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.