by ecancer Science Editor Dr Linda Cairns, European Institute of Oncology

 The PI3K/AKT/mTOR pathway is one of the most frequently dysregulated in cancer, and as a consequence, has become a major focus of interest for therapeutic intervention and drug development. 

However, the complexity of the pathway, as well as its relationship to other survival pathways, present significant challenges for drug development and many key questions still need to be answered.

For example, can the genetic background of tumours predict responses to PI3K/AKT/mTOR pathway inhibitors? How do perturbations in related proteins (e.g. receptor tyrosine kinases, members of the Ras/Raf/MEK/ERK pathway etc.) influence responsiveness to such inhibitors? What is the basis for tumour cell addiction to the PI3K/AKT/mTOR pathway, and how can this phenomenon best be exploited?

It is likely that answers to these questions will be necessary for the promise of PI3K/AKT/mTOR inhibitors to be fully realized. In an educational session at the 2012 AACR in Chicago some of these points were addressed and some promising new agents that affect this pathway were presented.

Jeffrey Engelman (Mass. General) discussed how PI3K signalling affects the growth and survival of tumour cells and how inhibitors of the PI3K signalling cascade, either alone or in combination with other therapeutics, can most effectively be used for the treatment of cancer.

He suggested that drugs targeting the PI3K pathway might most effectively treat cancers when they are used in combination with other targeted therapies, such as MEK inhibitors.

David Solit (MSKCC) used his presentation ‘Genomic complexity and AKT/mTOR-dependence’ to indicate that although effective oncoprotein-targeted therapies have not yet been developed for ovarian cancer the PI3K pathway alterations were common in ovarian tumours which could be sensitive to selective AKT inhibition.

Genetic and functional analysis of ovarian cancer cell lines and tumours indicated that a subset of ovarian tumours is sensitive to AKT inhibition, but the genetic heterogeneity of the disease suggests that effective treatment with AKT pathway inhibitors will require a detailed molecular analysis of each patient's tumour.

Although chemotherapeutic agents induce remissions in a large number of acute myeloid leukaemia (AML) patients, many of them eventually relapse and die.

New approaches for the treatment of AML include effective combinations targeting the PI3K/mTOR signalling pathway.

It now appears possible that a major limitation of the first generation of mTOR inhibitors can be overcome by a new class of catalytic inhibitors of mTOR. 

There is emerging evidence that such compounds target both TORC1 and TORC2 and elicit much more potent responses against early leukemic precursors in vitro.  

In addition, recent studies have shown that combinations of such agents with cytarabine result in enhanced antileukaemic responses in vitro, raising the prospect and potential of use of these agents in combination regimens for the treatment of AML.

Nahum Sonenberg (McGill University) in a ‘meet the expert session’ pinpointed the importance of mTOR-mediated translational control in cancer. Since 1989 it is well known that ribosomes play a critical role in cancer and mounting evidence links deregulated protein synthesis to tumourigenesis; p53 for instance is translationally regulated.

mTOR affects the activity of the translation initiation complex eIF4F which is overexpressed in many cancers, by phosphorylating eIF4E binding proteins. Inhibition of mTOR by rapamycin (sirolimus) and more potent rapamycin analogues (rapalogues), such as everolimus, temsirolimus and deforolimus all retard cancer growth.

Cancers that are sensitive to rapamycin contain mutations in negatively regulators mTOR and these mutations have been shown to increase eIF4F formation and consequently to enhanced translation initiation and cell growth.

Thus, inhibition of translation initiation through targeting the mTOR-signalling pathway is emerging as a promising therapeutic option. New catalytic inhibitors such as Torin inhibit both TORC1 and TORC2 and are under investigation.

A study from the MD Anderson Cancer Center linked four proteins involved in translation with poor prognosis in breast cancer.

All of these translational proteins are regulated by the PI3K/mTOR molecular signalling pathway.

"Cancer cells need a lot of protein synthesis to grow and survive," Meric-Bernstam said. She and colleagues systematically analysed several major translation-regulating proteins in tumours from 190 patients with stage 1 to stage 3 hormone receptor-positive breast cancer. Median follow-up was 96 months. These data underline the importance of the PI3K/mTOR pathway also in hormone receptor-positive breast cancer and could lead to potential new prognostic factors and therapeutic targets.

Study info:

Presenter: Funda Meric-Bernstam, M.D.

Abstract Number: CT-03

Title: Aberrations in translational regulation are associated with poor prognosis in hormone receptor-positive breast cancer.

Author Block: Funda Meric-Bernstam1, Huiqin Chen1, Argun Akcakanat1, Kim-Anh Do1, Ana Lluch2, Bryan Hennessy3, Gabriel Hortobagyi1, Gordon Mills1, Ana Gonzalez-Angulo1. 1UT M.D. Anderson Cancer Ctr., Houston, TX; 2Hospital Clinico Universitario de Valencia, Valencia, Spain; 3Beaumont Hospital, Dublin, Ireland.

Purpose: Translation initiation is activated in cancer through increase in eukaryotic initiation factor 4E (eIF4E), eIF4G, phosphorylated eIF4E-binding protein (p4E-BP1) and ribosomal protein S6 (pS6), and decreased programmed cell death protein 4 (pdcd4), a translational inhibitor. Further, translation elongation is deregulated though alterations in eukaryotic elongation factor 2 (eEF2) and eEF2 kinase (eEF2K). We sought to determine the association of these translational aberrations with clinical-pathologic factors and survival outcomes in hormone receptor-positive breast cancer.

Methods: Primary tumors were collected from 190 patients with stage I-III hormone receptor-positive breast cancer. Expression of eIF4E, eIF4G, 4E-BP1, p4E-BP1 T37/46, p4E-BP1 S65, p4E-BP1 T70, S6, pS6 S235/236, pS6 S240/244, pdcd4, eEF2 and eEF2K was assessed by reverse phase protein arrays.: Univariable and multivariable analyses for recurrence-free survival (RFS) and overall survival (OS) were performed.

Results: High eEF2, S6, pS6 S240/244, p4E-BP1 T70, and low pdcd4 were significantly associated with node-positivity. Median follow-up for alive patients was 96 months. High p4E-BP1 T36/47, p4E-BP1 S65, p4E-BP1 T70 and 4E-BP1 were associated with worse RFS. High p4E-BP1 T70 and pS6 S235/236, and low pdcd4, were associated with worse OS. In multivariable analysis, in addition to positive nodes, p4E-BP1 S65 remained a significant predictor of RFS (HR=1.62, 95%CI=1.13-2.31; P=0.008). In addition to age, pS6 S235/236 (HR=1.73, 95%CI=1.03-2.90, P=0.039), eEF2K (HR=2.19, 95%CI=1.35-3.56, P=0.002) and pdcd4 (HR=0.42, 95%CI=0.25-0.70, P=0.001) were associated with OS.

Conclusions: Increased pS6, p4E-BP1, eEF2K and decreased pdcd4 are associated with poor prognosis in hormone receptor-positive breast cancer; suggesting their role as prognostic markers and therapeutic targets.