gleevec
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 Gleevec as Maintenance Therapy for Glioblastoma Multiforme
 
Original posts by Hong Lan on 06/24/07
 
Hi all,
 
I want to throw out an idea, and hope to generate some discussions on using Gleevec as maintenance therapy for high-grade glioma, especially for gbm. Following a brief background introduction about Gleevec, I will lay out my reasons for promoting the awareness of this drug. For those of you who are interested in pursuing it, I would like to ask you please ask your physician's opinion on this drug for brain tumor, and share the feedback with us. The more opinions we have from the professionals, supporting or opposing, the better we can understand the drug, on both good and bad aspects. I hope such information collection and discussion can help us finding a better treatment.
 
Gleevec (Glivec in Europe/Australia; imatinib mesylate, STI-571) is a receptor tyrosine kinase inhibitor (http://en.wikipedia.org/wiki/Imatinib). It works very well for chronic myelogenous leukemia by completely blocking the growth signaling through bcr-abl, a mutated tyrosine kinase receptor. It also suppresses PDGF signaling by inhibiting its receptor (PDGF-Rß). As we all know, gbm is very aggressive. Multiple growth signaling pathways have been reported activated in gbm, such as EGF/EGFR, VEGF/VEGFR, PDGF/PDGFR. The effect of Gleevec on PDGFR promoted me to collect literature on its use on brain tumors. Below are a few examples:

1. A Phase II study at Duke using Gleevec/Hydroxyurea in 33 recurrent gbm patients showed PFS6 = 27%, mPFS = 14.4 wks (Reardon et al., Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme. J Clin Oncol. 2005 Dec 20;23(36):9359-68). 

2. A Phase I/II study at Dana-Farber using Gleevec as a monotherapy in 34 gbm and 21 AA patients showed very disappointing results (PSF6 = 3% for gbm and 10% for AA) (Wen et al. Phase I/II study of imatinib mesylate for recurrent malignant gliomas: North American Brain Tumor Consortium Study 99-08. Clin Cancer Res. 2006 Aug 15;12(16):4899-907). In my view, this study again argues against monotherapy, no matter how promising the drug might be.

3. Another Phase II study at Duke using Gleevec/Hydroxyurea in 39 recurrent Grade III patients showed an overall PSF6 of 24%. For those archived stable disease, PFS6 = 53% and PFS12 = 29% (Desjardins et al. Phase II study of imatinib mesylate and hydroxyurea for recurrent grade III malignant gliomas. J Neurooncol. 2007 May;83(1):53-60).

4. A key question for using Gleevec on brain tumor is whether or not it can cross blood-brain barrier. Two studies showed limited brain permeability: 

4.1. A French group showed that Gleevec can penetrate rat brain slowly, and it is independent of hydroxyurea (Bihorel et al. Influence of hydroxyurea on imatinib mesylate (gleevec) transport at the mouse blood-brain barrier. Drug Metab Dispos. 2006 Dec;34(12):1945-9). To me, this means Gleevec doesn't have to be paired with hydroxyurea, opening the possibility for Gleevec to be combined with Temodar for non-pregressive patients.

4.2. An abstract from the 2007 ASCO meeting showed treatment of gbm patients with Gleevec results in measurable levels of the drug in the tumor (Razis et al. Biochemical evidence of tumor response and measurable levels of the drug in glioblastoma tissue from patients treated with imatinib. 2007 ASCO Annual Meeting. Abstract No: 2023).

5. Abstract 2055 of the ASCO 2007 meeting: in 30 non-progressive gbm patients using Gleevec/Hydroxyurea, 6, 12 and 18 m PFS was 60%, 40% and 30% respectively; 6, 12 and 18 m OS is 90%, 67% and 53%. PFS for more than 24 m occurred in 3/6 pts with secondary and in 2/24 pts with primary gbm (Dresemann et al. Single center phase II trial analysing the role of imatinib/hydroxyurea in patients (pts) with pretreated non-progressive glioblastoma (GBM) as maintenance treatment. 2007 ASCO Annual Meeting, Abstract No: 2055).

6. Abstract 2056 of the ASCO 2007 meeting showed 800 mg/day Gleevec in 18 recurrent gbm patients with PDGFR expression archived PSF6 of 52% (Viola et al. Phase II trial of high dose imatinib in recurrent glioblastoma multiforme (GBM) with platelet derived growth factor receptor (PDGFR) expression. 2007 ASCO Annual. Abstract No: 2056).

7. In Al Musella's virtual trail, five patients use Gleevec. Among the 4 alive, medium survival has archived 26 months so far.
I should point out that Gleevec maybe more beneficial for patients with secondary gbm, those that developed from a lower grade astrocytoma. Secondary gbm is thought to be more associated with PDGF/PDGFR. (Ref: Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007 May;170(5):1445-53.)

As you know, the recurrence rate of gbm is near universal. We as patients or caregivers need to search aggressively for better treatment options in an attempt to delay or prevent the recurrence. As some of you may recall, I previously asked for opinions about Temodar/Avastin. Now I wish to ask for feedbacks on Temodar/Gleevec, or even Temodar/Avastin/Gleevec. When I asked my wife's NO about adding Gleevec, he said it was an "intriguing idea". He also said Gleevec is "a good PDGF inhibitor, and may be good maintenance therapy". I wish to hear more discussions from people on this list. Both supporting and opposing opinions are equally valuable. It would greatly appreciate it if you could bring this topic to your physicians and share their opinions here. If you like you can print out this post. Many other issues remain: safety profile, drug interaction, insurance coverage, etc. Again, we need to know as much as possible on both positive and negative sides of a potential drug. All comments/suggestions/advices will be highly appreciated.

As Al pointed out a few days ago, a hypothetically ideal treatment would be a combination that simultaneously target tumor growth, angiogenesis and tumor invasion. We are not there yet, but I hope we are working together towards the right direction.

Thanks for your attention and participation.

Hong

Summary of follow up discussions
 
There have been 10 follow ups. A summary of main points:
 
1. The sales representatives from the drug maker (Novartis for Gleevec) may be a good source of knowledge, but they may be restricted from saying anything not on the "protocol".

2. About blood-brain-barrier (BBB):

2.1. In the original post, I laid out two studies indicating showing Gleevec can cross BBB.

2.2. Loice followed up with a few more abstracts showing the permeability of Gleevec through BBB is poor, if any. There are some preclinical data showing that using brain protein pump inhibitor such as P-glycoprotein inhibitor may increase the brain tumor concentration.

2.3. My follow-up thoughts: Besides anti-tumor growth effect, PDGF pathway is also involved in tumor angiogenesis. PDGFRalpha stimulates cell growth; PDGFRbeta is involved in angiogenesis by recruiting pericytes to form new blood vessels (Ref: Song S et al., PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol. 2005 Sep;7(9):870-9.) For anti-angiogenesis purpose, Gleevec does not have to cross BBB to work. Gleevec may sensitive the anti-angiogenesis effect of VEGF/VEGFR inhibitors.

3. A further follow up point: Sunitinib is a VEGF and PDGF receptor protein kinase and angiogenesis inhibitor. It is a second generation receptor tyrosine kinase inhibitor. It has been approved for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST).  I cannot find any clinical studies on glioma.

4. A similar story for Sorafenib. We need to watch their clinical development in brain tumors.



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