Phase 2 study of weekly bortezomib in mantle cell and follicular lymphoma

Gerecitano, John F.; Portlock, Carol S.; Moskowitz, Craig H.; Hamlin, Paul A.; Straus, David J.; Zelenetz, Andrew D.; Zhang, Zhigang; Dumitrescu, Otilia; Sarasohn, Debra; Lin, Dana T.; Pappanicholaou, Jennifer; Cortelli, Barbara Mac-Gregor; Neylon, Ellen; Hamelers, Rachel; Wright, John J.; O’Connor, Owen A.

doi:10.1111/j.1365-2141.2009.07775.x

Cited by 48 publications

(55 citation statements)

References 14 publications

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“…14 We chose the conventional schedule for this trial because of data suggesting that response rates and clinical activity in lymphoma are highest with the conventional schedule when bortezomib is used as a single agent. 22 A series of 12 patients treated with weekly bortezomib and bendamustine (no rituximab) had results inferior to those observed in our study. 23 In our study, only 17% of patients had grade 3 or 4 neuropathy, which reversed on dose adjustment of bortezomib.…”

Section: Discussioncontrasting

confidence: 80%

The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

Friedberg

Vose

Kelly

et al. 2011

Blood

183

100

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Section: Discussioncontrasting

confidence: 80%

The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

Friedberg

Vose

Kelly

et al. 2011

Blood

183

100

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“…15,16 Most notably, in a phase 3 study in myeloma, clinical outcomes including 3-year progression-free and overall survival were similar between different bortezomib dosing groups (nonrandomized) but with a markedly lower incidence of neuropathy with for weekly dosing versus the traditional schedule. 17,18 Subcutaneous administration of bortezomib appears to be another alternative with reduced neurotoxicity.…”

Section: Discussionmentioning

confidence: 99%

Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia

Blum¹,

Schwind²,

Tarighat

et al. 2012

Blood

125

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“…This agent has been approved for the treatment of mantle cell lymphoma (29,30) and is undergoing extensive testing in other lymphoma subtypes (31)(32)(33)(34)(35)(36)(37). The ability of Bcl-2 to protect from bortezomib-induced apoptosis provides a potential explanation for the recent observation that bortezomib is unable to induce remissions in follicular lymphomas (36), which universally express Bcl-2 at high levels because of the t(14;18) translocation (85,86).…”

Section: Discussionmentioning

confidence: 99%

“…This anti-neoplastic agent is approved for the treatment of multiple myeloma (27,28) and refractory mantle cell lymphoma (29,30) and is being examined in additional lymphoid malignancies (31)(32)(33)(34)(35)(36)(37). The events leading from bortezomib-induced proteasome inhibition (38) to the unfolded protein response and subsequent cell death in highly secretory myeloma cells are well established (39,40).…”

mentioning

confidence: 99%

Noxa/Bcl-2 Protein Interactions Contribute to Bortezomib Resistance in Human Lymphoid Cells

Smith

Dai²,

Correia³

et al. 2011

Journal of Biological Chemistry

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Previous studies have suggested that the BH3 domain of the proapoptotic Bcl-2 family member Noxa only interacts with the anti-apoptotic proteins Mcl-1 and A1 but not Bcl-2. In view of the similarity of the BH3 binding domains of these anti-apoptotic proteins as well as recent evidence that studies of isolated BH3 domains can potentially underestimate the binding between full-length Bcl-2 family members, we examined the interaction of full-length human Noxa with anti-apoptotic human Bcl-2 family members. Surface plasmon resonance using bacterially expressed proteins demonstrated that Noxa binds with mean dissociation constants (K D ) of 3.4 nM for Mcl-1, 70 nM for Bcl-x L , and 250 nM for wild type human Bcl-2, demonstrating selectivity but not absolute specificity of Noxa for Mcl-1. Further analysis showed that the Noxa/Bcl-2 interaction reflected binding between the Noxa BH3 domain and the Bcl-2 BH3 binding groove. Analysis of proteins expressed in vivo demonstrated that Noxa and Bcl-2 can be pulled down together from a variety of cells. Moreover, when compared with wild type Bcl-2, certain lymphoma-derived Bcl-2 mutants bound Noxa up to 20-fold more tightly in vitro, pulled down more Noxa from cells, and protected cells against killing by transfected Noxa to a greater extent. When killing by bortezomib (an agent whose cytotoxicity in Jurkat T-cell leukemia cells is dependent on Noxa) was examined, apoptosis was enhanced by the Bcl-2/Bcl-x L antagonist ABT-737 or by Bcl-2 down-regulation and diminished by Bcl-2 overexpression. Collectively, these observations not only establish the ability of Noxa and Bcl-2 to interact but also identify Bcl-2 overexpression as a potential mechanism of bortezomib resistance.Regression of sensitive tumors such as lymphomas after effective chemotherapy is thought to reflect the induction of apoptosis (1). Chemotherapy-induced apoptosis results largely from activation of the mitochondrial or intrinsic apoptotic pathway (2, 3), which is regulated by Bcl-2 family members (4 -8). This group of proteins consists of three functionally distinct subfamilies. The multidomain proapoptotic proteins Bax and Bak oligomerize upon death stimulation to induce mitochondrial outer membrane permeabilization, thereby allowing release of cytochrome c and subsequent caspase activation. Anti-apoptotic family members, including Bcl-2, Bcl-x L , Bcl-w, Mcl-1, and A1, prevent mitochondrial outer membrane permeabilization. Conversely, BH3-only proteins 3 such as Bim, Puma, and Noxa, which share only limited sequence homology with other Bcl-2 family members in a single 15-amino acid region known as the BH3 domain (9), serve as sensors of various cellular stresses and facilitate apoptosis when activated (6, 9 -14).Although it is clear that BH3-only proteins are activated through transcriptional up-regulation or post-translational modification (7, 10), the manner in which these proteins subsequently initiate apoptosis has been controversial. Two models have emerged to explain this process (15,16). The direct a...

show abstract

Phase 2 study of weekly bortezomib in mantle cell and follicular lymphoma

Cited by 48 publications

References 14 publications

The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma

Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia

Noxa/Bcl-2 Protein Interactions Contribute to Bortezomib Resistance in Human Lymphoid Cells

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