Insulin-like growth factor 1 receptor inhibition may be an effective accompaniment to chemotherapy in cancer treatment, former DHMC fellow Anthony Olszanski said in the Norris Cotton Center Grand Rounds last Thursday.
At normal levels, insulin-like growth factor 1 (IGF-1) and its receptor (IGF-1R) are important in promoting cell proliferation and, subsequently, human growth. Because of this, individuals with a mutation in the IGF-1R gene may be small in stature, as is the case for those with Loran dwarfism. However, a recent study has revealed that these individuals with loss of IGF-1R function also have a significant resistance to cancer, said Olszanski.
In light of this, scientists are now pursuing means by which IGF-1R can be blocked and tumor growth thus inhibited. This is important not only in inhibiting IGF-1R’s direct role in tumor growth, said Olszanksi, but also in disabling the tumor-growth-promoting crosstalk between IGF-1R and both epidermal growth factor receptor (EGFR) and the mammalian target of rapamycin (mTOR).
Currently, scientists have found that the binding of tyrosine kinases or monoclonal antibodies to IGF-1R is effective to this end, and Olszanski himself has been researching the use of the latter. Various humanized and human igG1 class antibodies – such as AMG 479, RO1507, MK-0646, and AVE-1642 – have shown promise.
The most extensively studied thus far, however, has been CP-751,871, which is a human antibody that has been tested by dose escalation in combination with chemotherapy drugs paclitaxel and carboplatin. Each of the three treatments – CP-751,871, paclitaxel and carbonplatin – were shown to have some negative effect on tumor growth, none as great as their additive effect, said Olszanski.
However, there are some shortcomings of the use of monoclonal antibodies. Most consistent throughout trials of various antibodies was the side-effect of grade-three hyperglycemia. Despite this, Olszanski noted that all cases were “easily managed and reversible.”
Another drawback is that this target-specific approach is naturally limited to to tumors in which IGR-1R are present. This leaves not otherwise specified (NOS) tumors untreatable by this method. However, IGR-1R is especially effective in squamous cell tumors, said Olszanski, because there is high expression of IGR-1R in squamous cell carcinoma.