|Year : 2018 | Volume
| Issue : 5 | Page : 155-158
Precision cancer therapeutics for glioma
Danny Tat Ming Chan
CUHK Otto Wong Brain Tumour Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
|Date of Web Publication||25-Oct-2018|
Dr. Danny Tat Ming Chan
CUHK Otto Wong Brain Tumour Centre, Department of Surgery, Prince of Wales Hospital, Shatin, New Territories, Hong Kong
Source of Support: None, Conflict of Interest: None
Malignant glioma is the most common primary brain tumor. Over the past four decades, intensive researches and studies have made breakthroughs in survival. However, the overall prognosis is still very poor with short survival. Glioblastoma was one of the first selected tumors for the Cancer Genome Atlas project which had gained understanding in tumor biology and gliomagenesis. Despite all these understandings, targeted therapies and precision therapeutics have not made any impact in the overall survival and outcomes. The concept of precision personalized cancer therapy is appealing and is desperately needed to be materialized for glioma. The issues of tumor heterogeneity in glioma and drug screening are crucial to our further understanding and to the ultimate solution. This article will discuss the potential and challenges of precision cancer therapeutics for glioma.
Keywords: Drug screening, glioblastoma, heterogeneity, molecular profiling, precision therapeutics
|How to cite this article:|
Chan DT. Precision cancer therapeutics for glioma. Glioma 2018;1:155-8
| Introduction|| |
The mainstays of treatment for glioblastoma are surgery, radiation therapy, and chemotherapy. Radiation therapy is the first treatment modality proved to prolong the survival of high-grade glioma in 1978. The additions of brain mapping and fluorescence-guided surgery (5-aminolevulinic acid) to surgical techniques have facilitated maximum safe resection of the glioma. The first chemotherapy proved effective against glioblastoma is an interstitial carmustine polymers. While temozolomide is the first proven systemic chemotherapy for glioblastoma (2000 for recurrent high-grade glioma and 2005 for primary glioblastoma), bevacizumab was approved for recurrent glioblastoma in 2008., Many novel treatment agents have been tested. These included established and novel cytotoxic chemotherapy agents, antiangiogenic agents, signal transduction modulators, biologic agents, and immunotherapies. Early studies recognize that drug delivery across the blood-brain barrier may limit the efficacy of many therapeutic agents; novel routes of delivery have been tried. These include direct tumor injection, intra-arterial delivery, tumor perfusion using convection-enhanced delivery, and implantation of slow release vehicles (i.e., carmustine wafer). Despite all of these efforts, the portfolio of effective agents remains quite limited. It is a disease whose outcome has not been substantially altered in 40 years despite new molecular discoveries and numerous efforts to improve treatments. Only recently, a non-pharmacological therapy, tumor-treating fields, has demonstrated a modest survival benefit in glioblastoma. Each of the modalities has made an incremental improvement in the survival of the patients. However, glioblastoma remains incurable despite decades of laboratory and clinical investigations. It is a predictable result of therapeutic disappointment with a median survival time of 18 months. A breakthrough is desperately needed.
Glioblastoma was one of the first selected tumors for the Cancer Genome Atlas More Details (TCGA) project in 2006. TCGA project had yielded important insights into the heterogeneity of these tumors and shed light on the understanding of the molecular subtypes, genomic alternations, major molecular markers, and signal pathways of glioblastoma. The discovery of IDH1 and IDH2 mutation is a major lead to the understanding of the evolution of molecular changes (molecular pathways in gliomagenesis) from low-grade to high-grade glioma., It revives better clinical correlation of molecular changes, i.e., IDH1, over the pathological grading. The WHO has made its latest version of histological classification of glioma by this knowledge of molecular subtypes. Now, we can make a more precise diagnosis and prognostication for different subtypes of the glioma.
| Precision Therapeutics for Other Cancers|| |
This genomic information has already helped to shape the development and use of some of the newest cancer treatments. For example, the drug imatinib was designed to inhibit an altered enzyme produced by a fused version of two genes found in chronic myelogenous leukemia. Another example is the breast cancer drug trastuzumab, which works only for women whose tumors have a particular genetic profile called HER2 positive. Studies have also found that lung cancer patients whose tumors are positive for epidermal growth factor receptor (EGFR) mutations respond to gefitinib and erlotinib – two drugs targeting this mutation., On the other hand, colon cancer patients whose tumors have a mutation in a gene called KRAS derive little benefit from cetuximab and panitumumab.
| Precision Cancer Therapeutics for Glioma?|| |
The progress in developing effective chemotherapy regimens for primary brain tumors lags behind that of other cancers. Most first-line chemotherapy drugs do not have biomarkers to guide their applications. Molecular classification of most primary brain tumors has identified many potential targets [Table 1]. The type of genomic information should drive research to develop similar treatment strategies for a given set of genomic changes in glioma. Major efforts have been invested in targeting these pathways, but in spite of numerous therapeutic trials, treatment options remain limited and inefficient. There are initial results of case series that shows the dramatic response of recurrent BRAF V600E-mutated glioblastoma to dabrafenib and vemurafenib., The magnitude of the effect is still far from any significance in the major subtypes of glioma and in overall survival data. Basket study design has opened up the opportunity, other than disease-specific studies, for small patient number diseases, i.e., glioma. Basket study requires a molecular profiling platform and collaborations between disciplines and centers for testing the effect of a drug on single mutation in a variety of cancer types. STARTRK-2 trial is an ongoing, multicenter, global phase II basket study of entrectinib (RXDX-101) for the treatment of participants with solid tumors that harbor an NTRK1/2/3, ROS1, or anaplastic lymphoma kinase gene fusion. About 1%–3% of glioblastoma carry the NTRK1 gene fusion. Moreover, 3% of all astrocytomas carry NTRK2 gene fusion. Results from these basket studies will provide more information in precision therapeutics in glioma.
| Challenges for Precision Cancer Therapeutics for Glioma|| |
If colon cancer, breast cancer, and lung cancers all have responded to precision cancer therapeutics, what are the factors failing the targeted therapies for glioma?
Intratumor heterogeneity, or spatial heterogeneity within tumors, has explained the negative results of many trials. Studies have shown that clonal and subclonal genomic alternations arise early in the tumor growth. Multisector biopsy and sequencing were performed in ten primary glioblastoma. All were treatment-naïve. Hypermutators were found in two samples. After excluding the hypermutators, only 73% of the mutations were clonal and shared among the biopsies taken in different sectors of the same tumor. Subclonal and private mutations were found in 23%. Targeted treatment, even at its best efficacy, would have left out the private mutations which would go dormant until recurrence. Intertumor heterogeneity was also reported that multifocal tumors of glioblastoma sequenced genetically different mutations. The situation is further complicated by the temporal tumor heterogeneity at recurrence. Studies have demonstrated that biopsies taken from the recurrent tumor were genetically distant from the primary tumor (Nei's genetic distance)., Cancer genome project has broadened our understanding on the one hand and it has also led us to a larger area of uncertainty of cancer epigenome on the other hand. Mutation events in genetic, epigenetic, transcription factors, and receptors levels have multiplied the complexities of the tumor heterogeneity.
Drug screening – personalized cancer therapy
Drugs toward actionable target yielded limited success. Studies found that tumors did not simply respond to the class of drugs, i.e., EGFR-driven tumor types. It may respond to a specific drug of the class but not to the others. Thus, we will need tumor models that reflect the true biology and subject the models to drug screening. It will be a high-throughput drug and a combination drug screening to identify potential new therapies. The conventional tumor cell lines are not applicable to its lack of genomic signatures. Transplanting tumors, which retain their widely varying genetic characteristics, into mice to create a panel of tumor-laden mice (patient-derived xenograft [PDX]) are the current direction to address the variability of tumor genomics. However, PDX is not practical for glioma (glioblastoma) model for its prolonged incubation time and the high cost. It would take 4–6 months for the incubation of xenograft before it is suitable for drug testing. This is practically too long for the fast-growing glioblastoma. Allowing drug repositioning, there are over 2000 FDA approved and pipeline drugs available for screening. Single-agent and combination drugs would add up a large number of mice for testing. The high cost would forbid its translation.
| Current Status of Precision Cancer Therapeutics for Cancers|| |
So far, large randomized cancer studies of precision cancer therapy have not led to gains in survival. Only 30% to 50% of the patients had suspected driving mutations identified. Moreover, only 3% to 13% had druggable treatment. Combination therapy sounds synergistic in vitro and is attractive clinically. However, drug toxicity and expensive cost have made it clinically unrealistic.
| Conclusion|| |
The concept of precision personalized cancer therapy is appealing and is desperately needed to be materialized for glioma. The proposed strategy for precision glioma treatment is to obtain multiple biopsies of patients at the time of surgery within the enhancing and the nonenhancing region of the tumor. Paired samples should always be taken at the time of recurrence for profiling and retreatment. Extensive genome-wide profiling and drug selection are to be individualized. Before a practical high-throughput drug screening platform is available, drugs are carefully chosen and considered with the knowledge about the patient's past treatment history, known molecular profiles, and pharmacokinetics. Drugs that target ubiquitous truncal, as well as private genetic alternations, are the key to success in treatment. Multiple agents are allowed while taking into account of the potential toxicity and safety of using combination therapy. The precision glioblastoma therapy should be materialized in a platform of the well-designed collaborative program, with researches to overcome the above-named challenges.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Walker MD, Alexander E Jr., Hunt WE, MacCarty CS, Mahaley MS Jr., Mealey J Jr., et al.
Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial. J Neurosurg 1978;49:333-43.
Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, et al.
Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: A randomised controlled multicentre phase III trial. Lancet Oncol 2006;7:392-401.
Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, et al.
Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. The polymer-brain tumor treatment group. Lancet 1995;345:1008-12.
Yung WK, Albright RE, Olson J, Fredericks R, Fink K, Prados MD, et al.
Aphase II study of temozolomide vs. procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer 2000;83:588-93.
Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96.
Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, et al.
Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol 2009;27:740-5.
Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, et al.
Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 2009;27:4733-40.
Stupp R, Taillibert S, Kanner A, Read W, Steinberg D, Lhermitte B, et al.
Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A Randomized clinical trial. JAMA 2017;318:2306-16.
Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al.
Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 2010;17:98-110.
Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, et al.
IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009;360:765-73.
Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, Aldape KD, Yung WK, Salama SR, et al.
Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015;372:2481-98.
Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al.
The 2016 World Health Organization classification of tumors of the central nervous system: A summary. Acta Neuropathol 2016;131:803-20.
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, et al.
Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: Randomised trial. Lancet 2004;364:1127-34.
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, et al.
Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 2011;365:1273-83.
Mok T, Wu YL, Au JS, Zhou C, Zhang L, Perng RP, et al.
Efficacy and safety of erlotinib in 1242 East/South-East Asian patients with advanced non-small cell lung cancer. J Thorac Oncol 2010;5:1609-15.
Leung L, Mok TS, Loong H. Combining chemotherapy with epidermal growth factor receptor inhibition in advanced non-small cell lung cancer. Ther Adv Med Oncol 2012;4:173-81.
Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S. Cetuximab and panitumumab in KRAS wild-type colorectal cancer: A meta-analysis. Int J Colorectal Dis 2011;26:823-33.
Burger MC, Ronellenfitsch MW, Lorenz NI, Wagner M, Voss M, Capper D, et al.
Dabrafenib in patients with recurrent, BRAF V600E mutated malignant glioma and leptomeningeal disease. Oncol Rep 2017;38:3291-6.
Kieran MW, Bouffet E, Tabori U, Broniscer A, Cohen K, Hansford J, et al
. The first study of dabrafenib in pediatric patients with BRAF V600-mutant relapsed or refractory low-grade gliomas. Ann Oncol 2016;27 (Suppl 6):LBA19_PR.
Mahlokozera T, Vellimana AK, Li T, Mao DD, Zohny ZS, Kim DH, et al.
Biological and therapeutic implications of multisector sequencing in newly diagnosed glioblastoma. Neuro Oncol 2018;20:472-83.
Lee JK, Wang J, Sa JK, Ladewig E, Lee HO, Lee IH, et al.
Spatiotemporal genomic architecture informs precision oncology in glioblastoma. Nat Genet 2017;49:594-9.
Wang J, Cazzato E, Ladewig E, Frattini V, Rosenbloom DI, Zairis S, et al.
Clonal evolution of glioblastoma under therapy. Nat Genet 2016;48:768-76.
Liu F, Mischel PS, Cavenee WK. Precision cancer therapy is impacted by oncogene-dependent epigenome remodeling. NPJ Precis Oncol 2017;1:1.
Prados MD, Byron SA, Tran NL, Phillips JJ, Molinaro AM, Ligon KL, et al.
Toward precision medicine in glioblastoma: The promise and the challenges. Neuro Oncol 2015;17:1051-63.
Tannock IF, Hickman JA. Limits to personalized cancer medicine. N Engl J Med 2016;375:1289-94.