Submitter: Rosemary J. Akhurst | rakhurst@cc.ucsf.edu
UCSF Mt. Zion, Cancer Research Institute
Published August 14, 2003
To the Editor:
Following on from my commentary last year entitled "TGF-beta antagonists : Why suppress a tumor suppressor" (1), I appreciate the prompt from Dr. Cordeiro to discuss current clinical trials for cancer using TGFbeta antagonists. As pointed out by Dr. Cordeiro (2), her laboratory has shown that TGFbeta is instrumental in causing post-operative scarring after ocular surgery, and that both pre-clinical and clinical studies have shown benefit in the use of anti-TGFbeta2 antibodies and antisense oligonucleotides for reduction of scarring (3-5). Moreover, clinic trials have shown that, in this ocular application, anti-TGFbeta2 antibodies are well tolerated with no adverse side- effects (4). However, as discussed by Kuwahara et al (2), this particular application only requires transient treatment at a small isolated body site (subconjunctival injection), and the long-term safety of chronic high dose TGFbeta antagonism has yet to be assessed. It is rewarding to see progress in this area with the recent announcement that a single course of TGF-beta2 antisense phosphorothioate oligonucleotide injected intratumorally into patients with high-grade glioma demonstrated excellent safety and tolerability (6). As yet no specific systemic small molecule inhibitors of TGFbeta, which could be used in chronic treatment applications, have entered clinical trials, although this is currently the goal of several pharmaceutical companies (7).
References
1. Akhurst, R.J. (2002) TGF-beta antagonists: why suppress a tumor suppressor? J Clin Invest, 109, 1533-1536.
2. Cordeiro, M.F. (2003) Transforming growth factor-beta function blocking already effective as therapeutic strategy. Circulation, 107, E37-37; author reply E37-37.
3. Cordeiro, M.F., Gay, J.A. and Khaw, P.T. (1999) Human anti- transforming growth factor-beta2 antibody: a new glaucoma anti- scarring agent. Invest Ophthalmol Vis Sci, 40, 2225-223
4. 4Siriwardena, D., Khaw, P.T., King, A.J., Donaldson, M.L., Overton, B.M., Migdal, C. and Cordeiro, M.F. (2002) Human antitransforming growth factor beta(2) monoclonal antibody--a new modulator of wound healing in trabeculectomy: a randomized placebo controlled clinical study. Ophthalmology, 109, 427-431.
5. Cordeiro, M.F., Mead, A., Ali, R.R., Alexander, R.A., Murray, S., Chen, C., York-Defalco, C., Dean, N.M., Schultz, G.S. and Khaw, P.T. (2003) Novel antisense oligonucleotides targeting TGF-beta inhibit in vivo scarring and improve surgical outcome. Gene Ther, 10, 59-71.
6. ASCO Annual Meeting 2003. Abstract number 436. A TGF(- specific antisense oligonucleotide (AP12009) as continuous treatment of recurrent high-grade glioms patients: A clinical phase I/II extension study. G. M. Stauder, P. Hau, U. Bogdahn, A. Steinbrecher, A. Brawanski, J. Schlaier, G. Wurm, J. Pichler, M. Kunst, K.-H. Schlingensiepen; Antisense Pharma GmbH, Regensburg, Germany; Dept. Neurology, University Regensburg, Regensburg, Germany; Dept. Neurosurgery, University Regensburg, Regensburg, Germany; Dept. Neurosurgery, Wagner-Jauregg, Linz.
7. www.sciosinc.com/scios/469_tgf_beta
Submitter: M Francesca Cordeiro | M.Cordeiro@ucl.ac.uk
Moorfields Eye Hospital & Institute of Ophthalmology, University College London
Published July 23, 2002
To the Editor:
Rosemary Akhurst is to be congratulated on a perceptive and insightful commentary (June 15 2002)(1) on two very important publications on TGF-ß antagonists. (2, 3) She concludes that the investigation of TGF-ß antagonists and agonists has previously been avoided because of a fear of "non-specificity" and "side-effects", which considering this key molecule in the body has been identified since the early 1980's, is really quite remarkable. However, in such a fast moving field it is perhaps not surprising that Akhurst was not fully aware that trials of TGF-ß antagonists involving human subjects are now already taking place.
Therapies targeting excessive TGF-ß activity in wound healing have been particularly important in work looking at effective anti-scarring treatments. In ocular disease in particular, modulation of post-operative scarring has been shown to dramatically increase success rates of the surgical treatment of glaucoma - currently the most common cause of irreversible blindness worldwide.(4, 5)
Two different and successful strategies for TGF-ß antagonism have been utilized. Firstly, a fully human monoclonal neutralizing antibody to TGF-ß2 has been shown to significantly improve outcome in patients undergoing glaucoma filtration surgery, by reducing post-operative scarring.(6, 7) This is the first time an anti-TGF beta antibody has been used in humans, and is currently in Phase III clinical trials. Secondly, we have recently reported efficacy of novel second-generation antisense phosphorothiate oligonucleotides against TGF-ß in vivo.(8) After only a single perioperative administration, a significant reduction in scarring after glaucoma surgery was apparent, offering great potential clinically.
Although both these agents have been shown to be useful in the eye, they could have widespread applications anywhere in the body where TGF-ß activity requires modulation, and results so far suggest them to be safe and non-toxic.
References:
1. Akhurst, RJ. 2002. TGF-ß antagonists: Why suppress a tumor suppressor? J Clin Invest. 109, 1533-1536
2. Muraoka, RS, et al. 2002. Blockade of TGF-beta inhibits mammary tumor cell viability, migration, and metastases. J Clin Invest. 109, 1551-9
3. Yang, Y , et al. 2002. Lifetime exposure to a soluble TGF-ß antagonist protects mice against metastasis without adverse side effects. J Clin Invest. 109, 1607-1615
4. Cordeiro, MF. 2002. Beyond Mitomycin - TGF-ß and wound healing. Prog Ret Eye Res. 21, 75-89
5. Quigley, HA. 1996. Number of people with glaucoma worldwide. Br J Ophthalmol. 80, 389-93
6. Cordeiro, MF, Gay, JA , Khaw, PT. 1999. Human Anti-TGF-ß2 monoclonal antibody: a new anti-scarring agent for glaucoma filtration surgery. Invest Ophthalmol Vis Sci. 40, 2225-2234
7. Siriwardena, D, Khaw, PT, King, AJ, Donaldson, ML, Migdal, C, Cordeiro, MF. 2002. Human anti-Transforming Growth Factor beta-2 monoclonal antibody - a new modulator of wound healing in trabeculectomy: a randomised placebo controlled clinical study. Ophthalmology. 109, 427-431
8. Cordeiro, MF, et al. 2002. Novel Antisense Oligonucleotides Targeting TGF-ß Inhibit In Vivo Scarring & Improve Surgical Outcome. Gene Therapy. In press