Jennifer E. Adair, Sandra K. Johnston, Maciej M. Mrugala, Brian C. Beard, Laura A. Guyman, Anne L. Baldock, Carly A. Bridge, Andrea Hawkins-Daarud, Jennifer L. Gori, Donald E. Born, Luis F. Gonzalez-Cuyar, Daniel L. Silbergeld, Russell C. Rockne, Barry E. Storer, Jason K. Rockhill, Kristin R. Swanson, Hans-Peter Kiem
Submitter: Michael Platten | Michael.Platten@med.uni-heidelberg.de
Authors: Michael Platten and Wolfgang Wick
University of Heidelberg and German Cancer Consortium (DKTK)
Published September 23, 2014
Alkylating chemotherapy, specifically temozolomide (TMZ) and nitrosoureas, remain a mainstay in the treatment of patients with glioblastoma, despite primary resistance owing to cellular DNA repair mechanisms, chiefly O6-methylguanine DNA methyltransferase (MGMT). MGMT is mainly regulated by promoter methylation and is active in approximately 60% of glioblastoma patients (1). Adair and coworkers aim at optimizing treatment of patients with a glioblastoma harboring an unmethylated MGMT promoter (MGMTunmeth) (2). They present a small patient series and compare the outcome to matched historical controls. Median progression-free survival (PFS) was 9 months, median overall survival (OS) was 20 months (3.5 months to 57 months). Initial treatment was radiotherapy only and patients proceeded to receive HSCT with stem cells genetically engineered to express the O6-benzylguanine (O6BG)-resistant MGMT mutant P140K after conditioning with the nitrosourea BCNU. Patients then received a median of 4 cycles of adjuvant O6BG/TMZ chemotherapy. In this highly selected patient population treatment effects are overestimated, which makes it difficult to take the not even remarkable outcome of 7 patients as “strong evidence for increased therapeutic benefit of the study protocol over standard of care”. More recent studies have demonstrated considerably higher OS over results from the pivotal registration trial (4) even in patients with MGMTunmeth receiving TMZ (1,3). All patients in the present series received BCNU for conditioning. Additionally to their use at recurrence, nitrosoureas have been used for the treatment of newly diagnosed glioblastoma (5) and BCNU is a considerable confounder in this study, particularly as the repair of DNA damage conferred by nitrosoureas is not solely dependent on MGMT (6). Furthermore, the concept of depleting MGMT to sensitize MGMTunmeth gliomas should be viewed with caution. The RTOG0525 phase III trial was initiated based on preclinical and clinical observations that intensifying the TMZ schedule – like O6BG - results in depletion of MGMT in tumor cells (7). Yet this study did not demonstrate that intensifying TMZ improves outcome in newly diagnosed patients regardless of the MGMT status. Importantly, intensifying alkylating chemotherapy came at a cost of non-hematopoietic toxicity such as fatigue (8).
In summary, while we agree that optimizing the treatment for patients with MGMTunmeth glioblastoma is clearly warranted for instance by replacing TMZ with targeted agents in clinical trials (9), depleting MGMT from tumor cells by O6BG and/or intensifying TMZ may not be the right approach. Research into resistance mechanisms (10,11,12) and novel approaches to this poor prognosis patient population is urgently needed.
1. Wick, W., Weller, M., van den Bent, M., Sanson, M., Weiler, M., von Deimling, A., Plass, C., Hegi, M., Platten, M., and Reifenberger, G. 2014. MGMT testing-the challenges for biomarker-based glioma treatment. Nat Rev Neurol 10:372-385.
2. Adair, J.E., Johnston, S.K., Mrugala, M.M., Beard, B.C., Guyman, L.A., Baldock, A.L., Bridge, C.A., Hawkins-Daarud, A., Gori, J.L., Born, D.E., et al. 2014. Gene therapy enhances chemotherapy tolerance and efficacy in glioblastoma patients. J Clin Invest.
3. Wick, W., Gorlia, T., Van Den Bent, M.J., Vecht, C.J., Steuve, J., Brandes, A.A., Platten, M., Kosch, M.A., Hegi, M.E., Lhermitte, B., et al. 2014. Radiation therapy and concurrent plus adjuvant temsirolimus (CCI-779) versus chemoirradiation with temozolomide in newly diagnosed glioblastoma without methylation of the MGMT gene promoter. ASCO Meeting Abstracts 32:2003.
4. Stupp, R., Mason, W.P., van den Bent, M.J., Weller, M., Fisher, B., Taphoorn, M.J., Belanger, K., Brandes, A.A., Marosi, C., Bogdahn, U., et al. 2005. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987-996.
5. Weller, M., Muller, B., Koch, R., Bamberg, M., and Krauseneck, P. 2003. Neuro-Oncology Working Group 01 trial of nimustine plus teniposide versus nimustine plus cytarabine chemotherapy in addition to involved-field radiotherapy in the first-line treatment of malignant glioma. J Clin Oncol 21:3276-3284.
6. Bobola, M.S., Blank, A., Berger, M.S., and Silber, J.R. 1995. Contribution of O6-methylguanine-DNA methyltransferase to monofunctional alkylating-agent resistance in human brain tumor-derived cell lines. Mol Carcinog 13:70-80.
7. Wick, W., Platten, M., and Weller, M. 2009. New (alternative) temozolomide regimens for the treatment of glioma. Neuro Oncol 11:69-79.
8. Gilbert, M.R., Wang, M., Aldape, K.D., Stupp, R., Hegi, M.E., Jaeckle, K.A., Armstrong, T.S., Wefel, J.S., Won, M., Blumenthal, D.T., et al. 2013. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J Clin Oncol 31:4085-4091.
9. Wick, W., Steinbach, J.P., Platten, M., Hartmann, C., Wenz, F., von Deimling, A., Shei, P., Moreau-Donnet, V., Stoffregen, C., and Combs, S.E. 2013. Enzastaurin before and concomitant with radiation therapy, followed by enzastaurin maintenance therapy, in patients with newly diagnosed glioblastoma without MGMT promoter hypermethylation. Neuro Oncol 15:1405-1412.
10. Agnihotri, S., Burrell, K., Buczkowicz, P., Remke, M., Golbourn, B., Chornenkyy, Y., Gajadhar, A., Fernandez, N.A., Clarke, I.D., Barszczyk, M., et al. 2014. ATM regulates 3-Methylpurine-DNA glycosylase and promotes therapeutic resistance to alkylating agents. Cancer Discov.
11. Weiler, M., Blaes, J., Pusch, S., Sahm, F., Czabanka, M., Luger, S., Bunse, L., Solecki, G., Eichwald, V., Jugold, M., et al. 2014. mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy. Proc Natl Acad Sci U S A 111:409-414.
12. Wiestler, B., Claus, R., Hartlieb, S.A., Schliesser, M.G., Weiss, E.K., Hielscher, T., Platten, M., Dittmann, L.M., Meisner, C., Felsberg, J., et al. 2013. Malignant astrocytomas of elderly patients lack favorable molecular markers: an analysis of the NOA-08 study collective. Neuro Oncol 15:1017-1026.
Submitter: Hans-Peter Kiem | email@example.com
Authors: Maciej M. Mrugala, Jennifer E. Adair, and Hans-Peter Kiem
Fred Hutchinson Cancer Research Center
Published September 23, 2014
We would like to thank Drs. Platten and Wick for their letter and thoughtful comments regarding our manuscript (1). We agree that our current study is based on a small sample size, yet we disagree that our patient population was highly selected. We designed the study for patients with unmethylated MGMT promoter as this group exhibits the worst prognosis and no successful treatments exist. The authors of the letter agree that MGMT is a resistance mechanism against alkylating agents like temozolomide (TMZ) and BCNU, which are an important part of the current treatment. Our study simply addressed this critical, well-established resistance mechanism in glioblastoma patients by specifically disabling MGMT expression and thus sensitizing the tumor. We did not pre-select for superior performance status or the extent of surgical resection (other known prognostic factors in GBM). We disagree that we overestimated treatment results, we clearly discuss the issue of sample size and we asked to interpret the data cautiously. The study is ongoing and additional data will help validate this treatment approach.
We agree that more recent studies have also shown improved survival in patients with unmethylated MGMT status and we compared our results to these studies cited by the authors of the letter. We chose one dose of BCNU before infusion of the modified cells because it has demonstrated activity in glioblastoma and it also provided an excellent nonmyeloablative conditioning for patients to maximize engraftment of the TMZ-protected blood cells. We do not believe BCNU was a significant confounding factor since it did not affect the ability to administer TMZ after treatment with O6BG, and, with regard to outcome, we believe it is unlikely that one dose of the drug would have a profound effect on overall survival. The authors cite the RTOG 0525 study in which patients received dose-dense TMZ (TMZ was given for 21 days of a 28 day cycle). The study did not demonstrate improved efficacy over the standard dosing regimen (5/28) (2). While higher doses of TMZ can deplete MGMT in blood cells gradually via the known resistance mechanism (i.e. repair of TMZ-damages DNA), the mechanism of action of O6BG is completely different (direct MGMT binding and rapid depletion to undetectable levels), and thus cannot be compared to our study (3-8). Our study was specifically designed to combine O6BG-mediated MGMT depletion in glioblastoma with concurrent TMZ treatment to maximize the TMZ benefits in tumor cells while minimizing hematologic toxicity (1,9). Our study showed that this gene therapy strategy can circumvent marrow toxicity seen in previous trials without genetically modified cells, allowing more effective TMZ administration (10).
Glioblastoma has remained a devastating disease and we agree that better, more targeted therapy is needed. However, for the patient population with unmethylated tumor and poor outcome the currently available strategy of depleting MGMT and thus sensitizing the tumor may actually help patients now and should not be discouraged.