Temsirolimus in the treatment of relapsed and/or refractory mantle cell lymphoma

Figures & data

Figure 1 mTOR as central regulator of the cell nutrition and growth. Conditions outside of the cell, such as nutrient and energy levels, growth factors, hormones, and stressful conditions, control the mTOR activation. After activation, mTOR stimulates cell growth, increases angiogenesis, and responds to bioenergetics necessities.

Figure 2 mTOR upstream pathway. Amino acid, glucose levels, growth factors, and genes, such as Bcr-Abl and Ras, induce activation of the PI3K/Akt pathway and consequently of the mTOR. The Akt pathway is inhibited by PTEN and LKB1 through the TSC1–TSC2 complex.

Figure 3 mTOR downstream pathway. mTOR activates the kinase activity of S6K1 and mediates the release of eIF4E translation initiating factor, thus regulating the synthesis of proteins involved in growth, proliferation, survival, angiogenesis, and bioenergetics.

Table 1 In vitro activity of mTOR inhibitors on MCL cell lines: relevant data from literature

Drug	Antiproliferative effect	p27	Akt	Cyclin D1	Cyclin D3	Reference
Rapamycin	G0/G1 arrest	Increased	No change decreased	No change	Decreased	Dal Col et al^Citation48
Rapamycin	G0/G1 arrest			Decreased		Peponi^Citation53
Rapamycin	G0/G1 arrest	No change		No change	Decreased	Hipp et al^Citation54
Temsirolimus			Decreased			Younes^Citation52
Temsirolimus	G0/G1 arrest autophagy	No change	Increased	No change	No change	Yazbeck et al^Citation57
Everolimus	G0/G1 arrest					Haritunians et al^Citation50

Table 2 Temsirolimus in MCL patients: results from clinical trials

Schedule	No. of patients	Overall response	Complete response	Median overall survival	Median progression-free survival	Reference
Temsirolimus 250 mg/wk	35	38%	3%	12 mo	6.5 mo	Witzig et al^Citation76
Temsirolimus 25 mg/wk	29	41%	3.7%	14 mo	6 mo	Ansell et al^Citation78
Temsirolimus 175-75 vs 175–25 vs chosen therapy	162	22% vs 6% vs 2%		11.1 mo vs 8.8 mo vs 9.5 mo	7.4 mo vs 3.4 mo vs 1.6 mo	Hess et al^Citation79
Temsirolimus 25 mg/wk + rituximab 4×	71	48%	20%		9.5 mo	Ansell et al^Citation81

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