Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia

Figures & data

Table 1. Clinical trials involving inhibitors of PI3K/AKT/mTOR pathway in AML

Target	Agent(s)	Reference or clinicaltrials.gov registry ID	Phase	n	Clinical setting	Efficacy outcome
mTORC1 (rapalog)	Rapamycin (Sirolimus)	Recher et al, 2005	pilot	9		4 w/ at least PR, DOR 28d; 1 SD
		Callera et al, 2008	I	7	Elderly pts with AML transformed from MDS	No responses
		Perl et al, 2009	I	29	c/w MEC	4 CR, 2 PR
		Boehm et al, 2009	pilot	5	5 patients	2 w/ WBC response
		Liesveld et al, 2013	I	13	c/w decitabine	After cycle 1, 4 w/ decline in blasts (1 CR), 4 SD, med OS 4 mo
	Deferolimus	Rizzieri et al, 2008	II	55	Multiple hem CAs (n: 23 AML, 2 MDS)	No AML/MDS responses but SD in 5 pts for 1–3 cycles
	Everolimus	Yee et al, 2006	I/II	27	Multiple hem CAs (n: 9 AML, 5 MDS)	1 pt had hem response
		Park et al, 2013	Ib	28	c/w ‘3+7’; pts in first relapse	19 (68%) CR, med OS 19.5 mo
		NCT00819546	I	—	w/ PKC-412 (FLT3i)	Results awaited
	Temsirolimus	Amadori et al, 2011	II	53	c/w clofarabine	CR/CRi 21%, DFS 3.5 mo, OS 4 mo
AKT	Triciribine	Sampath et al, 2013	I	43	Multiple hem CAs (n: 39 AML, 3 MDS/CMML)	No responses but SD in 17 pts after cycle 1
	MK-2206	Konopleva et al, 2014	II	19	2^nd salvage for R/R AML	No responses except for 1 CRi
	GSK-2141795	NCT01907815	II	—	w/ trametinib (MEKi)	Ongoing trial
	GSK-2141795	NCT00881946	I	—	Multiple hem CAs	Results awaited
	BKM-120	NCT01396499	I	—		Ongoing trial
Dual PI3K/mTOR	BEZ-235	Wunderle et al, 2013	I	22	Multiple hem CAs (n: 11 AML)	SD in 4 AML pts, w/ DOR 4 mo
	BEZ-235	NCT01756118	I	—		Ongoing trial
PI3Kδ	Idelalisib	NCT00710528	I	—	Multiple hem CAs	Results awaited

AML, acute myeloid leukemia; CAs, cancers; CR, complete remission; CRi, complete remission with incomplete blood count recovery; c/w, combined with; DFS, disease free survival; DOR, duration of remission; FLT3i, inhibitor of fms-related tyrosine kinase 3; hem, hematologic; MDS, myelodysplastic syndrome; MEC, mitoxantrone/ etoposide/ cytarabine; mo, months; mTORC, mammalian target of rapamycin complex; n, number of patients; OS, overall survival; PI3K, phosphoinositide 3-kinase; PR, partial remission; pts, patients; R/R, relapsed or refractory; SD, stable disease; w/, with

Figure 1. PIK3/AKT/mTOR signaling pathway in acute myeloid leukemia. Red boxes depict several inhibitors of specific pathway components undergoing preclinical or clinical studies. Dashed lines represent escape mechanisms of cell survival emerging after blockade of mTORC1 and/or mTORC2.