Molecularly targeted therapy FOR CANCER ( INNOVATION TOWARDS LIFE )

ABSTRACT

Malignant gliomas are relatively uncommon but lethal cancers. Despite recent research efforts in cancer therapy, the prognosis of patients with malignant gliomas has remained dismal. Understanding the molecular pathogenesis of glioma may lead to a rational development of new therapies. Despite the genetic heterogeneity of malignant gliomas, common aberrations in the signaling elements of the growth and survival pathways are found. New treatments have emerged to target molecules in these signaling pathways with the goal to increase specific efficacy and minimize toxicity. Monoclonal antibodies and low molecular-weight kinase inhibitors are the most common classes of agents in targeted cancer treatment. Most clinical trials of these agents as monotherapies have failed to demonstrate survival benefit in unselected malignant glioma patient populations. Several mechanisms of treatment failure have been demonstrated. In response, multitargeted kinase inhibitors and combinations of single-targeted kinase inhibitors have been developed to overcome therapeutic resistance. In addition, multimodality combinations of targeted agents with radiation, chemotherapy, or immunotherapy/vaccines may enhance treatment efficacy. Future development of these agents will require advances in discovery and validation of new molecular targets, improvement of therapeutic delivery, and identification of correlative biomarkers. Novel clinical trial designs and endpoints may increase the efficiency of new drug evaluation. In this review, the authors discussed the current understanding of molecular pathogenesis and the development of molecularly targeted therapies in malignant cancer.


An estimated 18,500 cases of primary malignant central nervous system (CNS) tumors were diagnosed in the United States in 2005.
1 Malignant gliomas are the most common primary CNS tumors in adults accounting for 78% of all primary malignant CNS tumors. Astrocytomas are the most common type of gliomas. The World Health Organization (WHO) classified astrocytomas into 4 grades according to histopathology.

2 Malignant astrocytomas refer to WHO grade III (anaplastic astrocytoma; AA) and IV (glioblastoma multiforme; GBM). The median survival of patients with AA is 2–3 years and that of GBM is only 9–12 months.

3 Favorable prognostic factors include young age, absent or minimal neurological signs, complete 
surgical resection, and good performance status. The current standard treatments for malignant gliomas include surgical resection, radiation therapy, and chemotherapy. When feasible, maximal surgical resection of tumor improves survival.

4 Until recently, radiation has been the main standard-of-care treatment with a minimal role for systemic chemotherapy.

5 However, in a recent phase 3 study, Stupp et al reported that adjunctive chemotherapy (concurrent temozolomide with radiation followed by 6 months of monthly temozolomide) improves median survival by 2.5 months compared with radiation therapy alone.

6 Thus, temozolomide has become a standard adjuvant therapy for malignant gliomas. Despite this multimodality treatment, clinical recurrence or progression is nearly universal. Intracavitary carmustine wafer implantation in surgically resectable cases of recurrent GBM provided only an 8-week survival benefit.

7 Available systemic chemotherapies offer modest clinical benefit with a 6-month progression-free survival (PFS) of <15% for GBM and 31% for AA.

8 The median overall survival is 25 weeks for recurrent GBM and 47 weeks for recurrent AA. Taken together, novel therapies for these devastating tumors remain an unmet need. In this article, we will examine the current understanding of molecular abnormalities associated with aberrant signal transduction pathways underlying malignant glioma pathogenesis and how to target these abnormalities with novel therapeutics. We regret that limited space will prevent a complete discussion of all relevant therapies and clinical trials.

MOLECULAR AND GENETIC ALTERATIONS OF GLIOMAS

Gliomas share common essential characteristics with other cancers—self-initiated proliferation, evasion of apoptosis, invasion, avoidance of immune surveillance, and ability to form and sustain new blood vessels.9Gliomas are strikingly heterogeneous in terms of pathology and genetic changes, even within a single tumor. However, common genetic alterations that maintain malignant phenotypes of tumors are frequently found. Low-grade astrocytomas (WHO grade II) often display inactivating mutations of tumor-suppressor gene TP53 and overexpression of platelet-derived growth factor (PDGF) ligands and receptors. Progression to anaplastic astrocytomas (WHO grade III) involves accumulation of other genetic alterations of retinoblastoma-associated cell-cycle regulatory pathways, including deletion or mutations of cyclin-dependent kinase inhibitor p16INK4A/CDKN2A or the retinoblastoma susceptibility locus 1 (pRB1), as well as amplification or overexpression of cyclin-dependent kinase 4 (CDK4) and human double minute 2 (HDM2).9 Transformation to GBM (so-called, secondary GBM) is associated with deletion of chromosome 10, which includes tumor-suppressor phosphatase and tensin homolog (PTEN). However, most GBMs are diagnosed without antecedent lower grade tumor—termed primary GBMs, which are seen more commonly in the elderly. Primary GBMs share some similar genetic abnormalities with secondary GBMs such as loss of PTEN, deletion or mutation of p16INK4A (which shares a locus with p14ARF on chromosome 9), and amplification of HDM2 or CDK4.10 However, few molecular changes distinguish primary and secondary GBMs. Molecular analyses have identified epidermal growth factor receptor (EGFR) amplification as predominant in primary GBMs and TP53 loss as a genetic hallmark of low-grade astrocytoma and secondary GBMs.11 Future molecular and genetic profiling may lead to discovery of new pathogenetic pathways and may convert to clinical application of targeted therapies against each subtype of malignant glioma.

Figure

Molecularly targeted therapy for Malignant Glioma. Several signal transduction pathways are inappropriately activated in malignant glioma. A simplified representation of signal transduction pathways and relevant therapeutic targets in glioma tumor cells (left) and tumor-associated endothelial cells (right) is illustrated. Several points in these cascades are targets of therapies in development for malignant gliomas, some of which are shown. EGF indicates epidermal growth factor;

ERK, extracellular regulated kinase; GDP, guanine diphosphate; GTP, guanine triphosphate; HDAC, histone deacetylase; TGF-α, transforming growth factor; HGF/SF, hepatocyte growth factor/scatter factor; IGF, insulin-like growth factor; MEK, mitogen-activated protein extracellular regulated kinase; mTOR, mammalian target of rapamycin; PDGF, platelet-derived growth factor; PIP2, phosphatidylinositol (4,5) bisphosphate; PIP3, phosphatidylinositol (3,4,5) trisphosphate; PI3K, phosphatidylinositide-3-kinase; PKC, protein kinase C; PLC, phospholipase C; PTEN, phosphatase and tensin homolog.

Figure 2.

 

Magnetic resonance imaging (MRI) demonstrates radiographic response in a patient with malignant glioma at 4 months and 12 months of treatment with bevacizumab and irinotecan.

Gd indicates gadolinium contrast; FLAIR, fluid-attenuated inversion recovery.