A NEW AND PROMISING
TREATMENT FOR
BLADDER CANCER
CCI-001 is one of the most promising recent approaches in the treatment of bladder cancer, stopping and shrinking tumours in experimental models with a high rate of efficacy.
The goal of modern cancer drug development is to kill cancerous cells and spare healthy cells. PharmaMatrix’s CCI-001 represents a more targeted approach to cancer treatment, designed to preferentially interfere with the growth of cancer cells.
CCI-001 is shown to effectively “shut off” cancerous tumour growth by interfering specifically with βIII-tubulin, a cellular component essential for the rapid cell division characteristic of cancer cells.
Now in phase 1 clinical trials.
CCI-001: A new microtubule-disrupting agent, based on Colchicine
Cells grow through the process of cell division, and the cells of cancer tumours grow much faster than normal tissues. The protein Tubulin is vital to the process of cell division. It is clear in the scientific literature that βIII-tubulin is the isotype of tubulin that is present in almost all cancer cells, but almost never expressed by normal cells with the exception of brain tissue and testes. A strategy targeting βIII-tubulin by colchicine, a drug that does not pass the blood-brain barrier, offers more promise that any other tubulin-targeting drugs.
Our research finds that the colchicine binding site has the greatest diversity among tubulin isotypes.
Colchicine is a well-known bioactive alkaloid derived from plants. As a microtubule-disrupting drug, colchicine is not currently used to treat cancer because of its overbearing systemic toxicity, producing unacceptable side effects when administered intravenously. However, our research finds that, at the right dosage, the effects of colchicine profoundly inhibit microtubule formation and arrest tumour growth, leading to cell death by apoptosis, with fewer side effects than chemotherapy to the patient. Colchicine’s water solubility, commercial availability, and low cost have renewed interest in our research into modifying this molecule and developing less toxic hybrid compounds.
Treatment Pathway
Instead of a tumour growing unchecked, CCI-001 binds at the source of βIII-tubulin expression, stopping cell division, and ultimately destroying the tumour at its root.
The Testing Cascade For Cancer
In silico screening of possible compounds.
In vitro binding assays to target proteins from tumour cells.
Inhibition of growth of cultured cancer (and normal cells).
Tumour growth in animals.
Pharmacokinetic studies including minimization of brain penetration, protection of vital organs, rare toxic events.
Approval process (GLP, GMP, IND).
Tumour growth in experimental models.
Government regulatory approval for a clinical trial.
The Benefits
Binds at the most optimal site to stop tubulin expression and destroy bladder tumours.
More promising against bladder cancer in cell-based assays that some licensed anti-cancer products.
Enhances tumour sensitivity compared to other tubulin inhibitors.
Fewer off-target effects compared to other tubulin inhibitors.
May be effective against other kinds of cancers and gout.
Research Team
Other key contributors to the CCI-001 Project
Lorelei Johnson, MD
Torin Huzil, PhD
Jonathan Mane, PhD
International Collaborators
Richard Luduena, University of Texas Health Sciences Center, San Antonio, USA.
Lloyd Demetrius, Harvard University and Max Planck Institute, Berlin.
Nicolas Carels and Tatiana Tilli, Oswaldo Cruz Institute, Rio de Janeiro, Brazil
Ed Rietman, University of Massachusetts, USA
Michael Levin, Tufts University, Boston, USA
Massimo Cocchi, University of Bologna, Italy
Andrea Danani and Marco Deriu, SUPSI, Lugano, Switzerland
Marco Pettini, University Aix-Marseille, France
Adam Huczynski, A. Mickiewicz University, Poznan, Poland
For further information on team and publications, visit PharmaMatrix.ca.
Further Reading
Publications on colchicine derivatives from Jack Tuszynski’s group
L. Johnson, I.S. Goping, A. Rieger, J. Mane, T. Huzil, A. Banerjee, R.F. Luduena, B. Hssani, P. Winter and J.A. Tuszynski, Novel Colchicine Derivatives and Their Anti-Cancer Activity 17: 22, 2538-2558 (2016), Current Topics in Medicinal Chemistry.
Mane JY, Semenchenko V, Perez-Pineiro R, Winter P, Wishart D, Tuszynski JA (2013) Experimental and computational study of the interaction of novel colchicinoids with a recombinant human αI/βI-tubulin heterodimer. Chem Biol Drug Des 82:60–70.
Ashrafuzzaman M, Tseng CY, Duszyk M, Tuszynski JA (2012) Chemotherapy drugs form ion pores in membranes due to physical interactions with lipids. Chem Biol Drug Des 80:992–1002.
Huzil JT, Mane J, Tuszynski JA (2010) Computer assisted design of second-generation colchicine derivatives. Interdiscip Sci Comput Life Sci 2:169–174.
Huzil JT, Winter P, Johnson L, Weis AL, Bakos T, Banerjee A, Luduena RF, Damaraju S, Tuszynski JA (2010) Computational design and biological testing of highly cytotoxic colchicine ring A modifications. Chem Biol Drug Des 75:541–550.
Tseng CY, Mane JY, Winter P, Johnson L, Huzil T, Izbicka E, Luduena RF, Tuszynski JA (2010) Quantitative analysis of the effect of tubulin isotype expression on sensitivity of cancer cell lines to a set of novel colchicine derivatives. Mol Cancer 9:131.
Bartusik D, Tomanek B, Lattová E, Perreault H, Tuszynski J, Fallone G (2010) Derivatives of thiocolchicine and its applications to CEM cells treatment using 19F magnetic resonance ex vivo. Bioorg Chem 38:1–6.
Bartusik D, Tomanek B, Lattová E, Perreault H, Tuszynski J, Fallone G (2009) The efficacy of new colchicine derivatives and viability of the T-Lymphoblastoid cells in three-dimensional culture using 19F MRI and HPLC-UV ex vivo. Bioorganic Chemistry 37 193–201.
Huzil JT, Barakat K, Tuszynski JA (2009) Electrostatic contributions to colchicine binding within tubulin isotypes. Electromagn Biol Med 28: 355–364.
Mane JY, Klobukowski M, Huzil JT, Tuszynski J (2008) Free energy calculations on the binding of colchicine and its derivatives with the α/β-tubulin isoforms. J Chem Inf Model 48:1824–1832.
PATENT
J.A. Tuszynski,"Novel Colchicine Derivatives, Methods and Uses Thereof", International PCT Patent Application No. PCT/CA2010/001199, Sim&McBurney, Toronto, filed on July 30, 2010, allowed by USPTO June 1, 2016; allowed by the Canadian patent office October 18, 2017, allowed by the EPO December 4, 2017.