"From what I understand the Calistoga compound has been doing very well in some B-cell lymphoma's"
Indeed. You saw the slide where it implies other isoforms are involved with insulin signaling, implying there would be off target effects if you didn't specifically target the delta isoform? Poking around, I'm not sure if that's entirely true. The delta isoform does have a role in insulin signaling in the J774.2 macrophage cell line. But that's tumor derived, right? So if there is a little off target action in that area, that would be OK. I think.
Anyhow, the gamma isoform is more involved in inflammation. I gather the idea of combining certain PI3K isoforms with HDAC, MEK, mTOR, or whatever, is that the dual inhibition keeps the cancer from using an alternate pathway so easily. This could also be the case with inhibitors of two PI3K isoforms. Going after delta and gamma might make sense as the inflammatory component of cancer is becoming established. See, for example:
"Inflammation: a driving force speeds cancer metastasis"
landesbioscience.com
Another random example . . . in PTEN negative tumors it helps to inhibit the beta isoform. An example is PC3, which is a prostate cancer cell line. But in the breast cancer line MF7 (PTEN+), alpha/delta inhibition was sufficient.
One wonders if if Calistoga's delta specific inhibitor might encounter pay for its specificity with earlier resistance. Interestingly, Amgen's AMG 319 is about to start P1. It appears to be a PI3K delta inhibitor:
amgentrials.com
Indeed the patent app for it was filed a year ago.
Anyhow, Infinity seems to have the only delta/gamma inhibitor going, for better or worse.
Cheers, Tuck |
