Mutations Linked to Breast Cancer Treatment Resistance

cp418

http://www.sciencedaily.com/releases/2013/11/131104101049.htm

Researchers at the University of Michigan Comprehensive Cancer Center have identified a type of mutation that develops after breast cancer patients take anti-estrogen therapies. The mutations explain one reason why patients often become resistant to this therapy.

gpawelski

It is known by laboratory oncologists that on-off switches and back up switches constitute the controls of cancer. When one of these switches stops working and a cell "short circuits," cancer is the result.

Study findings were reported a 2011 American Association of Cancer Research Meeting (AACR), on novel compounds that target two parallel circuits in cancer cells. These compounds, or small molecules, disrupt the signal that drives cancer cell survival and proliferation. While the profiles of each drug alone were of interest, the study found the profiles of the drugs in combination were better still.

The phenomenon of cross-talk defines an escape mechanism whereby cancer cells blocked from one passage, find a second. When therapists have the capacity to block more than one pathway, the cancer cell is trapped and often dies. This is what's observed with duel inhibitor combinations.

What was also interesting was the fact that these activities cut across various tumor types. Melanomas, colon cancers and lung cancers seem to have similar propensities to drive along these paths, demonstrating that cancer biology is non-linear. Cancers share pathways across tumor types in pathways that might not intuitively seem related.

It is the beauty of phenotype analysis that allows exploration of drugs and combinations that most clinicians wouldn't think of. It will be these counterintuitive explorations that will lead to meaningful advances.

lekker

Thank you for that response. I know this is a simplistic view of a complex process (I am not a scientist) but I've often wondered why the success of the HIV "triple cocktail" hasn't been attempted in treating cancer. If a tumor appears to be fueled by estrogen, you take tamoxifen or an AI, but what about the mTOR/PIK3C/AKT etc pathways - the very pathways that are sometimes activated in the absence of estrogen? Is it a matter of toxicity? Affinitor is used with an AI in advanced breast cancer, but what about using it as a first line treatment? Would that even be enough? I'm sorry to ask so many questions, but I've been mulling all of this for quite a while now. My oncologist doesn't really have the time for the kind of in depth discussion that I would like. When I was diagnosed, I said "I should've gone to med school." Maybe I still should!

gpawelski

You're right in that cancer medicine has learned a lot from HIV. A diagnosis of AIDS was a death sentence until the advent of drug cocktails in the 1990s, which helped patients suppress the disease indefinitely. Now researchers say a similar combination strategy may change the course of cancer. At least some researchers.

For a decade, researchers have crafted drugs to disrupt the precise cellular processes that fuel cancer. So far, survival benefits are measured in months, not years. That's because cancer, like HIV, evolves rapidly to evade a single treatment. Rather than mixing and matching approved drugs, scientists are now developing combinations designed to work in tandem to block cancer.

Among the most sought after attributes of chemotherapy drug combinations is drug synergy. Synergy, defined as supra-additivity wherein the whole is greater than the sum of the parts, reflects an elegant interaction between drugs predicated on their modes of action. While some synergistic interactions can be predicted based upon the pharmacology of the agents, others are more obscure.

The application of synergy analyses may represent one of the most important applications of the functional profiling platform (phenotype analysis); enabling clinicians to explore both anticipated and unanticipated favorable interactions.

Equally important may be the platform's capacity to study drug antagonism wherein two effective drugs counteract each others’ benefits. This phenomenon, characterized by the whole being less than the sum of the parts, represents a major pitfall for clinical trialists who simply combine drugs because they can.

The problem with these "targeted" drugs is the same thing that was a problem with AZT for HIV/AIDS. Early results, then rapid resistance. The solution is "combination therapy" to attack all the different targets. It's going to take "combination" anti-vascular therapy to make the big difference, but this is definitely coming and it's the most promising thing on the therapeutic horizon.