Syk not Sick

When a B cell (either CLL or NHL) signals through the b cell receptor - a sequence of enzymes gets activated.  This starts with Syk, goes to BTK, and then onto PI3 Kinase after several steps.  S-Y-K stands for "spleen tyrosine kinase"

Back in 2005 as a fellow at Stanford, I figured it might be useful to shut off this pathway, so I proposed using a drug that was being developed for nasal allergies to treat NHL.  The idea was a little far fetched at the time, so I had to prove my point in the lab before we could take it to the clinic.  Didn't take long for me to realize I had no business trying to be a laboratory scientist although we did present the very first abstract on this idea back in 2007 at ASCO.

Our Syk inhibitor worked ok and was the first time we ever saw a "small molecule tyrosine kinase inhibitor" work against NHL/CLL.  It was presented in the plenary session at ASH and eventually published in Blood here.

Richard Miller who was the chief medical officer at Pharmacyclics at the time but also saw patients with us at Stanford worked in the same clinic as me.  He saw some of the patients responding to our drug (fostamatinib) and deduced that a compound he was working on called PCI-32765 that he got for free (best deal in pharma EVER) from Celera would work even better since it went after BTK. We took a casual gentleman's bet about which was the better target.  I voted for Syk, he voted for BTK.  Too bad because I could be retired by now had I picked BTK.  PCI-32765 became ibrutinib.  We treated the first CLL patients with it here in Eugene (I had left Stanford by then).  The story is nicely told in a Forbes article (linked here). 

Anyhow, I always believed the problem with going after Syk was not about the target, but about the drug we were using.  So when the chance came up for us to try again with a new drug, I had to jump at the chance.  Enter ENTOSPLETINIB.

After working on the phase I studies of idelalisib (back when it was CAL-101), we built some really nice relationships with Gilead.  They are honestly a really nice group of folks.  They picked up a drug (GS-9973) and we started testing it on patients with NHL and CLL.  Like most of the drugs that inhibit BCR signaling, we got a really nice signal of efficacy and tolerability in CLL.  Today, our first paper on the topic was published in Blood - link here.

Entospletinib looks to have pretty good efficacy in CLL.  It is a twice daily pill.  You really cannot compare across studies, but some of the early numbers look a lot like idelalisib.  Lots of work left to be done and the trial is still recruiting patients with CLL (trial link here).  Talk to your own doctor or seek an opinion at one of the centers offering the trial.

Thanks for reading.

Frontline video

Some time ago, I wrote a blog post about dying (link here).  It was an in depth reflection about the choices I see people make when confronting disease that has escaped control.  While the post was well received and I got a lot of positive feedback, I recognize that I barely scratched the surface of a really important topic.

I would therefore like to continue to put up a variety of multimedia topics on the post that I think do a good job diving into a very difficult topic - because the topic is strangely taboo for many doctors and patients.

A while back, I added a podcast on hospice that I thought was especially good (link here)

Now Atul Gawande has put together a frontline video.  Not sure if you ever watch frontline - but it doesn't pull any punches.  Atul writes regularly for the New Yorker and really has a clear voice on many important topics.  The video is getting very favorable reviews - so I wanted to post a link to it from the blog.  Not necessarily a happy joyful topic, but a sober view to consider (link here).

In the meantime, we ARE making huge progress against CLL and NHL.  I am more excited about research than ever before.  I now find myself wondering if CLL or even follicular lymphoma might become curable cancers in the next ten years with emerging technologies.  Please know that there is a lot of plausible hope out there - just putting these links out there to expose something that doesn't get the attention it deserves.

Thanks for reading (and listening and viewing).