It’s that time of year in the dog days of summer when many people in the industry are either incredibly busy, heads down, rolling out new things for the third quarter or else it’s a pleasant lull between the strategic and tactical phases and a good time to catch your breath. Here in the Icarus office, we’re busy creating and writing a new series of syndicated reports in a variety of different tumour types and pathways. I have hundreds of snippets and notes saved electronically from various cancer meetings this year, making it a great opportunity to collate and process them into broader insights. If you have any particular needs in this area, now is a good time to let us know, so do email me and your wishes may get added to the list.
Last week I was in Boston and happened by chance to walk past the Whitehead Institute. This reminded me that I had David Sabatini’s new mTOR paper in Science queued up to blog about on Pharma Strategy Blog.
The mTOR pathway is highly complex and consists of a huge network of interwined proteins and kinases:
Hsu et al., (2011) described what they found from defining the mTOR-regulated phosphoproteome using quantitative mass spectrometry and protein libraries to build a complete picture:
“The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1.
Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.”
We know, for example, that mTORC1 inhibits PI3K-Akt signaling, but the precise molecular connections involved are poorly understood. S6K1 phophosphorylation, which destabilises the insulin receptor substrate 1 (IRS1), is one mechanism known to be involved. Hsu et al., demonstrated that other mechanisms are also critical:
“mTORC1 inhibits and destabilizes IRS1 and simultaneously activates and stabilizes Grb10.”
They went to separate the effects of acute and chronic stimulation of mTOR:
“Whereas acute mTORC1 inhibition leads to dephosphorylation of IRS1 and Grb10, chronic mTORC1 inhibition leads to changes in the abundance of IRS and Grb10 proteins, which are likely the most important effects of mTOR inhibitors to consider in their clinical use.”
This important article is particularly relevant because not long after the publication, Novartis announced positive data with their mTOR inhibitor, everolimus (Afinitor) in patients with tuberous sclerosis complex (TSC).
TSC is a genetic disorder that affects affects approximately 1-2 million people worldwide and is associated with a variety of resulting disorders including seizures, swelling in the brain, developmental delays and skin lesions. It can also cause non-cancerous tumours to form and can affect many different parts of the body such as the brain and kidney, for example.
The rationale behind such as study was described in the Novartis press release:
“Tuberous sclerosis complex is caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR activity is increased, which can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism, leading to the formation of non-cancerous tumors throughout the body, including the brain.”
In other words, giving an mTOR inhibitor such as everolimus may help by reduce cell proliferation, blood vessel growth and glucose uptake associated with the TSC defect.
In patients with brain lesions, surgery is usually considered the only viable option, so a study showing a 35% response rate (50% reduction or more) in the SEGA lesions, is a positive step forward. The new data was from a phase III trial (n=117) and appears to support the initial positive phase II study, so it will likely lead to a registration filing in this indication for everolimus.
Hsu, P., Kang, S., Rameseder, J., Zhang, Y., Ottina, K., Lim, D., Peterson, T., Choi, Y., Gray, N., Yaffe, M., Marto, J., & Sabatini, D. (2011). The mTOR-Regulated Phosphoproteome Reveals a Mechanism of mTORC1-Mediated Inhibition of Growth Factor Signaling. Science, 332 (6035), 1317-1322 DOI: 10.1126/science.1199498