Cross-talk: what it is and how it impacts cancer research
A Pharma friend who regularly reads this blog attended the ASCO GI meeting last weekend and phoned me to say that cancer is indeed getting much more complex. She was also highly amused at the buzzword bingo post from the AACR Molecular Targets meeting:
"Well, I just thought you might like to know that the latest buzzword bingo is 'cross-talk'"
Funnily enough, I was writing a report on cross-talk at the very moment she called. Cross-talk occurs when two powerful signaling pathways interact, leading to interactive processes between them downstream of the original receptors.
Another Pharma buddy sent me the slides from a presentation on the Merck IGF-1R inhibitor, MK-0646, phase I results of which were reported in pancreatic cancer. One of the focus of the presentation was 'cross-talk' according to the abstract:
"Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/Akt pathways mediate resistance to anti-EGFR agents such as erlotinib. IGF-1R + EGFR antagonists result in synergistic antitumor activity in preclinical pancreatic cancer models."
When you actually look at the pathways involved, you can see that things are indeed very complex and cross-talk is not surprising, as Pollak et al., showed in 2004:
This means that inhibiting the IGF-1R pathway alone with a inhibitor such as Pfizer's figitumumab or Merck's MK-0646 is unlikely to be effective because cross-talk between the receptor and AKT/mTOR or MEK pathways may well have an impact and lead to an escape route for the cancer cells to continue surviving. For this reason, we can see that the recent futility reported in the figitumumab lung cancer trial is not completely surprising. However, combining the drug with an AKT or MEK inhibitor may well yield better results.
In the Merck study, the majority of patients had an objective response or stable disease when the IGF-1R inhibitor was combined with erlotinib, an EGFR inhibitor. Cross-talk between IGF-1R and EGFR has been shown in preclinical models of pancreatic cancer.
These early results are promising for the compound, but much work is still needed to determine suitable predictive biomarkers and ideal combinations/sequencing before moving forward into a phase III trial.
Pollak, M., Schernhammer, E., & Hankinson, S. (2004). Insulin-like growth factors and neoplasia Nature Reviews Cancer, 4 (7), 505-518 DOI: 10.1038/nrc1387
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3 Responses to “Cross-talk: what it is and how it impacts cancer research”
Merck is actually in a Phase 1 study combining MK-0646 with MK-8669, an oral mTOR-inhibitor.
No results (as usual), still in trials. Seems like everything Merck is doing with their mTOR is always hidden under a blinded trial, so, we have no idea how it is working.
I know there were some in vivo studies which showed combining and IGF-1R-inhibitor with an mTOR stopped the negative feedback and actually increased, quite a bit, the efficacy of the IGF-inhibitor.
Indeed there is, Craig.
Here’s the dalotuzumab + ridoforolimus phase I trial:
http://clinicaltrials.gov/ct2/show/NCT00730379?term=MK-0646&rank=15
I love reading about stuff like this. You take very complicated subjects and make them accessible for the average cancer survivor to stay engaged. Thank you for all you do!
On a side note, you note:
“Cross-talk occurs when two powerful signaling pathways interact, leading to interactive processes between them downstream of the original receptors”
This seems like a fluid dynamics equation. I wonder if the mechanics of fluid enginnering could ever be extended to this scenario? Fascinating!
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