HDF (but not U373) with amiloride. 3) Preliminary data (n=2) of Golgi-enriched fractions from TM601 treated U373 cells showed that TM601 treatment significantly affected levels of several peptides. Further evaluation by Western blots is planned. Summary: Our data show similarity between glioma, lung carcinoma and the normal vascular endothelial cells in the cellular uptake/transport of TM601 toward Golgi complexes. These cells differ drastically from other normal cells such as HDF and NHA which present low cytoplasmic level of TM601. It is expected that endothelial cell transport of TM601 may occur via receptor mediated clathrin dependent endocytosis pathway as in the glioma cells. In addition, our preliminary data showed TM601 effect on the level of several Golgi associated proteins in glioma cells. A similar study with endothelial cells is planned. The information obtained from these studies will assist in understanding how TM601 affects angiogenesis and tumor progression.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4510.

01 Jan 2010·Anticancer research

Potent pleiotropic anti-angiogenic effects of TM601, a synthetic chlorotoxin peptide.

Article

Author: Dahlberg, William ; Yalcin, Murat ; Jacoby, Douglas B ; Mousa, Shaker A ; Johnson, Eric W ; Dyskin, Evgeny ; Ratliff, Judson ; Kesavan, Kamala

Chemically synthesized chlorotoxin (TM601) has been studied as a tumor targeting peptide. In this study, the anti-angiogenic properties of TM601 are reported.MATERIALS AND METHODSIn vitro and in vivo models of angiogenesis and tumor growth were used to characterize the anti-angiogenic effects of TM601.RESULTSTM601 bound to proliferating vascular endothelial cells, decreased human umbilical vein endothelial cell (HUVEC) invasion, and reduced secretion of bioactive matrix metalloproteinase-2 (MMP-2). Using the chick chorioallantoic membrane assay (CAM), TM601 inhibited angiogenesis stimulated by any of eight pro-angiogenic factors, and when TM601 was co-administered with bevacizumab, the combination was significantly more potent than a ten-fold increase in bevacizumab dose. TM601 did not alter tumor or vascular endothelial cell growth in vitro, but TM601 treatment of tumors grown on the CAM decreased tumor growth and intra-tumoral hemoglobin levels. Intravenously injected TM601 was also shown to significantly decrease new blood vessel growth in mice.CONCLUSIONTM601 inhibits angiogenesis stimulated by many factors and potentiates the anti-angiogenic effect of bevacizumab.

10 Dec 2009·Molecular Cancer Therapeutics

Abstract B217: Annexin A2 is a novel molecular target for TM601, a peptide with specific tumor targeting and antiangiogenic properties

Author: Johnson, Eric ; Jacoby, Douglas B. ; Kesavan, Kamala ; Ratliff, Judson ; Dahlberg, William

AbstractIn this study we sought to identify the cell surface target for TM601, a peptide with tumor-targeting and anti-angiogenic effects. The 131I-radiolabeled form of TM601 is currently in clinical trials for having been shown to specifically bind several human tumor types including malignant glioblastoma, colorectal, pancreatic, prostate and non-small cell lung carcinomas. We used a biochemical approach of surface cross-linking followed by affinity-binding assays in conjunction with mass spectrometry and siRNA knock-down to identify and validate the target for TM601 on tumor and vascular endothelial cell. We identify annexin A2 as a novel binding partner for TM601 in multiple human tumor cell lines and HUVEC vascular endothelial cells. We demonstrate that the surface binding of TM601 to the pancreatic tumor cell line, Panc-1 is dependent on the expression of annexin A2. Annexin A2 is over-expressed in several human cancers and has functions in angiogenesis by binding to tissue plasminogen activator (tPA) and regulating plasminogen activation on vascular endothelial cells. In HUVEC cells, TM601 inhibits both VEGF and bFGF induced tPA activation which is in turn required for activation of plasminogen to plasmin. Consistent with inhibition of cell surface protease activity, TM601 also inhibits PDGF-CC induced trans-well migration of both HUVEC vascular endothelial and U373-MG glioma cells. In conclusion, we have identified annexin A2 as a novel cell surface target for TM601 that might mediate both the tumor-targeting and anti-angiogenic effects of the peptide. Importantly, our results also support a role annexin A2 as a molecular target in cancer therapeutics.Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B217.

100 Deals associated with TransMolecular, Inc.

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Drug(Targets)	Indications	Global Highest Phase

TM-604	Neoplasms More	Discontinued
131-I-Chlorotoxin ( chloride channel )	Metastatic melanoma More	Discontinued
Chlorotoxin ( chloride channel )	Oligodendroglioma More	Pending

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