Duvelisib Trial

OncLive has been producing some interesting videos lately, mostly of experts in oncology discussing recent developments in the field.

The most recent is a series of videos focusing on PI3 kinase inhibitors, featuring Dr. Ian Flinn and Dr. Jennifer Brown. You can watch all four videos in the series at the same link, though I'm mostly going to focus on Dr. Finn's discussion of Duvelisib.

First, some background (some of this is covered in the other videos in the series, and you can always  read about lots of targeted pathway treatments at Lymphomation.org).

Duvelisib is a type of Kinase Inhibitor. The other Kinase Inhibitors that get talked about a lot in Follicular Lymphpoma circles are Idelalisib and Ibrutinib. Duvelisib and Idelalisib are examples of PI3 Kinase Inhibitors, so it makes sense to look at them together (which the OncLive videos do).

In general, a protein kinase is a kind of enyzme that attaches to other proteins to allow them to help a cell function, by growing or dividing or doing its basic job. So a Kinase Inhibitor is a treatment that inhibits a Kinase from attaching to the those proteins. If you look at the Lymphomation link above, you'll see that inhibitors are part of a larger group of treatments called pathway targeting treatments -- a kinase allows the cell to perform an action, and when that action is done, it allows another action to happen, etc., etc., almost like a pathway. So if you cut off one of those actions, the rest of the pathway can't happen. Inhibit a kinase from attaching to a protein, and it messes up the rest of the cell's pathway. Do that to a cancer cell, and you keep the cancer from growing.

PI3 (short for Phosphoinositide 3) Kinase inhibitors focus on a specific part of a larger pathway known as the PI3K/AKT/mTOR pathway. Just like other pathway targeting treatments, messing with one part of this pathway will shut the whole thing down, and there are treatments that target AKT and mTOR in different stages of development. This pathway is important for a cancer cell being able to grow, feed itself, and copy itself, so messing it up will mean that the cell can't grow and divide and do the bad things that makes cancer so horrible.

But of course, nothing is easy when it comes to cancer.

In the body, proteins have different isoforms. This means when they get copied, they don't come out exactly the same. They might be pretty close to the same, but they aren't exact. This is actually a good thing, usually. It allows for protein diversity, and in evolution, diversity is a good thing.

Imagine it this way -- you make a batch of chocolate chip cookies. The first dozen come out a little crispy, so with the second batch, you take them out a minute sooner, so they are less crispy and more chewy. The third batch, you forgot about, so they stay in three minutes longer and are downright hard. Same recipe, three very different cookies. Fortunately, you have three kinds who drive you crazy by not agreeing on anything, and one likes chewy cookies, one likes crispy cookies, and one likes them hard so she can dunk them in milk. Same recipe, three different cookies, but three happy outcomes. No one complains about the cookies. Diversity is good.

Same with protein isoforms. One protein that gets copied, but with slight variations. They all came from the same source (or recipe) and they all do the same function (make your kids shut up because they aren't really hungry, just bored, because it's summer and they won't admit that they really do want to go back to school).

So, to get back to PI3 Kinase inhibitors. Naturally, they have different isoforms, known as p110 alpha, p110 beta, p110 gamma, and p110 delta. Without knowing that, someone could think they are targeting all PI3 kinase, but are really only targeting one isoform.

Fortunately, researchers are aware of the different isoforms. Idelalisib targets the p110 delta isoform, and Duvelisib both gamma and delta isoforms.


There are a bunch of other PI3 kinase inhibitors in different stages of testing, targeting differennt isoforms and different cancers, including a few more for Follicular Lymphoma.

Dr. Finn's video on Duvelisib discusses a particular phase I clinical trial that looked at single agent Duvelisib (it has been in other trials as a combination treatment with other agents). This trial looked at Duvelisib as a treatment for patients who had tried Rituxan and chemo and were no longer seeing any results from them. Early results for single-agent Duvelisib look great -- 70% Overall Response with "nearly one third" having a Complete Response.

The four videos focus in PI3 Kinase inhibitors, but they touch on lots of different treatments (Dr. Finn is excited about R squared). Worth watching.

Hope the background info helped.

Always nice to know we have some more potential arrows for our quivers.