Improtant Discoveries leading us to a CURE for CML
This is a report filed by our President, Mrs. Cheryl-Anne Simoneau from the Philadelphia Chromosome Conference. A conference celebrating the 50th anniverary of the discovery of the Philadelphia Chromosome.
Reported from Philadelphia. The conference was supported by a variety of sponsors which included the Fox Chase Cancer centre.
Well I guess I am a geek CML patient. How else do I explain getting excited about spending an entire long day listening to some of the people who worked together to make sense of CML and come up with a drug therapy to slow down progression of the disease.
Continental breakfast was served at 8:00 this morning. I went into the meeting room and scoped out a table right next to the faculty of the days event and saved places for Greg and Gary and Gary’s Mom.
Sitting at the faculty table was Peter Nowell, Janet Rowley, Felix Mitelmen, (Maintains a concise database of chromosomes aberrations in cancer) Dr. Michael Seiden (President of the Fox Chase Cancer Centre) Dr. Joseph Testa (Co- Director for the Cancer Biology Program) Nora C. Heisterkamp, PhD, (proved that the translocation was reciprocal – localized c-abl & BCR (which stands for Break point cluster region – simply because that name actually describes it best)). At the second faculty table was Mrs. Alice Hungerford, Widow of co-discoverer of the Ph Chromosome – she is a dedicated lady and carrier of the torch, we should all be so happy with the work she is doing to preserve the history of this important discovery. Owen Witte MD, – identified ABL tyrosine kinase activity. Nicholas Lydon ( who was then at Ciba Geigy (later through a merger with Sandoz it became Novartis), he found the compound in the lab library and Jurge Zimmerman slightly altered the compound (which had originally been formulated to work against glioblastoma’s) – et voila, the altered compound became Gleevec/Glivec (but first it was STI571…) Dr. Charles Sawyer who along with Dr. B. Druker, M. Talpaz, and John Goldman were the first doctors to work with Gleevec in clinical trials with patients. Dr. William Sellers from Novartis who talked about the newer work going on in finding new agents for all types of cancers – there are tons of them….Dr.. John Goldman chaired the afternoon session of the day and spoke very eloquently about early trials and what lies ahead in the future.
Dr. Felix Mitelman gave an interesting talk about how he started cataloguing all of the chromosomal aberrations in cancers. He tells us that originally the Philadelphia Chromosome was referred to as Ph1, but the 1 was later dropped because there wasn’t a Ph 2 – meaning that there is only one chromosomal aberration driving this disease. However, he did say as long as the disease is stable in the chronic phase, otherwise if the disease progresses other chromosomal abnormalities will be discovered, but those abnormalities are also what we see in acute leukemia’s.
Dr. Mitelman also spoke about a suggestion made in 1914 by Th. Buveri was that chromosome change may cause leukemia!!!! (follow this link… http://www.nature.com/nature/journal/v453/n7196/edsumm/e080605-06.html) He also pointed out that 80% of the “normal” people have the fusion gene (BCR ABL) but they will not develop full blown CML – they still do not understand why this is so. Are there genetic – epigenetic windows of vulnerability? Is there something in the microenvironment that controls the aberration?
Next up was Peter Nowell – It was fascinating to discover that the discovery happened in a very innocent way. He was looking at cells from two male patients with CML and he inadvertently washed the cells in tap water. The cells he was working with were dividing cells, rinsing them with tap water caused the cells to expand and exposed the chromosomes. He was puzzled and didn’t know what he was looking at, and searched for someone to work on this with him. He was pointed to a young researcher who was doing his thesis on human chromosomes. That person was David Hungerford and they started to collaborate. Nowell cultured the cells and Hungerford examined them. They noticed that there was an additional chromosome and they repeated the tests several times to confirm the discovery. It was written up in 1960. Just imagine, were it not for a splash of tap water – who knows what would be our story today?
Next up was Dr. Janet Rowley. I cannot say enough about how swell it was to meet her – I think I have idolized her from afar for such a long time (well ten years at least…) She is a very eloquent lady and is the first person to say that everything was a collaboration and she was one person of many who had a hand in the important events that led up to Gleevec and now beyond… Dr Rowley was working part time so that she could still look after her children and husband, when she had heard about a new technique for banding cells. Conveniently she had saved cells form her CML patients in a freezer and couldn’t wait to try this banding technique on the cells. Sitting at her dinning room table she noticed that in each patients cells parts of two of the chromosomes were breaking off and trading places. It took another decade for people realize the claims she was making; that these genetic changes were causing cancer….Dr. Rowley patiently asked all the young cytogenetics in the room to take up the issue of del (9) in CML as we do not understand this very well and it may mean a more difficult prognosis to patients who harbor it. She asked them to be challenged enough to decide to work on it.
Next up was Nora C. Heisterkamp, PhD, She worked on proving what Dr. Rowley was claiming all along. In 1982 they still did not know that the translocation was reciprocal. By March 1983 they had developed the southern blot and my November 1983 she had localized c-abl adjacent to a translocation break point named BCR – which stand for breakpoint cluster region (which describes what it does). She finished her talk with saying that the human genome still has a few secrets left. For example – with stromal support cells don’t die, take away stromal support and TKI’s and the cells die….We still do not know what gives rise to CML and she theorizes that perhaps it is something to do with stress response genes – not clear if they are encoding a protein….
Owen Witte: – Witte’s talk was around his work with mice to recreate CML so that he could study what was happening….“Witte characterized a protein produced by a gene from the Abelson virus, which causes leukemia in mice. The protein results from the fusion of the viral gene with a mouse gene. discovered that human CML cells produced a larger version of the fused Abelson/mouse protein. Further work made it clear that the human protein also resulted from two fused genes: BCR and ABL (the human form of the Abelson gene).”
“Witte identified BCR-ABL as a tyrosine kinase, a protein that can transfer a phosphate group to the amino acid tyrosine. Tyrosine kinases are important in controlling other enzymes. BCR-ABL’s structure allowed it to circumvent the usual methods that cells use to regulate tyrosine kinases, leading to uncontrolled cell growth. “(Ref: http://www.hhmi.org/research/investigators/witte_bio.html)
Nick Lydon was the next to talk and he spoke about how Novartis was working with Dan Farber and that B. Druker was a young post doc in the lab and they worked together to find a chemical compound that could inhibit the protein kinases and leave normal cells alone. It was a daunting task but Nick was up to the challenge. They had found an earlier slew of inhibitors, many that were developed by the Japanese, but there was one important paper that stood out and led them in the right direction, it was work by Levitsky on Tyrphostins which were chosen because of their specific in-hibition of tyrosine kinases and their low cytotoxicity. (Levitski, 1990). This pointed them to the molecule that they had in the lab that was originally designed for Glioblastoma. Jorge Zimmerman slightly altered the molecule and Dr. Druker tested it and found that this would work.
Charles Sawyers gave an eloquent presentation describing some of the hard work going on and how difficult it was to convince Novartis to bring the drug to market. There was great reluctance to do so as CML was such a small disease and it would be difficult to see how it might be financially feasible to bring it to market. He also spoke about resistance to Gleevec and his collaboration with Dr. Shah to work with BMS to develop Dasatinib. I should also say that Dr. Sawyers remembered to mention you Jerry and this website and how patients on the internet were able to influence much of what went on….THANK YOU JERRY!!!!
Side note – Thanks also to Suzan M – who was a very sick patient here in Montreal failing Interferon and desperately trying to get on a Gleevec trial. She called Dr. Druker who urged her to rally patients and do a petition. Which she did. In Nov 1999 Novartis relented and expanded the trials and made a commitment to bring the drug to market. Suzan went to Oregon in January 2000 and recovered well enough to go back to school to earn her PhD in Leukemia research from McGill University in June 2009. She is a scientific advisor for the CML Society of Canada –she asks me not to use her full name as she wants to be known for her current work and value and I agree with her 100%. People have a habit of stigmatizing patients….
Dr. Goldman spoke about the future and the need to have a drug for the dreaded T315I and how we need to see if we can either eradicate the last CML stem cell or at least get our bodies to eradicate it for us….
The main point is that there were lots of young scientist in the room and it was very clear that these seasoned researchers were doing their best to encourage them to pick up the torch, there is so much more about CML that needs to be discovered. The excitement in the room was palpable.
I introduced myself to as many people as I could and I hope they see what a great difference they have made and continue to make for us all. I also hope the spark of imagination and innovation was lit today. Who knows, maybe research from today’s meeting will lead to the complete eradication of the CML stem cell and/or cure!
We can all start to sing: “Oh Philadelphia freedom shine on me, we love you, Shine a light through the eyes of the ones left behind, Philadelphia freedom we love you, yes we do” – Elton John and Bernie Taupin….
Love and Peace from Philadelphia – HOME OF THE CHROMOSOME!