- Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington, U.S.A
- Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
- Alvord Brain Tumor Center, University of Washington, Seattle, Washington, U.S.A
Correspondence Address:
Eric C. Holland
Department of Neurological Surgery, University of Washington School of Medicine, Seattle, Washington, U.S.A
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, U.S.A
Alvord Brain Tumor Center, University of Washington, Seattle, Washington, U.S.A
DOI:10.4103/2152-7806.151351
Copyright: © 2015 Ene CI. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.How to cite this article: Ene CI, Holland EC. Personalized Medicine for Gliomas. Surg Neurol Int 13-Feb-2015;6:
How to cite this URL: Ene CI, Holland EC. Personalized Medicine for Gliomas. Surg Neurol Int 13-Feb-2015;6:. Available from: http://sni.wpengine.com/surgicalint_articles/personalized-medicine-for-gliomas/
Abstract
Personalized medicine for cancer entails tailoring therapy for each patient based on unique features of the patient's tumor; physiologic, molecular, genetic and epigenetic. Our ability to molecularly characterize tumor cells has increased dramatically and shown that there are significant differences between samples from patients with the same tumor type. Given this extensive variability in mutations and pathways driving tumors in patients, seeking a single bullet is an unrealistic approach for achieving a cure. In glioblastoma multiforme (GBM), the most common adult brain tumor, this inter-tumoral heterogeneity is further complicated by intra-tumoral heterogeneity within the tumor. This suggests that for personalized therapy to work for GBMs, pharmacologic agents would not only be tailored to target the differences from patient to patient but also the clonal diversity within each patient's tumor. In this review, we provide a historical perspective on clinical trials for cancer. We also discuss the current state of molecular biology and immunology based strategies for personalized therapies for glioblastoma multiforme.
Keywords: Glioma, glioblastoma multiforme, personalized medicine, targeted therapy, tumor heterogeneity, tumor vaccines
INTRODUCTION
Personalized medicine for cancer entails tailoring therapy for each patient based on genomic or epigenomic mutations unique to the tumor. High throughput analysis of hundreds of glioblastoma multiforme (GBM) patient samples show that gliomas may contain many types of mutations, including mutations to TP53, INK4A/ARF, PTEN or NF-1.[
The fight against cancer in the 1950s was driven by the philosophy that one did not need to completely understand the molecular and cellular biology to find a cure.[
More recently, the promise of personalized medicine for cancer using molecular information was exemplified following the discovery of Imatinib (Gleevac®), a drug that inhibits a specific over-active tryosine kinase fusion protein BCR-Abl in chronic myelogenous leukemia (CML). Given that this translocation event represents the driver mutation in CML, Gleevac became one of the first cancer drugs to selectively target cancer cells based on a unique alteration resulting in clinically significant remission in patients. Following this discovery, identification of similar targets in other cancer types became and remains an intense area of research. Unfortunately, targeting single gene products or alterations may not be feasible in a majority of tumors especially GBMs given significant clonal diversity inherent to this tumor type. This represents one of the most frustrating aspects of research seeking to develop targeted therapy or personalized medicine for GBMs.
This review provides an overview of three unique and cutting edge strategies for personalized medicine for GBM. These include targeting inter-tumoral heterogeneity, inter-tumoral heterogeneity and tumor immunology. We also describe the state of research in each of these areas and speculate on diagnostic methods that may guide clinical decision making in the future.
Classification of gliomas
Gliomas are classified into four grades by the World Health Organization (WHO) based on pathologic features of such as cellularity, pleomorphism, endothelial proliferation/abnormal angiogenesis, mitotic figures and necrosis [
Targeted therapy for glioblastoma multiforme
There is currently no Food and Drug Administration (FDA) approved drugs designed for personalized therapy for patients with gliomas. There are signs, however, that this advance is in the near future. The DNA alkylating agent Temozolomide (TMZ) improves the survival of patients with GBM when used in combination with radiation therapy. Furthermore, GBMs with hypermethylation and suppression of O-6-Methylguanine DNA methyltransferase (MGMT) are more sensitive to the TMZ.[
Inter-tumoral heterogeneity
Four GBM sub-types were recently reported based on gene expression profiling [
There is significant progress towards developing a robust pre-clinical model for testing the susceptibility of the various GBM sub-types to anti-cancer agents. To achieve this, the predominant molecular alteration within each GBM sub-group is over-expressed or deleted within specific clone of cells using cell type specific factors unique to the clone as drivers for recombinase enzymes (for instance, Cre-loxP recombinase system® for genetic deletion). Interestingly GBMs have arisen from inducing recombination in mouse neural stem cells, oligodenrocyte precursor cells or astrocytes.[
The pro-neural sub-group of GBM is dominated by platelet derived growth factor receptor (PDGFR) signalling.[
Following pre-clinical studies in mouse models using candidate chemotherapeutic agents, clinical trials that assess the effectiveness of these agents in clinic would be warranted. Currently, there are no prospective randomized double blind clinical trials designed using these GBM sub-types as enrolling criteria. In the foreseeable future however, retrospective analysis of prior trials may help determine if these sub-types have clinical relevance for therapy. Results from such analysis would inform the design of prospective randomized clinical trials using molecular information derived from large scale studies such as the cancer genome atlas (TCGA). Given our limited understanding of tumor heterogeneity, however, these studies remain premature and may not yield any useful results. Further complicating issues is the possibility that these GBM sub types potentially interconvert during the evolution of glioma formation. Ultimately, if the mutations that define the subgroups occur late in the evolution of GBM development they may not be very good therapeutic targets.
In terns of diagnostics, research into non-invasive means of detecting the GBM sub-types is ongoing.[
Intra-tumoral heterogeneity
The discovery of cells with different driver mutations existing side by side within tumors suggests that targeting a single mutation may be an ineffective strategy in GBMs. Recent evidence suggests that cells with mutations to Epidermal growth factor receptor (EGFR), Platelet derived growth factor receptor (PDGFR) and Receptor tyrosine kinase (RTK) co-exist within the same GBM.[
For instance, till date, no mouse model demonstrates the significant intra-tumoral heterogeneity seen in human GBM. Some have speculated that developing a mouse model that is constantly evolving may result in a heterogenous population.[
Clinical trials targeting intra-tumoral heterogeneity are not in the foreseeable future because there is limited understanding of drivers of heterogeneity- micro-environment, unstable genome, tumor evolution and terminally blocked CSC differentiation. Furthermore, the functional relevance of various clones within GBM remains unclear. Do these clones show a hierarchal or stochastic co-existence? If hierarchal, then the goal clinically would be to target the founder cell or the cancer stem cell potentially with single agents.[
Clinically, determining the extent of tumor heterogeneity would require a tumor biopsy. Following this, some have used fluorescent in situ hybridization (FISH) to detect the identity of multiple clones within GBM.[
Tumor immunology
The differential expression of antigens also provides an avenue for personalized medicine for GBMs. Tumor vaccines are being developed from exposure of immune cells to patient tumor antigens.[
Mouse studies over the last several decades have utilized patient derived tumor xenografts (PDX) to perform pre-clinical tests on hundreds of putative anti-cancer agents.[
Given these constraints, some have taken a unique approach to immunologic studies for GBM in genetically engineered mouse models (GEMMs) with intact immune systems. It was observed that GBM associated macrophages promote tumor progression. A recent study using an RCAS-hPDGFB driven GEMM showed that inhibition of macrophage colony stimulating factor 1R (CSF-1R) and hence GBM associated macrophages did not kill the macrophages but coerced them to eliminate glioblastoma cells.[
Several clinical trials are underway assessing the efficacy of targeting tumors via the immune system. Some expose immune cells such as dendritic cells to either single or multiple antigens.[
Non-vaccine mediated immunologic strategies are also demonstrating efficacy in human clinical trials for other cancers. It was shown that antibody mediated inhibition of the T-cell receptor programed death 1 (PD-1) or its ligand (PD-L1) induced objective responses in human patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma.[
As for diagnostics, a literature search showed no validated non-invasive methods for detecting tumor antigens. There are however ongoing clinical trials assessing whether tumor antigens can be detected in peripheral blood draws. Although these trials have not published data, such case controlled trials will hopefully provide insights about the hypothetical GBM circulating tumor cells and their utility for both vaccine and non-vaccine mediated immunological therapy.
Challenges and strategies for the future
‘Personalized medicine’ or ‘target specific’ therapy entails the use of agents that preferentially kill cancer cells based on unique molecular features or protein expression. This endeavour poses a challenge to both basic and clinical researchers given issues such as intra-tumoral heterogeneity discussed above. There is, however, significant progress in our understanding of the molecular biology of gliomas especially GBMs. This advance is driven by the invention of high-throughput assays that detect alterations at the clonal or cellular level across hundreds of patient samples. The cancer genome atlas (TCGA) project begun by the National Institutes of Health (NIH) in collaboration with multiple institutes across the country is providing useful information on not just GBMs but also other cancers. For GBMs, it led to the discovery that apart from the classic oncogenes and tumor suppressor genes such as TP53 and PTEN, there are other previously unrecognized mediators of gliomagenesis with high prevalence within GBM. Some of these mutations including NF-1 or PI3K were not previously recognized to be involved in gliomagenesis. Furthermore, the TCGA has also demonstrated that epigenetics may also represent an area of research that could provide an avenue for targeted therapy. For instance, it is reported that hypermethylation phenotypes may be associated with better prognosis in patients with GBM.[
This stagnation of translational research drove the National Institutes of Health to establish its newest institute called the National Center for Advancing Translational Science (NCATS).[
CONCLUSION
The lack of progress in therapies for GBM is a complex topic beyond the scope of this review. It is important to state, however, that a lack of progress in personalized therapy for this disease is most likely a limited understanding of the clonal heterogeneity within a single GBM sample that has been brought to light by technology not previously available.[
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