Tuesday, July 31, 2012

What is BCL-2 and why should we inhibit it?

Another class of investigational treatments working their way through the system are the BCL-2 inhibitors (named as the "B-Cell Lymphoma gene number #2).  These investigational therapies will likely be relevant to patients with CLL or NHL.   They may actually be relevant to a number of cancers but CLL/NHL will be be where they get evaluated first. 

BCL-2 inhibitors have been a long sought goal for the pharmaceutical industry but they have had to try targeting the protein a number of ways before they found what looks to be the promising set of compounds that are moving forward now.

I thought a little biology might be fun - so let's talk about the mechanism by which these work.  Within a cell, there are a variety of "organelles."  In the same way you have a liver and kidneys, cells have their own organs - known as organelles.  These have names such as the golgi apparatus, endoplasmic reticulum, mitochondria, lysozymes, etc.  The mitochondria is the equivalent of the "power plant" for the cell.  It is where the vast bulk of energy is synthesized for the normal function of the cell.

In normal physiology, it is important to have a way to get rid of cells that you don't need anymore.  The main mechanism by which this "programmed cell death" occurs is called "apoptosis."  It turns out that the mitochondria plays an important role in apoptosis.  It contains a variety of enzymes known as caspases tucked away between two membranes.  When the caspases are released from the mitochondria into the cell, they function as the "cellular executioners" to bring about an orderly demise of the cell.

At the outside surface of the mitochondria, there is a constant battle between two sets of proteins.  These conflicting proteins create a balance between the pro-survival and pro-death signals.  Depending on environmental cues or external signals, the cells fate is played out.  The main "pro-survival" protein is known as BCL-2.

You might ask why your body doesn't just turn to mush when you take one of these drugs as it should release the death signal throughout mitochondria everywhere.  It turns out though that cancers are "addicted" to BCL-2 in ways that most other cells are not.  The inside of a cancer cell is not as friendly as other cells and they need some mechanism to protect themselves from the death signals they constantly receive.  In follicular lymphoma, pieces from two chromosomes (14:18) break apart to ensure that too much BCL-2 is produced.  In CLL the mechanism is less clear, but may involve genomic alterations in the 13q14 region (see my prior post on micro-RNA's).  In either case, there is too much BCL-2 protecting the mitochondria, so no matter what "death signal" (i.e.. chemotherapy, immunotherapy, etc) you send to the cell, it survives.

For this reason, pharma has long wished to create a good BCL-2 inhibitor.  The first attempt was a molecule known as Genasense.  This used a technology known as "anti-sense technology" which has not proven itself to be a good way of making a drug.  The next significant foray into BCL-2 inhibitors was a series of compounds generated by the folks at Abbott Labs.  Abt-737 was an IV formulation of what became the oral Abt-263.

Abt-263 has reported activity in CLL - but as is often the case with drugs, we discover things along the way we didn't expect.  In this case, there is a protein very similar to BCL-2 known as BCL-xL.  It is the main protein keeping your platelets going and when you inhibit BCL-xL platelets drop really fast.  This makes it unappealing to think about combining it with other types of CLL/NHL treatment and may prevent the drug from finding a home in our treatment choices.

The next research treatment coming down the pipeline is Abt-199 which also has the designation of GDC-0199.  This drug was designed by the same folks at Abbott that made 737/263.   Abstract 546 at the 2012 European Hematology Association details the clinical experience to date.  This link downloads a long PDF.  Best to use the search function after getting it open.