Predictive Biomarkers in GBM

Transcription

1 Predictive Biomarkers in GBM C. David James, Ph.D. Professor & Associate Director, Brain Tumor Research Center Dept. Neurological Surgery and Helen Diller Comprehensive Cancer Center, University of California San Francisco

2 During the past 10 years, glioblastoma diagnosis has been refined by including molecular profiling that has promoted tumor subclassification Initial tumor classification, however, continues to be based on morphologic characteristics Presumed cell of origin: Astryocytes -> astrocytoma -> glioblastoma? Oliododendrocytes -> oligodendroglioma Ependymal Cells -> ependymoma oligodendroglioma astrocytoma

3 Numerical malignancy grading based on the presence or absence of specific morphologic features grade II vs. grade III: absence vs. presence of mitotic figures grade III vs. grade IV: absence vs. presence of necrosis and/or endothelial cell proliferation

4 Prognosis based on morphology is very imprecise Early attempt at glioma classification based on tumor genetic characteristics Am J Pathology 159: , 2001 Cancer Cell: 1: , 2002

5 First, widely referred to molecular classification scheme Cancer Cell 9: , 2006

6 The current, most frequently cited classifcation scheme for GBM was developed in association with The Cancer Genome Atlas project Cancer Cell 17:98-110, 2010.

7 The transcriptome defined GBM subtypes are associated with specific gene alterations Cancer Cell 17:98-110, 2010.

8 The TCGA analysis of GBM highlighted three core pathways that are deregulated during tumor development

9 Johns Hopkins Duke initiative sequenced 20,661 protein coding genes Identified IDH1 mutation in secondary GBM. This mutation was subsequently identified in large percentages of grade II and grade III gliomas. N Engl J Med. 360:765-73, 2009

10 The most recent additions to the catalogue of common GBM alterations involve genes that encode chromatin packaging and modifying proteins. Nature 482: , 2012

11 Recent presentation and attempt of a comprehensive, integrated model to account for GBM subgroups Cancer Cell 22: , 2012 Highlights an emerging avenue of investigation in brain tumor research: gene alterations causing GBM may have temporal (age) and neuroanatomical dependencies

12 All information presented thus far has involved tumor classifications based on somatic gene alterations What about inherited predisposition? Recent GWAS studies suggest inherited risk factors. Cancer Genetics 205: , 2012 Original source publications: Nat Genet. 44:1122-5, 2012 Nat Genet. 41:905-8, 2009

13 Attempts at associating molecular classification with morphologic features Is this necessary? A major point of the molecular classification is to move away from morphologic, descriptive classification. J Am Med Inform Assoc 19:317-23, 2012

14 Where does this leave us regarding treatment options, as informed by tumor molecular profiling? Each pathway provides multiple opportunities for treatment intervention

15 IDH mutations Brain Tumor Pathol 29:

16 Chromatin packaging/modifying mutations Cancer Cell 21: , 2012

17 13 years ago my lab began establishing GBM xenografts that are serially-passaged s.c. in athymic mice, rather than propagated in tissue culture X

18 GBM Panel of Genetically-Characterized Xenografts

19 This xenograft series found its way into the TCGA pipeline With their expression profile and genomic analysis revealing representation of 3 of the 4 GBM subtypes. Cancer Cell 17:98-110, 2010.

20 Many of the xenografts produce infiltrative intracranial tumors that are not typically formed when using established cell lines GBM 6 U87 c b a a b c

21 Predictive biomarkers for GBM response to therapy Complicating issue: standard of care Radiation 2 Gy M, W, F x 2 = 12 Gy total

22 Temozolomide ~ 40% GBM do not express MGMT MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352: , 2005.

23 Xenograft TMZ response analyses 66 mg/kg

24 EGFR was the first therapeutic target investigated for small molecule inhibition (erlotinib), using the xenograft panel. Mol Cancer Ther 6: , 2007

25 EGFR amplified xenograft showing erlotinib sensitivity

26 Phase I/II trial of erlotinib and temozolomide with radiation therapy in the treatment of newly diagnosed glioblastoma multiforme: North Central Cancer Treatment Group Study N0177. J Clin Oncol 26:5603-9, Because the favorable survival response in the current trial could have been a result of the TMZ, N0177 was compared with EORTC 26981/22981-NCIC, a trial of similar patients treated with RT and TMZ alone. Comparing the study results, there were no significant differences in OS between the two trials, which suggests there is no additional benefit for erlotinib when combined with RT and TMZ.

27 Therapeutic targeting points of oncogene addiction is a concept that is reasonably well accepted as a rational strategy for treating cancer. Most pre-clinical & clinical efforts to date have focused on targeting single points of addiction. Is it rational to simultaneously target multiple points of addiction?

28 BRAFV600E-p16 null mouse allograft results BRAFV600E-p16 null human xenograft results Huillard et al., PNAS 109:8710-5, 2012

29 Major obstacles to improved treatment outcomes Selection for and/or creation of therapy resistant subpopulations

30 Tumor adaptation to erlotinib in press, Cancer Discovery

31 2. The blood-brain-barrier: limits therapeutic access to intracranial tumor ~ 85 direct intratumoral ~ 90 ~ 17,000 < 1 Liposomal Packing Liposomal Packing + Direct Intratumoral Delivery

32 Direct intratumoral administration promotes increased extent of therapeutic anti-tumor activity, resulting in a reduced rate of tumor growth and improved survival * * Note high cure rate

33 Deserving of additional investigation? Sequencing of cytotstatic and cytotoxic therapies

34 Improved treatment outcomes for GBM may require innovative therapeutic fomulations as well as innovative approaches for administering therapy, in order to circumvent the limiting influence of the blood brain barrier. Summary and Conclusions As for nearly all types of cancer, our understanding and treatment of brain tumors, especially glioblastoma (GBM), is in an interesting time of transition that is being driven by the rapid increase in information about tumor-associated gene alterations. Appreciation of the need for multi-modality treatment of GBM is now pervasive within the field of neuro-oncology, and it can be anticipated that there will be a substanial increase in testing novel, molecularly informed combination therapies for treating this cancer. Standard of care therapy for treating GBM poses a complication for evaluating new therapies and therapeutic combinations.

35 Many colleagues/collaborators have contributed to these studies Mayo Clinic Jann Sarkaria Ajay Pandita Caterina Giannini UCSF Tomoko Ozawa Mike Prados Scott VandenBerg Rintaro Hashizume Martin McMahon Laura Serwer David Rowitch Claudia Petritsch Other Todd Waldman, GLCCC David Solomon, GLCCC Paul Mischel, UCLA David Nathanson, UCLA