Targeted Brain Tumor Treatment-Current Perspectives

Brain tumor is associated with poor prognosis. The treatment option is severely limited for a patient with brain tumor, despite great advances in understanding the etiology and molecular biology of brain tumors have lead to breakthroughs in developing pharmaceutical strategies, and ongoing NCI/Pharma-sponsored clinical trials. We reviewed the literature on molecular targeted agents in preclinical and clinical studies in brain tumor for the past decade, and observed that the molecular targeting in brain tumors is complex. This is because no single gene or protein can be affected by single molecular agent, requiring the use of combination molecular therapy with cytotoxic agents. In this review, we briefl y discuss the potential molecular targets, and the challenges of targeted brain tumor treatment. For example, glial tumors are associated with overexpression of calcium-dependent potassium (KCa) channels, and high grade glioma express specifi c KCa channel gene (gBK) splice variants, and mutant epidermal growth factor receptors (EGFRvIII). These specifi c genes are promising targets for molecular targeted treatment in brain tumors. In addition, drugs like Avastin and Gleevec target the molecular targets such as vascular endothelial cell growth factor receptor, platelet-derived growth factor receptors, and BRC-ABL/Akt. Recent discovery of non-coding RNA, specifi cally microRNAs could be used as potential targeted drugs. Finally, we discuss the role of anti-cancer drug delivery to brain tumors by breaching the blood-brain tumor barrier. This non-invasive strategy is particularly useful as novel molecules and humanized monoclonal antibodies that target receptor tyrosine kinase receptors are rapidly being developed

Introduction

Nearly 20,000 new primary brain tumors and about 200,000 metastatic brain tumor cases are reported each year in the U.S.A. (Levin, 2007). The overall survival of these patients is dismal and the majority of survivors suffer disabling toxicities from their treatments. Standard treatment for brain tumors includes combination of surgery, radiation therapy, and chemotherapy. Brain tumor poses unique challenges due to its distinct biology, genetics, treatment response, and survival. Despite extensive characterization of the brain tumor pathways, molecularly targeted approach is not available to brain tumor patients. Future research in brain tumors needs to focus on strategies for improving drug delivery, disruption of blood-brain-barrier (BBB), and molecular profiling of tumors. In addition, careful studies are needed to delineate pathways that aid and abate brain tumor progression. Identification of potential markers (genes and proteins) for targeted therapy will definitely help the clinicians to design the treatment accordingly. Usually, after surgical treatment, brain tumor recurs, severely shortening life expectancy (Friedman, Kerby and Calvert, 2000). Conventional treatments using radiation and intravenous chemotherapy are not successful because the cancer cells develop resistance to treatment. Anti-cancer drugs fail to penetrate the BBB in suffi cient quantities (Pardridge, 2001), allowing cancer cells to develop resistance to these agents. Therefore, understanding the biochemical regulation of the BBB (Fig. 1) in normal and tumor-invaded brain is of great importance to develop therapeutics that breach or circumvent BBB and directly target brain tumor cells (Ningaraj, 2006). The focus is now on the targeted cancer therapies (Butowski and Chang, 2005) that complement conventional treatments and reduce the drug resistance in cancer cells and the toxicity in normal brain (Newton, 2003). Novel cancer therapies include anti-angiogenic agents, immunotherapy, bacterial agents, viral oncolysis, cyclin-dependent kinases and receptor tyrosine kinase inhibitors (RTKIs), anti-sense agents, gene therapy, microRNA (miRNA), and combinations of various methods (Butowski and Chang, 2005).

Chemotherapy

Chemotherapy is a form of targeted therapy where cytotoxic drugs act on multiplying tumor cells. The drugs can also be used as sensitizers to augment the effects of radiation therapy. Chemotherapeutic drugs can be delivered directly to brain tumors through a polymer wafer implant such as a biodegradable wafer soaked with BCNU (Carmustine). Besides BCNU, several other chemotherapy drugs are used to treat brain tumors, which are administered by various routes. The chemotherapeutic drugs taken orally include Temozolomide (TMZ, Temodar), procarbazine (Matulane), and lomustine (CCNU). The intravenously administered drugs include vincristine (Oncovin or Vincasar PFS), cisplatin (Platinol), carmustine (BCNU, BiCNU), Carboplatin (Paraplatin), while Mexotrexate (Rheumatrex or Trexall) may be taken orally, by injection, or intrathecally. Treating brain tumors with chemotherapy can be difficult because the brain is protected by BBB, which keeps out harmful substances such as bacteria and chemotherapeutic drugs. Among many cytotoxic agents in the clinician’s arsenal, Temozolomide (TMZ) has shown some promise in treatment of low grade gliomas (Friedman, Kerby and Calvert, 2000), however, the effect on patient survival was modest (Balana et al. 2004). The problem is that glioblastoma multiforme (GBM) exhibits varying responses to TMZ (Hirose, Berger and Pieper, 2001), and in some cases gliomas have increased O6 -methyl guanine methyl transferase (MGMT) activity, which results in complete resistance to TMZ (Bocangel et al. 2002). The clinical utility of TMZ against all types of brain tumors remains limited due to its BTB penetration (some authors claim TMZ metabolite (MTIC) concentration in CSF to be as high as 30%), which demand repeated high doses to achieve in vivo therapeutically effective concentrations in brain tumors (Yung et al. 1999), and different phenotypes and genotypes that render some form of resistance against TMZ (Kanzawa et al. 2003). Most importantly, an extensive literature search and preliminary work on BBB/BTB penetration of TMZ did not convince us that suffi cient amount of drug penetrates the BBB or BTB to elicit anti-tumor effect. To circumvent the penetration problem, chemotherapy drugs can be delivered by intratumoral route or by drug impregnated wafers to attain higher concentration of drugs in the tumor cells, but the procedures are highly invasive.

Targeted brain tumor treatment

The human genome project has raised the expectation of the development of novel therapies for brain tumor because the conventional treatment strategies have not yielded any significant clinical outcome. Brain tumor treatment differs according to the grade and location of the tumor. Hence, combination of surgery, chemotherapy, and radiotherapy will be used in treating brain tumor patients (Stupp et al. 2005). Most promising anti-cancer drugs for pediatric and adult patients that are effective against cancers outside the brain have failed against brain tumors in clinical trails, in part, due to poor penetration across the BBB. For instance, aberrant expression of src family kinase (LCK) (Fabian et al. 2005) or mutation of c-KIT are involved in the pathogenesis of many cancers. Studies using imatinib mesylate (STI 571, Gleevec, Novartis, U.S.A.), an inhibitor of the tyrosine kinases BRC-ABL, c-KIT, and PDGFR, have shown signifi cant response in patients with chronic myelogenous leukemia (CML) and gastrointestinal stromal tumor (GIST). Clinical trials were recently conducted to test the effi cacy of Gleevec in brain tumors (Reardon et al. 2005; Wen et al. 2006; Pollack et al. 2007). Gleevec is an effective agent that targets specifi c gene/protein in cancer cells without harming normal cells and tissues. Drugs like Gleevec and Temozolomide attack abnormal chemical signals or molecules inside the cells or on the surface of the cells that have enabled brain tumor cells to escape the normal growth controls. Therefore, combating many forms of cancer will probably require a variety of targeted drugs used in combination, as cancer involves different types of dysfunctional genes and no single or two drugs will be sufficient. Some cancers, particularly primary and metastatic brain tumors of the breast and lung are diffi cult to treat because they are caused by multiple signaling pathways that are running amok, rather than just one, as observed in CML and GIST (Butowski and Chang, 2005). Gleevec may potentially target the above mentioned oncogenes in brain tumor (Holdhoff et al. 2005) provided it penetrates the BBB (Leis et al. 2004). Careful molecular studies would identify the stem cell factor/c-kit pathways in pediatric brain tumors, which might be the target of Gleevec. Characterizing the genetic and proteomic events that play a role in the biology of these tumors may allow molecular sub-typing which could lead to the development of novel therapeutic strategies, including treatment with Gleevec or with potassium channel modulators targeting tumor and tumor blood vessel endothelial cells (Ningaraj, 2006)