Current Diagnosis and Prognosis

At present, beyond the positive predictive value of increasing malignancy, as defi ned histopathologically (Table 1), survival of patients with GBM is predicated on clinical variables, including the patient’s age and condition (Karnofsky performance score) at diagnosis, tumor location and extent of surgical resection, and administration of adjuvant radiotherapy and/or chemotherapy [1–5]. With respect to each modality—surgery, radiation, or chemotherapy—the survival advantage for each remains modest, on the order of a few months, with an average overall survival from the time of initial diagnosis of about 12 months. Therefore, therapies that promote a meaningful survival advantage, while promoting and enhancing quality of life, are urgently needed.

Targeting Tumors with dsRNA

Because EGFR alterations are a common feature of many malignant tumors, including non-small-cell lung and colon cancers and malignant melanoma, among others, a variety of techniques have been designed to target the EGFR and its downstream agents, including antibodies, antisense RNAs, and a large number of small molecule inhibitors [7,8]. While many of these efforts have met with some success in other cancer types, none have had profound or lasting activity against GBM. Levitzki and colleagues have used a different strategy to target cells overexpressing EGFR: they use synthetic, double-stranded RNAs (dsRNAs), linked to EGF, to obtain selective and effi cient killing of EGFR overexpressing malignant gliomas in vitro and in vivo in a mouse model [6].

dsRNA motifs are central to immune regulation, and dsRNA may play several roles in eukaryotic cells—blocking tolerance to tumor-associated selfand foreign antigens; activation of RNaseL and protein kinase R, which effect transcriptional and translational inhibition while simultaneously spurring interferon expression; induction of apoptosis; activation of small RNA-mediated interference; promotion of extracellular or paracrine effects through secretion of interferons and other cytokines (a “bystander effect’); and release of dsRNAs from infected cells, thereby activating antigen-presenting cells [9,10].

Given this panoply of potential effects, Shir et al. coupled dsRNA (a polyinosine-cytosine or poly IC construct) to EGF, and demonstrated that EGFR-targeted poly IC induced rapid and pronounced apoptosis of EGFR overexpressing cells, but not of cells expressing low EGFR, no EGFR, or mutated constitutively active EGFR, which cannot bind EGF. A variety of cytokines, including interferon- α, Gro-α, and interferon-induced protein-10/CXCL10—all of which have been shown to have antitumor or antiproliferative activity—were also expressed by the tumor cells. Importantly, these results were replicated in vivo, where dsRNA treatment led to survival of all animals with intracranial tumors for greater than 244 days. In addition, dsRNA treatment was equally applicable in vitro and in vivo for two other EGFR overexpressing cell lines, A431 (a cervical carcinoma) and MDA-MD-468 (a breast carcinoma), suggesting that this approach has potential for other tumor types that overexpress EGFR.

Clinical Implications

While other treatments have had encouraging in vitro and in vivo debuts in animals, they have failed when translated to malignant gliomas in humans. Only clinical data will show whether the approach described above will be successful in human patients. However, there is reason for cautious optimism: based on recent advances in delivery of macromolecules to the brain, specifically by convection-enhanced delivery, pioneered by Edward Oldfield at the National Institutes of Health, it appears that ligand-guided delivery of dsRNA may hold significant clinical promise [11,12]. Convection-enhanced delivery permits selective delivery of heterogenous macromolecules to targeted-diseased regions within the brain both safely and efficiently, while minimizing or eliminating toxicities to the healthy brain or outside the central nervous system [11,12]. And since the system of Shir et al. can link dsRNAs to essentially any molecule, ligand-guided delivery might be broadly applicable to any cancer, and, quite likely, to benign disorders as well, so long as an endocytosed receptor is substantially overexpressed compared to normal cells. It appears to me that this is one method that should be fast-tracked to the clinic.