Gleevec and Gemcitabine: A New Combination and a Promising New Therapy
Dr. Giovanni Gaudino is an Italian biochemist and molecular biologist who researches the molecular mechanisms of asbestos and its relationship to the development of mesothelioma. In addition to his laboratory research in Italy, Dr. Gaudino conducts mesothelioma research in the United States as a visiting scholar at the Cancer Research Center of Hawaii (CRCH). Currently, Dr. Gaudino is conducting a clinical trial in Italy on mesothelioma patients using Gemcitabine in combination with a different drug, Imatanib Mesylate (trade name Gleevec).
Gleevec: A New Role for a Classic Drug
“So we started in this direction and we used … Gleevec and we observed, of course, Gleevec was blocking all the targets we identified . . . .”
– Giovanni Gaudino
Touted by some doctors as one of the most impressive drugs in 20 years when it first came into use in 2001, Gleevec is well known as a successful drug for the treatment of some forms of leukemia and gastrointestinal tumors. Gleevec is the brand name; the chemical name is imatinib mesylate. Imatinib mesylate is a specific inhibitor of the receptor tyrosine kinase (the “big button” described earlier) called PDGFRB. This receptor is widely expressed in most mesotheliomas and is one of the molecules critical to inducing chemoresistance. With the discovery of the importance of these receptors, it was thought that Gleevec, a classic drug, could be used to inhibit these receptors and thus overcome the tumor cells’ chemoresistance and allow conventional chemotherapeutic drugs to work better. Gleevec blocked all the identified targets. In lay terms, Gleevec kills abnormal cells and has very little effect on the normal cells. When it was first used in the treatment of chronic myeloid leukemia (CML), the use of Gleevec was a medical breakthrough. The primary investigator responsible for the leukemia research at the time dreamed of the day when Gleevec would be effectively used to fight other cancers. This repurposing of existing, approved drugs such as Gleevec helps to bring new treatment therapies to patients more quickly and efficiently.
The next step for Dr. Gaudino’s research project was to test Gleevec with different chemotherapeutic drugs to see if this specific inhibitor could be used in combination with standard chemotherapeutic drugs to impair tumor resistance.
The Animal Experimental Model
“We moved to [an] animal experimental model, and we used … quite a peculiar model. We exploited the so-called genetic engineering. We modified human mesothelioma cells by introducing a foreign gene – a gene coming from a fish – which induce luminescence on these cells. So these cells basically were emitting lights.”
– Giovanni Gaudino
Gleevec and its combination with other drugs had to first be tested on animals. In preparation for animal testing, Dr. Gaudino and his team created a very special model. By the use of genetic engineering, they modified human mesothelioma cells by introducing a foreign gene, a gene from a fish, which caused the cells to emit light. This enabled the researchers to follow the growth or reduction of the tumor in the live animals by the use of imaging, in the same way a physician uses CT scans or other imaging techniques to see what is going on inside his patient. So they injected special mice, called SCID mice, with the modified human mesothelioma cells and were able to observe the formation of the tumors by the use of imaging.
Gleevec and Gemcitabine: A New Combination
Next the cancer researchers treated the animals by infusing the tumors with Gleevec combined with different chemotherapeutic drugs, and they found that Gleevec and Gemcitabine were a successful combination.
“It’s quite clear that the treatment … with the two drugs, Gemcitabine and Gleevec . . . reduce a lot of the size of the tumors . . . . And also, increase quite remarkably the survival of the mice. … [T]he pictures of the mice, I think, are quite convincing because you can see that the right mouse is doing much better than the left one.”
– Giovanni Gaudino
Gemcitabine is an old and very well known drug. Gemcitabine is commonly called by its brand name Gemzar. Gemcitabine has been approved by the FDA since 1996 and is used to treat some lung cancers and pancreatic and ovarian cancers. Dr. Gaudino’s research team knew that Gemcitabine alone was not effective on mice, neither was it effective on mesothelioma patients. But it became quite clear that the combination of Gemcitabine and Gleevec resulted in the reduction in the size of the tumors, which they could measure through imaging, and it also increased, “quite remarkably,” the survival of the mice.
From Mice to Patients: From Pilot Study to Phase II Clinical Trial
The next step, of course, was to move from animal studies to patients. According to Dr. Gaudino who is involved in bench research, the network the scientists have established is very useful and important, because the results of their work will be published in scientific journals and this will “catch the interest of our clinician colleagues.”
So they started with what is known as a “pilot study” with the combination of Gleevec and Gemzar. A pilot study comes before the real clinical trial and is usually done on a limited number of patients. In this case there were 21 patients who had not responded to first-line conventional therapies. The results were very encouraging: In six patients there was no progression of the disease (stable disease); in one patient there was a complete disappearance of the cancer (complete response); in eight patients there was incomplete reduction of the tumor (partial response); and in six patients, the disease didn’t stop and unfortunately the cancer continued to grow (progression). Some patients respond better than others and some do not respond at all, which is common in clinical trials.
“And, you know, you may argue that this is not a big deal, just to stop the cancer – you won’t get rid of the cancer. But for mesothelioma, which is so aggressive, this is a very good result. We got also one complete response, which means complete disappearance of the cancer.”
– Giovanni Gaudino
This pilot study was followed by a phase II second line clinical trial, which is ongoing and is being validated by the National Cancer Institute (NCI). It is expected that the results of this study will be coming out in the next few months. Dr. Gaudino and his team are very optimistic that this therapy will lead to a longer survival. For mesothelioma patients, the research being done by Dr. Gaudino offers a great deal of hope and promise for longer survival rates and eventually a cure for mesothelioma.