Toward a rational combinaTORial therapy for multiple myeloma

Comment on Frost et al, page 4181, and comment on Raje et al, page 4188

The phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) signaling pathway regulates growth and survival in multiple myeloma (MM) in vitro. Of the many substrates regulating caspase activity and apoptosis downstream of Akt, the mammalian target of rapamycin, mTOR, has been thought to act as a special survival checkpoint kinase in several cell types. In 2 articles appearing in this issue of Blood, such a function has now been ascribed to mTOR also in MM cells in vivo.

Multiple myeloma (MM) is genetically and clinically a highly heterogeneous disease characterized by the expansion of slow-growing, and relatively apoptosis-insensitive, malignant plasma cells in the bone marrow.¹  The bone marrow microenvironment provides growth stimulatory signals (eg, insulin-like growth factor-1 [IGF-1] and interleukin-6 [IL-6]) to the tumor cells. Molecules within the IGF-I receptor (IGF-IR)/phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) signaling pathway, regulating preferentially survival/death, may therefore serve as important targets for therapy.

mTOR is a protein Ser-Thr kinase with key substrates involved in protein synthesis.²  Although the antineoplastic effect of rapamycin was known 20 years ago, the discovery of mTOR unleashed its potential anticancer activities. Previous in vitro studies have indicated its therapeutic potential in MM, and suggested that the constant or elevated Akt activity may be a major predictor of sensitivity to mTOR inhibitors.^3-5 

Frost and colleagues now confirm their previous findings in vitro and show that the rapamycin ester analog CCI-779 induces significant reduction of subcutaneous growth of MM cell lines in a mouse immunodeficiency model. The finding of induced apoptosis was somewhat surprising, since exposure to CCI-779 in vitro has only cytostatic effects. A possible explanation for this finding is an indirect angiogenic effect of CCI-779. The correlation between phosphatase and tensin homolog deleted on chromosome ten (PTEN) mutations, increased Akt activity, and high sensitivity to mTOR inhibitors observed in vitro turned out to be valid also in their mouse model of MM. The PTEN-mutated cell line was considerably more sensitive to CCI-779. However, 3 to 4 weeks after treatment, approximately 75% of the tumors reappeared and grew regardless of PTEN status.FIG1 

A parallel paper by Raje and colleagues in this issue of Blood supports the notion that anticancer therapy will be more effective when drugs are combined rationally to target distinct apoptosis-inducing signaling pathways. CC-5013 (Revlimid), a thalidomide analog, and rapamycin displayed synergistic antitumor effects in vitro. The clinical benefit of this combinatorial treatment is obviously that the combination of rapamycin and CC-5013, in contrast to the cytostatic effects observed by rapamycin alone, induces apoptosis at doses well below those pharmacologically achievable in vivo. Further implicating its in vivo potential, this treatment may override drug resistance and growth advantage conferred by multiple factors provided by the bone marrow environment. The specific downstream effectors of rapamycin- and CC-5013-induced apoptosis are, however, not fully detailed. One plausible and very attractive mechanism is that the combinatorial treatment targets survival pathways activated in parallel by one or several growth factors.

Although mTOR inhibitors have shown promising effects in preclinical studies, CCI-779 treatment has so far resulted in only modest responses in phase 2 studies, and have not yet been performed in MM. The clinical benefit of a combinatorial treatment was also recently suggested by the finding that rapamycin combined with conventional drugs (ie, dexamethasone, doxorubicin, or melphalan) induced apoptosis in MM cell lines and biopsy cells in vitro.³  Taken together, the studies by Frost et al, Raje et al, and Stromberg et al³  suggest that successful future treatment regimens of MM should be individualized and include a rational combination of drugs targeting select molecules of predominating survival- and growth-regulatory pathways, genetically deregulated or merely stimulated by the bone marrow microenvironment.