The IGF-1 receptor was first cloned in 1986 by a Genentech scientist, Axel Ullrich, and in 1989, Carlos Arteaga at Vanderbilt demonstrated that monoclonal antibodies that target the receptor could arrest tumours in mice.
The perfect target for cancer therapy, however, is one that is expressed only in cancer cells and not normal cells, thus reducing the potential for horrific side effects while attacking the cause of the disease. This approach has seen some spectacular success with Herceptin for HER2+ breast cancers and Gleevec in BCR-ABL Philadelphia-chromosome positive CML, for example. The goal is to target the aberration causing the proliferation, which essentially acts like as a thermostat switch with the heat permanently on during the hottest day of the year.
In contrast, chemotherapy as we all know, hits everything in it's path, attacking both normal and cancer cells, wreaking considerable biochemical toxicity and destruction as it goes round the bloodstream. Imagine my surprise, then, that many companies are suddenly looking at the insulin growth factor receptor (IGF-1R) as potential target for cancer therapeutics. This is frought with difficulties for several reasons.
Firstly, IGFR is ubiquitously expressed throughout the body in both cancer cells and normal cells. It is also overexpressed in many cancers, a suspicious fact in itself, and may not be the aberrant critical factor driving tumour growth. IGF-1 receptor signalling has been shown to block apoptosis, though it is not as strong in stimulating proliferation of cells, except when it stimulates angiogenesis.
Secondly, there is a solid reason why many drug companies hesitated for so long –
they were concerned about accidentally hitting the insulin receptor
with anticancer drugs might also block insulin receptor signalling and
cause diabetes, as well as the potential for cardiotoxicity.
Thus the big question in my mind, is how do you target the receptor tyrosine kinase (RTK) for IGF-1R in cancer cells while leaving the normal cells largely alone given the ubiquity? Is it even possible? In theory, what needs to happen is downregulation of the receptor so that the cells die, because if you give a drug that inhibits the IGF-1 receptor without downregulating, you may stop growth, but then it will merrily resume when you stop treatment.
Image via Wikipedia
Irrespective of the theoretical concerns, a number of companies have active research programs going now with small molecules and monoclonal antibodies to IGF-1R in the clinic. It is a fair question to test the concept out in research and at least see whether it is successful of not.
At last weekend's ASCO meeting there were a number of abstracts published with IGF-1R inhibitors in a range of cancers. These include the following examples, which is in no way exhaustive (abstracts via clickable link):
Inhibitor Company Phase Tumour Abstract
XL228 Exelixis I ST/Hem #3512
OSI-906 OSI I ST #2559
AMG-479 Amgen I ST #3545
R1507 Roche I Sarcoma #10503
Figitumumab Pfizer I NSCLC, CRC #8072
BMS-754807 BMS I ST #e14501
MK-0646 Merck II mCRC #4127
IMC A12 Imclone/Lilly II CRPC #5142
These are just a few examples, as there are many others in R&D, from companies such as sanofi-aventis, Novartis, Eisai, BiogenIdec etc, so it will be interesting to see how this class pans out. The data reported at ASCO this year was very preliminary and isolated responses were seen here and there so perhaps still too early to tell whether it will be a viable target or not.
Aside from monoclonal antibodies and small molecule TKIs, there are also other molecular agents such as antisense and small interfering RNAs. Over the next few years we will see what happens with toxicity due
to normal tissue IGF1R expression and cross-reactivity with the insulin
It's definitely a pathway to watch out for.
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