Incorporating Molecular Tools into Early-Stage Clinical Trials

PLoS Medicine, Jan 2008

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

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Incorporating Molecular Tools into Early-Stage Clinical Trials

et al. (2008) Antitumor activity of rapamycin in patients with recurrent PTEN- deficient glioblastoma. PLoS Med 5: e8. doi:10.1371/journal.pmed.0050008 In a phase I trial Charles Sawyers and colleagues investigated the role of rapamycin in patients with PTEN Incorporating Molecular Tools into Early-Stage Clinical Trials Robert J. Weil 0 1 0 Robert J. Weil is at the Brain Tumor and Neuro- Oncology Center, Department of Neurosurgery and the Neurological Institute, Cleveland Clinic , Cleveland, Ohio , United States of America 1 Abbreviations: EGFR , epidermal growth factor receptor; GBM, glioblastoma; MGMT, methyl guanine methyl transferase; MR, magnetic resonance; mTOR , mammalian target of rapamycin; PI3K , phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TK, tyrosine kinase; TKI, tyrosine kinase inhibitor; UCLA , University of California , Los Angeles - Dand with an accelerating pace uring the past several decades, in the past several years, a primary focus of cancer research and treatment has been the development and refinement of specific, biologically directed therapies [1,2]. A number of attractive targets have been identified, dissected, and validated molecularly and biochemically, including multiple members of the family of receptor tyrosine kinases [1,2]. These potent enzymes, frequently concentrated or overexpressed on the surface of cancer cells, phosphorylate target proteins, with varied and manifold effects on numerous downstream, intracellular signaling pathways, leading to profound alterations in transcription and translation, cell growth, differentiation, apoptosis, angiogenesis, and invasion and metastatic potential [1,2]. A number of small molecular inhibitors of these tyrosine kinases (TKs) have been developed in recent years. Imatinib, for example, has shown impressive activity in many patients with chronic myelogenous leukemia [3,4]. The success of imatinib in human trials, and subsequent work in the laboratory and the clinic in several other cancers in which TKs appear causative and where TK inhibitors (TKIs) appeared likely to be efficacious, spurred a great deal of interest and enthusiasm throughout the oncologic community [1,2]. This was equally true in neuro-oncology, where progress in treating patients with malignant gliomas, especially glioblastoma (GBM), has been slow and incremental [47]. Treating Glioblastomas GBM is an aggressive, primary tumor of the central nervous system [8]. Because of their intrinsic, infiltrative Research in Translation discusses health interventions in the context of translation from basic to clinical research, or from clinical evidence to practice. nature, GBMs follow a malignant clinical course. Classified as World Health Organization grade IV astrocytic tumors, GBMs have a pronounced mitotic activity, substantial tendency toward neoangiogenesis (microvascular proliferation), necrosis, and proliferative rates three to five times higher than grade III tumors, the anaplastic astrocytomas. The clinical behavior of GBMs is often mimicked by unusual pathological presentations, which gave rise to the old moniker of glioblastoma multiforme (Figure 1). Even with the survival advantage provided by the recently developed protocol of concurrent chemoradiation followed by adjuvant alkylating chemotherapy with temozolomide (the Stupp regimen), the prognosis of patients with GBM remains poor, with median overall survival in the range of 915 months and two-year survival rates of 26% in the most favorable subgroup [9]. Several common genetic alterations, such as EGFR (epidermal growth factor receptor) amplifications on chromosome 7p, as well as losses on 9p (p16), 10q (PTEN, or phosphatase and tensin homolog deleted on chromosome 10), and 17p (p53) have been identified in a significant proportion of patients with malignant gliomas (reviewed thoroughly in [8]). Two clinically recognized forms of GBM, de novo or primary and secondary or progression, have been identified clinically and recapitulated at the molecular genetic level [8]. In de novo or primary GBMs, EGFR gene amplifications, often combined with gene rearrangements that lead to a constitutively active, truncated receptor (the most common is EGFRvIII), occur in GBMs that generally express wildtype p53 [8,1016]. In secondary tumors, progression from a low-grade glioma to a GBM involves the serial accumulation of genetic alterations that inactivate tumor suppressor genes such as p53, p16, Rb, and PTEN, or activate oncogenes such as MDM2 and CDKs 4 and 6; alterations in EGFR are less common or absent [8]. Frequently, loss of PTEN function is a common feature in both types of GBMs [8]. Response to chemotherapy may be modified by the level of expression of methyl guanine methyl transferase (MGMT) [9]. MGMT hypermethylation decreases production of MGMT, which leads to a diminished ability to repair DNA damage caused by an alkylating agent; Competing Interests: T (...truncated)


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Robert J Weil. Incorporating Molecular Tools into Early-Stage Clinical Trials, PLoS Medicine, 2008, Volume 5, Issue 1, DOI: 10.1371/journal.pmed.0050021