A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas

Kim, Seung Ju; Shin, Dong‐Yeop; Kim, J.S.; Yoon, Dok Hyun; Lee, W.S.; Lee, H.; Do, Young-Rok; Kang, Hye Jin; Eom, Hyeon-Seok; Ko, Young Hyeh; Lee, S.H.; Yoo, Hae Young; Hong, Mineui; Suh, Cheolwon; Kim, Woo Seob

doi:10.1093/annonc/mdv624

Cited by 45 publications

(25 citation statements)

References 23 publications

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“…In a randomized phase II study to compare the effects of monotherapy with vinorelbine, which disrupts microtubules, versus combined vinorelbine and everolimus for second-line chemotherapy in advanced HER2-negative breast cancer, the combined therapy was not superior to the monotherapy, although the treatment was well tolerated [270]. In a phase II study of everolimus in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) as a first-line treatment for patients with peripheral T-cell lymphoma, the treatment was efficacious [271]. Immunohistochemistry revealed maintenance of PTEN expression among patients displaying a complete response.…”

Section: Combining Mtor Inhibition With Conventional Chemotherapies Amentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

172

128

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Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

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Section: Combining Mtor Inhibition With Conventional Chemotherapies Amentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

172

128

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“…The ORR was 90% with CR in 17 patients and PR in 10 patients. Interestingly, the efficacy was associated with loss of PTEN [65]. We investigated the salvage chemotherapy using gemcitabine, dexamethasone, and cisplatin (GDP) for patients with relapsed or refractory PTCL (CISL 1003).…”

Section: Ptcl and Other Subtypes Of T-cell Neoplasmsmentioning

confidence: 99%

Lymphoma epidemiology in Korea and the real clinical field including the Consortium for Improving Survival of Lymphoma (CISL) trial

Yoo

Lee²,

Suh

et al. 2018

Int J Hematol

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Lymphomas are a heterogeneous group of disease entities with well-defined clinical, morphological, immunophenotypic, and cytogenetic characteristics. Moreover, regional and racial differences have been reported in their incidence and subtype compositions. Here, we reviewed the epidemiology of lymphomas and summarized the recent achievements in specific subtypes prevalent in Korean population, focusing on clinical studies conducted by the Consortium for Improving Survival of Lymphoma (CISL) of the Korean Society of Hematology Lymphoma Working Party (KSH-LWP).

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“…Recently a phase I/II study on everolimus and alemtuzumab has been published but the authors concluded that results were not sufficiently efficacious (33% PR, no CR) to recommend further development of this regimen (Zent et al, 2016). Immunohistochemistry was used to evaluate the expression of PTEN and pS6K as a marker of response and the difference in CR rate among different subtypes was probably linked to PTEN loss (Kim et al, 2016). Thirty patients received everolimus for six cycles or until dose-limiting toxicity or progression.…”

Section: Lymphomasmentioning

confidence: 99%

“…Positive results (90% objective response) have also been shown in T-cell lymphoma when everolimus (5 mg/day from day 1-14) was combined with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). Immunohistochemistry was used to evaluate the expression of PTEN and pS6K as a marker of response and the difference in CR rate among different subtypes was probably linked to PTEN loss (Kim et al, 2016). Adding temsirolimus to rituximab in a phase II study in Rel/Ref MCL patients produced an ORR of 59%, with 19% CR .…”

Section: Lymphomasmentioning

confidence: 99%

m‐TOR inhibitors and their potential role in haematological malignancies

Calimeri

Ferreri

2017

Br J Haematol

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It is widely demonstrated that the PI3K-AKT-mTOR signalling is critical in normal myeloid and lymphoid development and function. Thus, it is not strange that this pathway is often deregulated in haematological tumours, providing a strong preclinical rationale for the use of drugs targeting the PI3K-AKT-mTOR axis in haematological malignancies. The main focus of this review is to examine the mammalian target of rapamycin (mTOR, also termed mechanistic target of rapamycin [MTOR]) signalling pathways and to provide a brief overview of rapalogs and second-generation mTOR inhibitors used to target its aberrant activation in cancer treatment. We will also discuss the results obtained with the use of these agents in patients with acute leukaemia, Hodgkin lymphoma, non-Hodgkin lymphomas, multiple myeloma and Waldenström macroglobulinaemia. Ongoing clinical trials in haematological malignancies that are investigating first- and second-generation mTOR inhibitors as single agents and as components of combination regimens are also presented.

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A phase II study of everolimus (RAD001), an mTOR inhibitor plus CHOP for newly diagnosed peripheral T-cell lymphomas

Abstract: The everolimus plus CHOP was effective for PTCL patients, and its efficacy might be related with the preservation of PTEN.

Cited by 45 publications

References 23 publications

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Lymphoma epidemiology in Korea and the real clinical field including the Consortium for Improving Survival of Lymphoma (CISL) trial

m‐TOR inhibitors and their potential role in haematological malignancies

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