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Ponencia en el "6th Latin American MTTC", Noviembre 2008, Buenos Aires: Molecular Targeted Therapy of Brain Tumors

A continuación está el script de la presentación del 21/11/2008 en Buenos Aires, en el marco del 6th Latin American Molecular Targeted Therapy Council Meeting.

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Desde la diapositiva 13 (Targeted therapy)

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1. My job in the next fifteen minutes or so is to put you up-to-date in the increasingly exciting area of molecular targeted therapy for brain tumors.The topic shall be devoted entirely to targeted therapy for malignant gliomas, specifically glioblastoma in which this approach is on the clinical phase of development.
2. Glioblastoma – or GBM is the most frequent and lethal of the malignant gliomas, with a median survival after diagnosis of about 12 months. It accounts for 2/3 of gliomas. From the clinical perspective, GBM is divided into primary and secondary GBM. Primary GBM is considered to be a de-novo neoplasm, and it tends to occur in older individuals with a median age at presentation of 60. Secondary GBMs are deemed to be the result of disease progression of lower-grade gliomas, they usually occur in at a younger age, with a median age at presentation of about 40.
3. From the pathologic perspective, GBMs are characterized by a dense proliferation of neoplastic-cells, extensive nuclear polymorphism, increased mitotic activity, and necrosis – often serpentine in nature, with pseudopalisade formation. Vascular endothelial cell proliferation is the hallmark of the disease. So much so, that a double layer of endothelial cell is the minimal pathologic requirement for tissue diagnosis of GBM. In this highly vascular tumor, it is no surprise that anti-angiogenic strategies have been actively explored.
4. Many DNA aberrations have been described in GBMs. In fact, it is postulated that malignant transformation in gliomas is te result of sequential accumulation of genetic aberrations and the deregulation of growth-factor signling pathways. Primary GBMs are characterized by EGFR and PDGF abnormalities; whereas secondary GBMs are characterized by p53 mutations. Both primary and secondary GBMs exhibit VEGF overexpression. Other
5. Tumor angiogenesis is central to the biology of GBM, and it appears to be driven by VEGF. Abnormal vascular developments results in dilated, abnormal and hyperpermeable blood vessels. Restoration of vascular integrity may decrease permeability with an ensuing improvement in oxygen delivery which may enhance the cytotoxic effect of ionizing radiation and chemotherapy.
6. One of the standards-of-care for GBM is chemo-radiation therapy with temozolamide after maximal surgical resection.
7. In a large phase III trial reported by Stupp et al. for the EORTC and the NCIC, published in the New England Journal of Medicine in 2005, 573 patients were randomly assigned to post-surgical radiation therapy or chemoradiation with temozolamide 75 mg/m2 every day while on radiotherapy, followed by single-agent temozolamide 150-200 mg/m2 for 5 days, every month, for 6 months, thereafter.
8. The overall survival 14.6 months in the combination arm, compared to 12 months in those treated with radiation therapy alone. Of even more significance, the two-year survival was 26% in the chemoradiation arm, compared with 10% in the radiation therapy arm.
9. Of relevance to this discussion is the finding, published in the same issue of the NEJM, that a silenced MGMT gene appears to confer increased chemo-sensitivity to temozolamide. The MGMT is a DNA repair protein that removes alkyl groups from the O6 position of guanine, an important site of DNA alkylation. High levels of MGMT activity restores DNA after damage by alkylating agents such as carmustine or temozolamide. MGMT gene silencing by promoter methylations increases survival
10. And confers increased susceptibility to the cytotoxic effects. Epigenetic MGMT silencing is associated with an increased in survival, 21 months in those treated with chemo-radiation as compared to15 months in patients treated with radiation therapy only, with a HR of 0.45.
11. Most patients with GBM progress after initial therapy, and there is no established second-line therapy. The 5 year survival rate is a meager 5%. Temozolamide re-challenge after relapse is associated with a 21% 6-month progression-free survival.
12. In order to advance 2nd line therapy in GBM it has been proposed to use a 15% cut-off for progression-free survival as a clinical meaningful threshold for further evaluation of novel therapeutic strategies in this disease, based on the composite of the results of several trials reported by Wong et al in 1999.
13. Targeted therapy
14. A has been previously shown, there are many potential targets for GBM
15. Highlighted are the more promising drugs in clinical development for recurrent GBM. It is important to point-out the disappointing results of single agent anti EGFR, PDGFR tyrosine kinase inhibitors, with only 0-15% 6-month PFS. As Dr. Lupera mentioned earlier in this meeting, the combination of mTOR inhibitor with an EGFR tyrosine kinase inhibitor, temsirolimus and gefitinib, respectively is promising with a 6-month PFS of about 25%.
16. But, by far, the most advanced area of targeted research in GBM is with antiangiogenic therapy.
17. It is only natural to exploit the highly vascular nature of GBMs. Bevacizumab has been used with irinotecan in Phase II trials with some very encouraging results. Dr. Artur Katz gave us an enlightened talk last year on the topic. Overall a response rate of 57-63% 6-mo PFS of 46% is to be expected in second-line therapy.
18. As an example, you can appreciate the outstanding result after 7 months of therapy with Bevacizumab + Irinotecan, with a virtual complete radiologic response.
19. Cediranib is a oral Pan VEGF tyrosine kinase inhibitor in clinical development. It has a long half-life that lends itself for once-a-day dosing.
20. A NCI sponsored phase II trial was updated last week in New York. Oral cediranib was taken on a daily basis; the primary end-point was 6-month PFS. Other end-points included: response rate, overall survival, toxicity, correlative biomarker and imaging studies.
21. The treatment strategy is outlined in the graph; and the expression of relevant biomarkers to Cediranib in GBMs is shown: As expected, most GBMs express VEGFR2, PDGFR alpha, PDGFR beta.
22. The results, reported 2 weeks ago in New York are: The median PFS and OS were 117 and 227 days in 31 patients enrolled in the trial, respectively. The 6-month PFS, the primary end-point, was 26%. This result compares favorably with the 15% cut-off previously mentioned. MRI scans were consisten with transient vascular normalization – as expected based on cediranib’s mechanism of action. There was a significant decrease in brain edema and a steroid-sparing effect was achieved in the majority of patients. The toxicity profile was manageable with diarrhea, hypertension and fatigue. Two patients were removed from the study due to side-effects – fatigue in both of them. Of note, there were no intracerebral hemorrhages in any patients. Several phase I-II trials have been initiated with cediranib with lomustine in relapsed GBM, and cediranib plus temozolamide and radiation therapy in newly diagnosed GBMs.
23. This imaging sequence illustrates a very good response with cediranib, with decrease in tumor size, edema, and permeability, as reported previously by the same group.
24. Integrins are novel targets for GBM. These molecules are important for the cell-to-cell interaction, specifically, for endothelial cell proliferation and migration. They are important for the vascular integrity. Integrin alpha n beta 3 (ANB3) is highly expressed in GBM, as can be seen with the coexpression of both the integrin and the vascular cell marker CD31 in the photograph. Anti integrin agents cause endothelial cell apoptosis.
25. Cilengitide is a selective alphavbeta3 and alphavbeta5 integrin antagonist that is being actively investigated in several diseases. The mechanism of action and its biologic implications are outlined in the slide.
26. Cilengitide is currently under investigation both in first-line and in second-line therapy.
27. As a single agent, Cilengitide 2000 mg was associated with a median overall-survival of 9 months in previously treated patients with GBM. 6 month PFS was also about 25% establishing cilengitide as an exciting agent in the field.
28. Concomitant therapy with cilengitide, temozolamide and radiation therapy has been reported in a cohort of 52 patients with newly diagnosed GBM. The drug was administered twice-weekly during chemoradiation.
29. The median overall survival was 16 months.
30. As expected, patients with epigenetic silencing of MGMT exhibited superior survival.
31. A phase III trial is being designed in newly-diagnosed chemo-sensitive (ie silenced MGMT) patients with or without concurrent cilengitide in patients treated with standard chemo-radiation therapy.
32. In conclusion, molecular targeted therapy is an active area of investigation for the therapy of GBM. Anti vascular agents are important, and several of these appear to be active in second line therapy. Cilengitide, cediranib, and bevacizumab may eventually reach widespread use, if further research confirm their efficacy and safety. Even conventional cytotoxics such as temozolomide can be considered targeted therapy: they target cells unable to abate their DNA damage. Thank you.

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