I've been running for DFMC for the last 5 years. My first DFMC training season started in October 2005. My reason for joining was two fold: 1.) Out of gratitude for discoveries at DFCI that led to the development of the drug Gleevec which my mom takes to treat her CML, a form of leukemia that did not have any long term treatments only a few year's prior to my mom's diagnosis. 2.) Out of hope that more could be done. Gleevec treats CML but does not cure it. The lack of a cure and hope of permanent remission was unacceptable to me.Today, I got the best email ever from DFCI. Proof that the funds raised in the last 5 years have had real tangible benefit in treating my mom's form of leukemia. This is just one of many hopeful emails I've received documenting the good works of the Barr Program Invesitgators this training season. Follow the link, "DFMC Dollars in Action" in the article below to see how DFCI is helping your loved ones win their cancer battles. This research started not 3 months after I first crossed that finish line on Boylston St. Use this as evidence that you CAN and DO make a difference whether you chose to run for DFMC or choose to be a loyal sponsor. The transcript of the email that made my day:
We're pleased to mark the one-week countdown to the opening of DFMC Check-In next Friday with a look at important research led by Nathanael Gray, PhD, Assistant Professor of Cancer Biology at Dana-Farber Cancer Institute (DFCI) and Barr Program funding recipient in July 2006-June 2008. The project, conducted in collaboration with colleagues at DFCI and elsewhere, was funded in part by the Claudia Adams Barr Program in Innovative Basic Cancer Research.
Robert Levy of DFCI Communications wrote the following overview in February 2010, and is pleased to share it as another example of “
DFMC Dollars in Action.”
Discovery opens way to treatment of recurrent form of leukemia Cancer cells’ Houdini-like ability to escape the shackles of drugs that restrain their growth is one of the chief challenges of cancer treatment. As cancer genes mutate and create misshapen proteins, drugs that once blocked these proteins become less effective.A prime example is in chronic myelogenous leukemia (CML), where the drug Gleevec® often produces dramatic remissions but tends to lose potency over time, particularly in cases where the disease was far advanced when treatment began.
In a new study in the journal Nature, Dana-Farber scientists and their colleagues show how a compound that enters a molecular “side pocket” of a key protein stops the proliferation of CML cells that are no longer susceptible to Gleevec®. They show, further, that combining this compound with a second-generation version of Gleevec called Tasigna® (nilotinib) may prevent CML from becoming resistant to the drugs to begin with.
“Our results offer a promising alternate route to attacking CML cell growth, even in disease that has become drug-resistant,” says study senior author Nathanael Gray, PhD. “The study offers an example of what can be accomplished when researchers at academic medical centers collaborate with colleagues from a pharmaceutical company – in this case, Novartis.
The next step will be to develop versions of the compound we studied into an active drug that can be tested in patients.”
Nooks and crannies
Gleevec® works by targeting a defective protein in CML cells called Bcr-Abl. By lodging inside a nook on Bcr-Abl’s surface, it blocks an enzyme known as a tyrosine kinase. The effect is like jamming the gears of a bicycle: the kinase cannot act as a growth stimulant, and the machinery of cell proliferation comes to a halt. As gene mutations produce subtle changes in Bcr-Abl’s chemical structure, Gleevec® no longer serves as an effective blocker, allowing cell proliferation to recommence.
Four years ago, Gray and his colleagues screened thousands of compounds to see if any could stop the proliferation of CML cells that were resistant to Gleevec®. They identified one named GNF-2.
They speculated that it blocks a separate niche on Bcr-Abl than Gleevec® does – a pocket known as the myristate binding site. Using a variety of techniques for analyzing chemical structure – nuclear magnetic resonance spectroscopy, X-ray crystallography, mutagenesis analysis, and hydrogen exchange mass spectrometry – they determined that GNF-2 does indeed target the myristate binding site. By contrast, Gleevec® and two recently approved drugs (nilotinib and dasatinib) target a section known as the ATP binding site.
“GNF-2 is the first compound that has been shown by crystallography [which shows the arrangement of individual atoms in chemical compounds] to lock onto to Bcr-Abl outside the ATP binding site and thereby inhibit kinase activity,” Gray remarks. Neither Gleevec®, nilotinib, dasatinib, GNF-2, nor its more potent cousin, GNF-5, can keep cell growth in check when the gene for Bcr-Abl undergoes what’s known as a “gatekeeper” mutation. “This mutation revs up the kinase’s ability to spark cell proliferation regardless of whether the ATP or myristate binding site is involved,” Gray explains.
Other Dana-Farber contributors include lead author Jianming Zhang, PhD, and co-authors Taebo Sim, Yongmun Choi, Amy Wojciechowski, and Xian-Ming Deng, PhD.Investigators found, however, that when an ATP-blocker such as Gleevec® is combined with a myristate-blocker such as GNF-5, the tandem reduces the chances that lab-grown CML cells will become drug-resistant. In animal studies, the combination also proved effective against human CML cells that already were resistant to either agent alone.
The investigators’ structural studies, led by Sandra Jacob-Cowan of Novartis, showed precisely how GNF-5 impedes CML cell growth: when GNF-5 settles inside the myristate binding site, it forms a connection with a distant region of the Bcr-Abl protein – “kind of like throwing a lasso around it,” Gray says. The result is a constriction of the enzymes’ activity.
