WHITHER BREAST CANCER IN 2013?

When I return from breast cancer meetings, I am often asked, “What’s new?”

Sometimes there is a spectacular new treatment.  At other times, there is new information that has not yet led to new treatments, but the information still raises hope because it means there are new ways to think about cancer that will help us design new and better treatments.

This year, the 11th International Congress on the Future of Breast Cancer was the second kind of meeting.  There were new ideas on the verge of becoming the basis of better treatments.

These ideas – like a lot of ideas – are not surprising when you think about them, but you ask yourself, “Why didn’t we think of that before?”

For example:

Cancer Dominoes

Genes are the units in chromosomes that carry the directions or codes for making proteins.  Each gene has the code for one protein.   When a specific gene is turned on, it makes the single protein that is specific for that gene.

What gets overlooked in the discussion is that these genes don’t act as one gene that starts (or stops) working and then you have cancer. 

The metabolism of cells is always controlled by a series of steps.  One gene makes one protein. That protein triggers another gene, and that second gene makes a second protein. That second protein triggers a third gene to make a third protein, and on it goes.  One step triggers another, and that triggers another, like a series of dominoes. 

The analogy of dominoes works pretty well, but it is important to go back and remember that it is not a direct “one gene triggers another gene” event.  In cell metabolism, an activated gene makes a protein, and it is this protein, made by the activated gene, that activates the next gene in the series.

A series of this kind of individual steps that works as a unit is called a “pathway”.

One of the “pathways” that got a lot of attention at the meeting was the PI3K/ AKT/ mTOR pathway.  In this pathway, the PI3K gene makes the PI3K protein that triggers the AKT gene to make the AKT protein which in turn triggers the mTOR gene.  Once mTOR is triggered, it triggers more genes that eventually lead to other specific genes that start cells growing, one of the major hallmarks of cancer.

A major difference between cell metabolism and the game dominoes is that in normal cells there are some genes that slow down the pathway.  In contrast, there is no easy way for a game domino to slow down a series of dominoes that are falling.

PTEN and p53 are two major genes that normally slow cells down. If either the PTEN or the p53 gene is damaged in a cell, that cell is more likely to become cancer because it has lost its “brakes” that should normally control that cell’s growth.

Whack-a-Mole

Doctors have known about metabolic pathways for a long time.  What is new is the realization that more than one pathway can keep a cancer growing. 

For example, it is often the case that the PI3K/ AKT/ mTOR pathway may not be the initial pathway in the cancer.  However, when drugs treat the pathway that started the cancer – and make that pathway inactive – instead of the cancer being stopped completely, the PI3K/ AKT/ mTOR pathway can take over and keep the cancer growing. 

Several researchers at the meeting compared this to Whack-a-Mole in the amusement park.  Push down one pathway, and another will pop up to take its place. 

This is a groundbreaking concept, and clinical scientists are working hard to figure out how to use this to treat cancer.  Instead of the old idea of targeting one pathway, the new idea is to figure out how to target two or perhaps even more pathways at the same time.

This is progress, not in the form of a specific new treatment, but rather in the form of a new way to plan therapy.  In the next few years there will be a lot of new information on how to use this. 

There is already a new plan to treat cancer that was responsive to hormone-based treatment but then stopped responding to treatment.  In the new two-drug approach, doctors treat two pathways.  One drug attacks the same initial hormone pathway with a different drug, while at the same time a different drug blocks the PI3K/ AKT/ mTOR pathway.  This is like hitting two Whack-a-Moles at the same time.

The Role of Environmental Chemicals

An important realization to me from this research is that the PI3K/ AKT/ mTOR pathway may not be a common pathway to cause cancer to take off, but it seems to be sufficient to keep cancer cells growing when the other pathways are blocked by treatment.  This is important because our research found that the environmental chemical bisphenol-A (BPA) activates the PI3K/ AKT/ mTOR pathway.

We are just beginning to understand how this affects treatment of women with cancer, but for now it seems prudent to avoid dietary BPA.