DCA Patient Trials

You may remember a few years ago, there was buzz out of the University of Alberta about a simple molecule, dichloroacetate (DCA), that was effective at inhibiting aerobic glycolysis and slowing the growth of cancer cells in vitro and in mouse models. This was hailed in some quarters as a miracle cure, others claimed it would never see the light of day because Big Pharma would keep it down, unscrupulous peddlers seized a money-making opportunity and more sensible people took the data for what it was and awaited further investigation and proper trials.

The first patient trials have now been done, and the results are in. Surgically excised glioblastomas showed signs of reversal of the Warburg effect and increased apoptosis.

The clinical trial was quite small, involving 5 patients with neuroblastoma being treated with various standard therapies plus DCA. Three showed regression of their cancers, though it's not certain whether it was the DCA or the existing treatment responsible for the change.

Both Abel Pharmboy [Dichloroacetate not yet an effective treatment for aggressive brain cancer] and Orac [Dichloroacetate (DCA) and cancer: Déjà vu all over again] have excellent descriptions of DCA, how it works and analysis of the trial on their respective blogs. The bottom line seems to be that DCA remains interesting, but needs to benefit from more research and well-designed trials before moving to a real treatment.

More on the Warburg Effect

We've blogged (and podcasted) before about the Warburg Effect: The observation that cancer cells rely primarily on glycolysis for energy production.

Two papers in Nature this week have identified a key player in this process (subscription required, summary here). The protein is the M2 isoform of pyruvate kinase (PKM2), which is the fetal form of this protein. PKM2 is also expressed in tumour cells, while normal adult tissue expressed the M1 form exclusively. These papers show that PKM2 is inhibited by phosphotyrosine affecting cellular metabolism. One of the papers suggests:

"this mechanism evolved to ensure that fetal tissues only use glucose for growth when they are activated by appropriate growth factor receptor protein-tyrosine kinases. Cancer cells, by re-expressing PKM2, acquire the ability to use glucose for anabolic processes."

In other words, re-activation of PKM2 allows the rapid growth associated with cancer. This was shown a variety of ways, by measuring glycolysis rate, cell proliferation and glucose incorporation into lipids after PKM2 knockdown/re-introduction or phosphatase inhibition (increasing the available phospho-tyrosine for PKM2 inhibition).

To further implicated PKM2 in cancer biology, the second paper showed that introduction of the M1 form into cancer cell lines increased their oxygen consumption and decreased lactate production (consistant with increased oxidative phosphorylation). Additionally, mice injected with cancer cells expressing the M1 isoform had slower tumour development, fewer tumours when they did develop and smaller tumours compared to M2 cell injections.

Both of these papers identify a key player in the Warburg effect, PKM2, and show it contributes significantly to tumorigenesis. Because PKM2 was found in all the tumour cells the authors analyzed, this unique biology could be exploited as a broad therapeutic target.

• Heather R. Christofk, Matthew G. Vander Heiden, Ning Wu, John M. Asara & Lewis C. Cantley. Nature 452, 181-186(13 March 2008) doi:10.1038/nature06667
  
  
• Heather R. Christofk, Matthew G. Vander Heiden, Marian H. Harris, Arvind Ramanathan, Robert E. Gerszten, Ru Wei, Mark D. Fleming, Stuart L. Schreiber & Lewis C. Cantley Nature 452, 230-233(13 March 2008) doi:10.1038/nature06734

Bayblab podcast Episode9

Finally available in all its glory..an epic two part series.

Part1: Steven Hawking presents... glycolysis and the Warburg effect in cancer and heart attacks, and road density in the United States.

part2: Pharming drugs and the production of interferon in transgenic tobacco plants and opportunities from advances in sequencing technology such as mapping the beer genome...

Also if you want to subscribe to this podcast, simply search for bayblab at the iTunes store...