Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3

Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock AR, USA.
Blood (Impact Factor: 10.45). 05/2011; 118(13):3512-24. DOI: 10.1182/blood-2010-12-328252
Source: PubMed


Gene expression profiling (GEP) of purified plasma cells 48 hours after thalidomide and dexamethasone test doses showed these agents' mechanisms of action and provided prognostic information for untreated myeloma patients on Total Therapy 2 (TT2). Bortezomib was added in Total Therapy 3 (TT3), and 48 hours after bortezomib GEP analysis identified 80 highly survival-discriminatory genes in a training set of 142 TT3A patients that were validated in 128 patients receiving TT3B. The 80-gene GEP model (GEP80) also distinguished outcomes when applied at baseline in both TT3 and TT2 protocols. In context of our validated 70-gene model (GEP70), the GEP80 model identified 9% of patients with a grave prognosis among those with GEP70-defined low-risk disease and 41% of patients with favorable prognosis among those with GEP70-defined high-risk disease. PMSD4 was 1 of 3 genes common to both models. Residing on chromosome 1q21, PSMD4 expression is highly sensitive to copy number. Both higher PSMD4 expression levels and higher 1q21 copy numbers affected clinical outcome adversely. GEP80 baseline-defined high risk, high lactate dehydrogenase, and low albumin were the only independent adverse variables surviving multivariate survival model. We are investigating whether second-generation proteasome inhibitors (eg, carfilzomib) can overcome resistance associated with high PSMD4 levels.

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Available from: Saad Z Usmani, Dec 28, 2015
    • "Orlandi et al., evaluated the association between VEGF-A sequence variants and prostate-specific antigen progression, progression-free survival and overall survival, in advanced castration-resistant prostate cancer patients treated with metronomic CPA (CTX), celecoxib and dexamethasone.[39] Pharmacogenomics of bortezomib has been investigated by John D. Shaughnessy et al.[40] In another study, Mercurio et al., have quantified the expression of several genes (ICAM1, CRK, CD36 and IQGAP1) by reverse transcriptase quantitative polymerase chain reaction in pilocytic astrocytomas and glioblastomas. "
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    • "Finally and most importantly, the so-called predictive classification should be able to estimate individual outcome of a specific therapeutic intervention and allow for selection and elimination of specific drugs. The UAMS group has reported post drug genomic data identifying patterns associated with drug specific responses [32], [33] and in our ongoing process we have planned pharmacogenetic microdosis studies for specific drugs [34]–[36]. Such data, in parallel with the present programme, are expected to evolve into a useful drug specific and predictive classification system. "
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