So PI 3 kinase inhibition looks like it's an important uh um uh therapy or PI3 kind is important targeting T cell lymphoma. It's really kind of a bed to bench side bedside to bench story. Um, you know, we did a phase one study starting in 2012 looking at PI 3 kinase across the spectrum of lymphomas, um, with at that time was Duvali said there are the PI 3 kinase, uh, therapy certainly in development at that time too. Um, do the list of his PF3 kinase delta gamma inhibitor and um what was seen in that study, uh, um, so it was picked because of, you know, lymphocyte signal through T cells through T cell receptors, through B cells through B cell receptors, um. And um Uh, and PA3 kindness is in that pathway, so it's kind of downstream of the external signal. But really, um, it was somewhat empiric in applying, um, in applying PA 3 kinase to lymphomas. What we saw in that study with two things is that patients with low grade B cell lymphoma, CLL, and flick lymphoma responded to relatively low doses of Duvali, and patients with indolent lymphoma could get on wait lists and take up all the spots for the clinical trial. So, uh, once we saw good activity in B cell lymphomas, my interest is mostly. Lymphoma, those patients were branched off into an expansion coord at 25 mg twice a day, which ended up being the FDA approved dose of uh Duvolica for low grade lymphomas. Um, and then we were treating patients with T cell lymphoma, uh, at 50 75 100 mg, uh, twice a day, 100 mg ended up being, uh, the MTD, um. Um, or 75 was the MTD 100 exceeded the MTD, and what we saw was about a 50% response in a small number, about 30 patients with peripheral T-cell lymphomas. Uh, and we were seeing that responses across different subtypes and really had not yet matched up the biology at all, and you know, we, we've taken some steps in that direction. So that was interesting that there was this response rate, uh, with T-cell lymphomas, which otherwise we had really uh very few effective therapies. Some laboratory scientists who we were collaborating with Dave Weinstock one at the time was then subsequently looking at this in the lab, and the first group of cell lines he looked at with P3 Kinas with Duval had no response, and it could have just ended there if you really tried to develop preclinical rationale, but we knew we already had this um. Um, this, uh, experiencing people where half the patients, uh, had a response. So looking further found other cell lines. It looked like cell lines that had elevated phospho AKT. So evidence of signaling through the PF 3 kinds pathway were the ones that responded, uh, um. Uh, to do Vici, we now think that there's other subtypes that don't have that that respond, but that may be more of a microenvironment effect, maybe partially brought in by the PI 3 kinase, uh, gamma, which can have some effect on uh on macrophages and maybe more of a microenvironment effect, but at least when you put those two together and you looked at more cell lines, you could kind of explain like, OK, there probably is a real response. Right here, probably some of it is on target on the cell, probably some of it is microenvironment, probably, uh, some of it is both. And then that's led to like subsequent, um, uh, studies and confirmatory studies. So now we know a little bit more, we don't totally know, but in the, um, studies of, um, the, the, uh, expansion studies of Duvaliib, we've seen particularly high response rates in, um, in angiomenoblastic T cell lymphoma, follicular upper T cell lymphomas. And we think certain subtypes, particularly those with uh ROA, may have strong signaling through the uh um PI3 kinase pathway. So those may be the ones that are most likely to respond. That's still a bit hypothesis because we see responses in patients with AITL without uh ROA mutations, but it looks like we're starting to understand the biology a little more where some of these patients really do have intensified signaling, probably downstream from the T cell receptor through the PI3 kinase pathway.
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