Mechanism of Action

Key Factors Addressed by CTO

The CTO mechanism is involved in non-voltage dependent calcium signaling, addressing several factors in malignant gliomas.

  • Angiogenesis: Demonstrated reduction in exosome-stimulated angiogenesis and both VEGF expression and secretion
  • Proliferation: Reduction of proliferation, adhesion, motility and vascular tube formation
  • Anti-Inflammation: Inhibition of inflammation has been demonstrated, accompanied by reduction of TNF-α and IL-1β levels
  • Molecular Targeting: Through non-voltage dependent calcium signaling, several transduction pathways are impacted, including multiple tyrosine kinase signaling pathways
  • Overcome Drug Resistance: Augments apoptosis through inhibition of tyrosine phosphorylation of BCr-Abl, ERK, and Wnt-β-catenin, offering a plausible mechanism by which CTO circumvents chemoresistance to Temodar® and other drugs.

 

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Source: Guo L, et al. Anti-Inflammatory and Analgesic Potency of Carboxyamidotriazole, a Tumorostatic Agent. JPET April 2008 vol. 325 no. 1 10-16; Corrado, et al. arboxyamidotriazole-Orotate Inhibits the Growth of Imatinib-Resistant Chronic Myeloid Leukaemia Cells and Modulates Exosomes-Stimulated Angiogenesis. PLoS One. 2012; 7(8): e42310; Sathornsumetee S, et al. Molecularly Targeted Therapy for Malignant Glioma. Cancer 2007(110) 13-24.

Based on pharmacodynamic markers, CTO has a suggested mechanism of action that inhibits genes associated with non-voltage dependent calcium signaling, which ultimately translates into the inhibition of multiple oncogenic pathways.

Pharmacodynamic Transcriptional Markers of CTO Exposure in ex vivo Anagen Hair Assay

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Assay Results:

  • The transcriptional signatures associated with inhibition of EGFR, MEK, HDAC and HSP90 were strongly suppressed at all doses of CTO
  • Genes associated with non-voltage dependent calcium signaling were strongly suppressed, with RAS and Growth Factor Signature
  • Modest suppression of transcription signatures of WNT signaling was evident at longer exposure to CTO
  • In contrast, activation of tumor suppressor signatures associated with P53 was observed

Through non-voltage dependent calcium signaling, CTO impacts several transduction pathways, including multiple tyrosine kinase signaling pathways

These results may provide the molecular MOA of CTO’s observed clinical benefit in a broad spectrum of tumors with different genomic types and a tool to design customized combination therapies of CTO with other agents Arm C of the phase I/II study expected to initiate in December 2013 will include pharmacodynamic marker analysis.

Source: EORTC Abstract A233, October 19-23, 2013; 2013 ASCO Breakthrough Session: Abstract 115114