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Dr. David Lee

The Imatinib Story - Dr. David Lee

Michaela Spence, MSc Candidate (Translational Medicine)

Many faculty, staff and students had the pleasure and privilege of hearing Dr. David Lee present “The Imatinib Story” at Medical Grand Rounds last week. Dr. Lee provided an overview of how Imatinib, a drug used to treat chronic myelogenous leukemia (CML), went from the laboratory bench to the bedside and inspired a new era of targeted therapy in research and medicine.
 

It is hard to believe that the story of leukemia’s wonder drug Imatinib began with the identification of the first viral cancer causing “oncogene” by Dr. Peyton Rous when he isolated a chicken sarcoma virus, showing that cancer causing genes did exist. Dr. Lee walked us through how this contributed to Dr. Peter Nowell and Dr. David Hungerford’s discovery of the genetic mutation that caused CML in the 1960s, which they identified by studying the genetic material of cells from patients with CML. Their discovery of this chromosome named the “Philadelphia chromosome”, coupled with improvements in technology allowing for a closer look at the genetic material, led to the subsequent discovery of the mutated cancer causing fusion gene BCR-ABL by Dr. Nora Heisterkamp in the 1980s. Then, by the 1990s a mouse model for CML had been created using a retrovirus encoding the BCR-ABL gene. These novel findings are what prompted pharmaceutical research into more specific drug targets for the treatment of the different cancers.
 

A pharmaceutical company called Novartis (formerly Ciba-Geigy), was one of the only pharmaceutical companies working on tyrosine kinase inhibitors at the time as most believed it would be too difficult to target a specific kinase without causing adverse side effects in the body. They ended up creating the drug Imatinib, which showed success in both cell and mouse models. The pivotal first clinical trial with Imatinib was completed by Dr. Brian Druker, an oncologist and researcher who worked with Novartis to test Imatinib’s efficacy in patients. Imatinib showed miraculous results, with all patients’ entering remission and their blood cancer counts returning to normal. Ultimately, this effect had never been seen before in phase 1 clinical trials. This led to the fastest approval time for a cancer drug of 72 days from the FDA.
 

In our post-round discussion with Dr. Lee we discussed how Imatinib’s success in treating CML can be accredited to the specificity of its target protein, as it is caused by a singular mutation found only in CML cancer cells. If you can stop the BCR-ABL fusion protein from sending abnormal signals within the cell, you can stop the cancer from progressing and allow a patient to enter into remission. Dr. Lee also emphasized the great improvement in quality of life that Imatinib has brought to patients. It has enabled them to lead nearly an entirely normal life in comparison to interferon alpha, which was the previous treatment prescribed to them and was associated with many debilitating adverse effects. Although some patients taking Imatinib have been known to develop a resistance to the drug, the development of Imatinib analogs such as Nilotinib has allowed for their continued treatment, even after initial resistance to the drug. In fact, Imatinib has worked so well that the results of some smaller studies have prompted the change of current treatment guidelines to allow for patients to trial discontinuing Imatinib when in remission with regular monitoring of their blood cancer count. Ultimately, Imatinib’s success both in trials and in clinic have prompted more pharmaceutical companies to study unique genetic mutations in hopes of identifying more personalized targets for treating cancer in the age of personalized medicine.
 

Dr. Lee chose to pursue a residency in haematology, as to him it presented the perfect blend between clinical interaction with patients and laboratory work. When asked if haematology was what he imagined it would be at the beginning of his residency or if his perspective on the specialty changed after completing his schooling, he left us with an inspiring take on the field. Hematology is a specialty that has remained as engaging and challenging as it was in the beginning of his residency. The longer he works with his patients, the greater his respect for the human condition becomes. In the end, he takes great joy in helping patients regardless of their prognosis.
 

It was a great pleasure to listen to Dr. Lee’s presentation on Imatinib at Medical Ground Rounds. On behalf of the TMED graduate students, we thank him for his time and invaluable insight into the realm of personalized medicine and it’s translation from bench to bedside.

Comments

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Melinda Chelva

Mon, 09/21/2020 - 14:04

Excellent post Michaela! You did an amazing job delving deep into the topics Dr. Lee discussed during the MGR last week!
As you mentioned, the resistance to Imatinib in patients has encouraged the development of analogs, such as Nilotinib, in order to allow patients to continue to be treated for CML.
After reading through some clinical trials, I came across Ponatinib, which is another analogue of Imatinib. This drug is thought to be 520 times more potent than Imatinib, and importantly, it has also been noted to inhibit both the wild-type and mutant BCR-ABL1 (including the T315I mutation). However, there is evidence that Ponatinib also leads to some adverse effects. This makes me wonder- does the level of side effects of Imatinib analogues play the most important role when differentiating and dictating one analogue as a “better” treatment for CML compared to others, or, could there be other factors that determine this? I wonder whether researchers and scientists will continue to study Imatinib analogues to find ways to ensure that their endpoints achieve similar efficiency and patient prognosis as Imatinib does?
Furthermore, I am super curious to see if there is a possibility to avoid CML patients from establishing resistance to Imatinib? I wonder whether this could be achieved with a more diverse treatment regime that alternates between medications?
Overall, I am super eager to continue to follow Imatinib in the literature, and I am very excited to see its advancements in the future!

Name
Melinda Chelva

Name
Max Moloney

Mon, 09/21/2020 - 15:56

Thank you, Michaela for your detailed and insightful post recounting Dr. Lee’s presentation of “The Imatinib Story” during Medical Grand Rounds last week.

Dr. Lee’s chronicling of chronic myelogenous leukemia research beginning with Dr. Peyton Rous’ isolation of a chicken sarcoma virus to the unlikely success of imatinib nearly a century later, demonstrated the ability of translational research to make exceptional improvements in patient outcomes. I was personally moved by Dr. Lee’s recounting of the first time he transitioned a patient from treatment with interferon alpha to imatinib and witnessed a substantial improvement in the patient’s quality of life, which was made possible by over one hundred years of research.

Furthermore, Dr. Lee’s presentation also provided a great learning experience on presentation skills for graduate students in the audience. As demonstrated through the presentation and the discussion that followed, Dr. Lee’s expert scientific communication will serve as an inspiration to students in the audience on how to effectively communicate in this format.

I am looking forward to following Dr. Lee’s work in the future and the exciting developments in personalized medicine that have been made possible by the success of imatinib.

Name
Max Moloney

Name
Kassandra Coyle

Tue, 09/22/2020 - 14:08

Thank you, Michaela, for the wonderful summary of Dr. Lee’s incredible talk.

An interesting topic that Dr. Lee brought up was in regard to the extensive training and collaboration that occurred during the development of Imatinib. Dr. Lee mentioned that during the process of development, many of the researchers involved took sabbaticals or went on leave to pursue further training experience. In addition, he praised the amount of collaboration that occurred between all of the groups involved in the developmental process.

I found this to be an interesting take on the use of sabbaticals and thought that it further elucidated the importance of collaboration in research. I wonder if the immense success of Imatinib will influence future researchers to adopt these unique strategies in their own studies. Further, since Imatinib has been such an important achievement for the field of Translational Medicine, I wonder what else we can take from this study and incorporate in other areas of research today?

Name
Kassandra Coyle

Name
Jordan Harry

Wed, 09/23/2020 - 11:00

Thanks Michaela for your excellent summary of Dr. Lee’s presentation. Attending Medical Grand Rounds and listening to Dr. Lee last Thursday was an absolute privilege. Dr. Lee presented using a timeline to seamlessly interweave numerous research contributions that lead to the development of Imatinib. As a student in Translational Medicine, Dr. Lee’s presentation was very inspirational. From basic science and seemingly small findings, to the unprecedented clinical application/advancement, “The Imatinib Story” shows a young aspiring clinical researcher what can be possible.
Aside from the inspirational aspect of Dr. Lee’s presentation, the discussion enabled students to discuss a few different aspects of Imatinib, such as resistance, its analogues, treatment selection, and a brief analysis of drug holidays. I am particularely interested in the long term success of the drug. Will it remain as the Gold Standard? Or will Imatinib be a stepping stone to something even better? Irregardless, Imatinib has given CML patients a significantly better quality of life.

Name
Jordan Harry

Name
Caitlyn Vlasschaert

Wed, 09/23/2020 - 11:48

What an excellent talk by Dr. Lee! Thank you, Michaela, for your expert moderation of the ensuing discussion with the TMED class.

Following our chat, I turned to Twitter to read more about how life-changing imatinib has been for patients. I landed on the page of the "longest surviving Gleevec patient", one of the first patients enrolled in its Phase 1 trials, Mel Mann (https://twitter.com/MelDMann). He has catalogued the events of his life since learning he had CML in the mid-'90s. He has shared newspaper clippings of articles asking the public to help him find a bone marrow donor in 1995 (https://twitter.com/MelDMann/status/942954135376334848) followed a video describing his miraculous convalescence from 1998 onward (https://twitter.com/MelDMann/status/942954135376334848). An inspirational story for all of us working in translational medicine.

Name
Caitlyn Vlasschaert

Name
Caitlyn Vlasschaert

Wed, 09/23/2020 - 11:57

I have another great resource to share. Yesterday was World CML Day (9/22). As part of this, a virtual patient-centered conference was held and live streamed via Zoom and Facebook. The feature presentationtitled "From the development of a life-saving drug to stopping treatment - 20 years of revolution in CML" and delivered jointly by several leaders in CML research including Dr. Brian Druker, can be viewed at: https://www.facebook.com/159982050717806/videos/1028542144289331.

Name
Caitlyn Vlasschaert

Name
Jummy Oladipo

Wed, 09/23/2020 - 12:01

Thank you, Michaela, for an excellent summary of Dr. Lee’s talk.

One thing that stuck out to me from Dr. Lee’s presentation is how the success of the Imatinib paved the way for a new field of research. Up until Imatinib was developed, kinome research was not an existing field. However, the effectiveness of Imatinib for treating patients with CML inspired researchers to explore kinome research. This highlights the multidimensional benefits of successfully translated medicine. Not only do effective therapeutics benefit patients, they can also create new research avenues. Imatinib is a great translational medicine story that serves as an inspiration for biomedical researchers. A question that comes to mind hearing the Imatinib story is whether there is enough media attention around it. There seems to be a belief in the lay public that biomedical research does not always translate to clinical care. I am wondering if this success story is enough to shift people’s perspectives.

Additionally, Dr. Lee’s presentation provided a great example of how to tell a compelling story during a presentation. The effective communication skills he demonstrated serves as a great example of what graduate students should strive for.

Name
Jummy Oladipo

Name
Charmi Shah

Fri, 09/25/2020 - 17:50

Great post Michaela, you effectively summarized “The Imatinib Story” by highlighting Dr. Lee’s key points and our class discussion!

One part of the discussion that amazed me is Dr. Lee’s discussion about the first time he used Imatinib and how it was the first day it was formally approved by Health Canada, but this was just a coincidence because he had already arranged approval from before to use Imatinib on that day. This showed me the confidence he had in the drug’s mechanism and accordingly, his patient was able to benefit from Imatinib for some time.

A concern for Imatinib is in regards to patients having intolerance or resistance to the drug. It would be interesting to see how the effects of combination therapy may alter these concerns of drug intolerance or resistance. From the articles, it was interesting to read that second-generation tyrosine kinase inhibitors (TKI) overcome most of the mutations that are correlated to Imatinib resistance. Ponatinib is a third-generation TKI that patients may be considered for if they have intolerance or resistance to the second-generation TKIs, namely, dasatinib or nilotinib. Currently, the safe dosage of ponatinib is being studied. I am excited to see what we learn about the survival rates for patients from these second and third-generation tyrosine kinase inhibitors, in comparison to the effects seen by Imatinib.

Dr. Lee’s lecture sparked my interest in Imatinib and I am eager to see the future evolution of tyrosine kinase inhibitor drugs. 

Name
Charmi Shah

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