Incorporating molecular tools into early-stage clinical trials

Abstract

The author discusses the implications of a new phase I trial investigating the role of rapamycin in patients with glioblastoma.

Figure 1. Clinicopathological Features of Glioblastoma

Left, a sagittal (top), contrast-enhanced, T-1 weighted magnetic resonance (MR) image from a patient shows a left posterior parietal GBM, centered within the red cross during intra-operative navigation. The tumor is overlaid in purple on the skull (left, bottom); the several small discs seen on the surface of the scalp are used for intra-operative localization. Middle, a sagittal (top), contrast-enhanced, T-1 weighted MR image from a different patient shows a GBM within the right anterior parietal and posterior temporal lobes, represented in green on the bottom image. Right, histological variability of GBMs. A, normal paucicellular temporal lobe. B, typical, hypercellular GBM from one patient 50 years of age. C, excessive stromal proliferation within a separate portion of the same patient seen in B. D and E, areas of pronounced vascular proliferation (arrows) found throughout the specimen from a second patient, also 50 years of age, whose clinical presentation (headache and seizure) and tumor on MR imaging was nearly identical to that of the patient in B. The patient in B had little vascular proliferation compared to the patient depicted in D; conversely, patient D had no areas of stromal proliferation. Magnification in A–D, 200×; 400× in E. Hematoxylin and eosin staining.

Figure 2. Cartoon Representation of Receptor Tyrosine Kinase and Phosphatidylinositol 3-Kinase (PI3K)/Akt/mTOR Pathways

The cell surface is represented as a light blue rectangle and contains a variety of receptor tyrosine kinases, such as EGFR, insulin-like growth factor 1 (IGF-1R), and a variety or other receptors such as integrins, G-protein-coupled receptors (GPCRs), and the receptor for vascular endothelial growth factor (VEGF). Activation of the RTK by ligand (dark blue triangle) on the cell surface leads to dimerization of two receptors and phosphorylation at the tyrosine kinases, with intracellular activation of Grb2 and then Sos. Canonical activation of Ras leads to downstream activation of Rad, Raf, and MKK (mitogen-activated protein kinase kinase). It also leads, directly and indirectly through Ras, to generation of 3′-phosphoinositides, with activation of Akt; PTEN opposes the function of PI3K by removing its 3′-phosphate groups. Akt acts on a number of molecules and processes, both by activation (arrowheads) and by inhibition (lines with cross hatches), as indicated to the right of the figure. For our purposes, Akt directly activates mTOR, which is present in two complexes, not depicted here: TORC1 (mTOR bound to Raptor, whose substrates include S6K1 and PRAS40 and which is inhibited by rapamycin and its analogues) and TORC2 (mTOR bound to Rictor). mTOR activates S6K1, as shown, an effect inhibited by rapamycin (in red). As Cloughesy et al. demonstrate, however, this effect may be more complex than previously appreciated, since loss of mTOR activity by rapamycin blockade initiates a loss of negative feedback control on Akt, which may enhance its other growth-promoting effects. Definitions: ASK-1, apoptosis signal-regulating kinase, involved in regulating progression to apoptosis; BAD, the Bcl2 antagonist of cell death, involved in regulating progression to apoptosis; FoxO, forkhead box, involved in transcription and proliferation; GSK3β, glycogen synthase kinase 3-beta, involved in cell metabolism and growth; IKK, IκB kinase; NFκB, nuclear factor κB; PIP2, phosphatidylinositol-3,4-biphosphate; PIP3, phosphatidylinositol-3,4,5-triphosphate; TSC2, tuberous sclerosis complex 2.

Figure 3. A Schematic Representation of the Potential for Novel Molecular Modeling of Human Cancer Therapy

One potential paradigm is illustrated. Other methods and paradigms are possible.