Activity of single agent temsirolimus (CCI-779) in non-mantle cell non-Hodgkin lymphoma subtypes

Smith, S. M.; Pro, Barbara; Cisneros, Angela; Smith, Scott E.; Stiff, Patrick J.; Lester, Eric P.; Modi, Sanjiv; Dancey, Janet; Vokes, E.; Besien, Koen van

doi:10.1200/jco.2008.26.15_suppl.8514

Cited by 24 publications

(19 citation statements)

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“…37 This reduced the thrombocytopenia to 39% and produced equal response (41% vs 38%) and DOR (6.0 months vs 6.9 month) as the greater dose. Temsirolimus also has activity in non-MCL as shown by Smith et al, 38 with 40% OR, 15% CR, and 26% PR.…”

Section: Akt Inhibitorsmentioning

confidence: 95%

Novel therapeutic agents for B-cell lymphoma: developing rational combinations

Reeder

Ansell

2011

Blood

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Several novel targeted therapies have recently emerged as active in the treatment of non-Hodgkin lymphoma, including small molecules that inhibit critical signaling pathways, promote apoptotic mechanisms, or modulate the tumor microenvironment. Other new agents target novel cell surface receptors or promote DNA damage. Although most of these drugs have single-agent activity, none have sufficient activity to be used alone. This article reviews the utility and potential role of these new agents in the treatment of non-Hodgkin lymphoma with a specific focus on data that highlight how these agents may be incorporated into current standard treatment approaches.

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Section: Akt Inhibitorsmentioning

confidence: 95%

Novel therapeutic agents for B-cell lymphoma: developing rational combinations

Reeder

Ansell

2011

Blood

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“…17,24 Additional trials of temsirolimus have produced similar results in relapsed follicular NHL and DLBCL. 25 Preliminary results using oral everolimus have demonstrated that approximately 30% of patients with relapsed DLBCL respond 7 ; the ORR is higher, at 40%, for MCL, Waldenström macroglobulinemia, 26 and Hodgkin disease. 27,28 These single-agent trials have provided proof-of-concept that mTOR inhibition can produce antitumor responses in relapsed lymphoma.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of histone deacetylase overcomes rapamycin-mediated resistance in diffuse large B-cell lymphoma by inhibiting Akt signaling through mTORC2

Gupta

Ansell

Novak

et al. 2009

Blood

150

161

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The mammalian target of rapamycin (mTOR) has emerged as an important therapeutic target for diffuse large B-cell lymphoma (DLBCL), as recent studies have demonstrated that 30% of relapsed patients respond to mTOR inhibitors. Why some lymphomas are resistant is incompletely understood. In the present study, we demonstrated that rapamycin inhibits mTORC1 in DLBCL lines and primary tumors but is minimally cytotoxic. Subsequent investigations revealed that rapamycin also activated eIF4E and the mTORC2 target Akt, suggesting a potential mechanism of rapamycin resistance. IntroductionDiffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma (NHL), is the most common type of lymphoma in the United States. With rituximab-based chemoimmunotherapy such as rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, approximately 60% of DLBCL patients are cured. 1,2 Salvage chemotherapy followed by stem cell transplantation is able to produce durable remissions in a minority of relapsed patients, and improved therapy is required for those who relapse after second-line treatment.Because deregulation of the PI3 kinase (PI3K)/mTOR pathway occurs in many human diseases, 3,4 targeting the mTOR pathway with small molecule inhibitors has become an intense area of research. Key components of this pathway, including Akt and mTOR, regulate cell growth and survival. 5 The mTOR kinase exists as 2 complexes. The rapamycin-sensitive mTOR complex 1 (mTORC1 or raptor/mTOR), consists of mTOR, raptor, and mLST8. mTORC1 regulates translation initiation through 2 distinct pathways: ribosomal p70 S6 kinase (p70S6K) and eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). In one pathway, mTORC1 phosphorylates and activates the ribosomal protein S6. In the second pathway, mTORC1 directly phosphorylates 4E-BP1 causing its dissociation from the translation initiation factor eIF4E. This allows eIF4E to stimulate cap-dependent RNA translation. In the absence of mTORC1 activation, 4EBP1 binds tightly to eIF4E, preventing it from binding to 5Ј-capped mRNA. 6 The mTOR complex 2 (mTORC2 or rictor/mTOR), which contains mTOR, rictor, and mLST8, is rapamycin insensitive and functions to regulate the survival kinase Akt by phosphorylation of serine 473. 5 Recent clinical trials of the mTORC1 inhibitors temsirolimus and everolimus, both analogues of the parent compound rapamycin, have demonstrated overall response rates (ORRs) of approximately 30% for relapsed DLBCL. 7 This single-agent activity of mTOR inhibitors in heavily pretreated DLBCL patients highlights the importance of the PI3K/mTOR pathway in these cells. To exploit the sensitivity of lymphomas to mTOR inhibitors through effective therapies, it is important to understand the mechanistic basis for resistance of DLBCL to mTOR inhibition.Histone deacetylase inhibitors (HDIs) have emerged as a potentially promising new class of anticancer drugs. The inhibition of histone deacetylases (HDACs) by HDIs results in increased gene-specific his...

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“…Temsirolimus yielded a 22% overall response rate (ORR, which represents complete or partial responses divided by the number of patients treated) in a phase III trial for refractory mantle cell lymphoma, in contrast to only 2% for investigator's choice of therapy (73). Similarly, rapalogs showed single-agent activity against other types of lymphomas (74)(75)(76) and are being evaluated in phase II trials for sarcomas, endometrial cancers, and other advanced solid tumors (77)(78)(79). For example, a recent phase I study of everolimus showed promise in patients with advanced colorectal cancer (80).…”

Section: Rapamycin and Rapalogs As Anticancer Therapiesmentioning

confidence: 99%