Multiple Myeloma Treatment Strategies with Novel Agents in 2011: A European Perspective

Ludwig, Heinz; Beksaç, Meral; Bladé, Joan; Cavenagh, Jamie; Cavo, Michèle; Delforge, Michel; Dimopoulos, Meletios Α.; Drach, Johannes; Einsele, Hermann; Façon, Thierry; Goldschmidt, Hartmut; Harousseau, Jean Luc; Hess, U.; Kropff, Martin; Costa, Fernando Leal da; Louw, Vernon; Magen-Nativ, Hila; Mendeleeva, Larisa; Nahi, Hareth; Plesner, Torben; Miguel, Jesús F. San; Sonneveld, Pieter; Udvardy, Miklós; Sondergeld, Pia; Palumbo, Antônio

doi:10.1634/theoncologist.2010-0386

Cited by 26 publications

(28 citation statements)

References 81 publications

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“…31 Interestingly, bortezomib, a reversible inhibitor of the 26S proteasome, is at present a valuable option for the first-line treatment of multiple myeloma. 32 Thus, characterization of TRAP1, a chaperone upregulated in about 60% of human CRCs, 5 as a protein involved in quality control and in protection against apoptosis in cancer cells provides a strong rationale for considering this network as a novel molecular target for treatment of human CRC.…”

Section: Resultsmentioning

confidence: 99%

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

et al. 2011

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Tumor necrosis factor receptor-associated protein-1 (TRAP1) is a mitochondrial (MITO) antiapoptotic heat-shock protein. The information available on the TRAP1 pathway describes just a few well-characterized functions of this protein in mitochondria. However, our group's use of mass-spectrometric analysis identified TBP7, an AAA-ATPase of the 19S proteasomal subunit, as a putative TRAP1-interacting protein. Surprisingly, TRAP1 and TBP7 colocalize in the endoplasmic reticulum (ER), as demonstrated by biochemical and confocal/electron microscopic analyses, and interact directly, as confirmed by fluorescence resonance energy transfer analysis. This is the first demonstration of TRAP1's presence in this cellular compartment. TRAP1 silencing by short-hairpin RNAs, in cells exposed to thapsigargin-induced ER stress, correlates with upregulation of BiP/Grp78, thus suggesting a role of TRAP1 in the refolding of damaged proteins and in ER stress protection. Consistently, TRAP1 and/or TBP7 interference enhanced stress-induced cell death and increased intracellular protein ubiquitination. These experiments led us to hypothesize an involvement of TRAP1 in protein quality control for mistargeted/misfolded mitochondria-destined proteins, through interaction with the regulatory proteasome protein TBP7. Remarkably, expression of specific MITO proteins decreased upon TRAP1 interference as a consequence of increased ubiquitination. The proposed TRAP1 network has an impact in vivo, as it is conserved in human colorectal cancers, is controlled by ER-localized TRAP1 interacting with TBP7 and provides a novel model of the ER-mitochondria crosstalk. Tumor necrosis factor receptor-associated protein-1 (TRAP1) was initially identified as a TNF-receptor-associated protein and is a member of the heat-shock protein-90 (HSP90) chaperone family. 1,2 Through an mRNA-differential display analysis between oxidant-adapted and control osteosarcoma cells, our group identified, among other proteins, TRAP1, whose expression was highly induced upon oxidant adaptation. 3 Furthermore, TRAP1 showed antioxidant and antiapoptotic functions, 4 while an involvement of this mitochondrial (MITO) chaperone in the multi-drug resistance of human colorectal carcinoma (CRC) cells was also established. 5 Little is known about TRAP1 signal transduction: the first most important finding on TRAP1 function came from studies by the Altieri's group, which identified TRAP1 as a member of a cytoprotective network selectively active in the mitochondria of tumor tissues. 6 The same group has recently proposed TRAP1 as a novel molecular target in localized and metastatic prostate cancer, 7 and is now involved in a promising preclinical characterization of mitochondria-targeted smallmolecule HSP90 inhibitors. 8,9 Besides some well-characterized TRAP1 functions in mitochondria, during preparation of this manuscript it was reported that interference by HSP90 chaperones triggers an unfolded protein response (UPR) and activates autophagy in the mitochondria of tumor cells. 10 A put...

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Section: Resultsmentioning

confidence: 99%

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

et al. 2011

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“…Therefore, we support the concept of the early use of novel agents such as bortezomib and lenalidomide in MM patients with high-risk disease. 31 We and others have shown that bortezomib and lenalidomide are active in MM, including patients with high-risk chromosomal aberrations such as del(17p13) and t(4;14). 7,32 In addition, thalidomide seems to be a treatment option for patient with standard-risk cytogenetics.…”

Section: Discussionmentioning

confidence: 97%

Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p

Neben

Lokhorst

Jauch

et al. 2012

Blood

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326

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In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For all analyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P ‫؍‬ .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P ‫؍‬ .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P < .0001) and OS (P < .0001) in arm A, whereas no statistically significant effect on PFS (P ‫؍‬ .28) or OS (P ‫؍‬ .12) was seen in arm B. In conclusion, the adverse impact of del (17p13)

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“…Depending on the initial response, treatment-free interval, drugrelated toxicities and the general condition of the patients, one can choose to retreat with the initial regimen, or to switch drug classes. For instance, a patient initially treated with bortezomib can switch to lenalidomide, and vice versa [19]. The odyssey of myeloma drug discovery is still ongoing with newer agents in several phases of clinical development.…”

Section: When Relapse Occursmentioning

confidence: 99%

Multiple Myeloma Treatment in the Elderly

Delforge

2013

Int. J. Hematol. Oncol.

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Multiple Myeloma Treatment Strategies with Novel Agents in 2011: A European Perspective

Cited by 26 publications

References 81 publications

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

TRAP1 and the proteasome regulatory particle TBP7/Rpt3 interact in the endoplasmic reticulum and control cellular ubiquitination of specific mitochondrial proteins

Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p

Multiple Myeloma Treatment in the Elderly

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