Pharmacological inhibition of PI K

Pharmacological inhibition of PI3Kα induces apoptosis of CLL glut1 in vitro [5,18], and inhibits CLL migration towards CXCL12 [5]. The PI3Kα/δ inhibitor copanlisib induces significantly greater apoptosis of CLL cells compared to idelalisib (IC50 of 450nM and >10μM, respectively) in vitro and is currently being assessed in phase II clinical trials for a number of haematological malignancies including CLL [19]. In addition, the pan-PI3K inhibitor NVP-BKM120 showed significantly greater cytotoxicity towards CLL cells than idelalisib (IC50 10μM vs. 40μM, respectively) [20], indicating that other PI3K isoforms may, at least in part, compensate for PI3Kδ inhibition in terms of CLL survival. Results from a phase I clinical trial using the pan-PI3K inhibitor pilaralisib with 10 CLL patients showed an acceptable safety profile with lymph node shrinkage (≥50%) in 60% patients and progression free survival (≥6 months) in 70% of patients [21]. However, it remains to be seen whether pan-PI3K inhibition improves clinical response over PI3Kδ inhibition alone in a larger patient cohort.
Pan-PI3K/mTOR inhibition as a potential therapeutic option in CLL mTOR is crucial for cellular proliferation and is an attractive therapeutic target; however the use of selective mTOR inhibitors is hampered by disruption of negative feedback mechanisms via S6 kinase and mTORC2 and subsequent over-activation of PI3K and AKT, respectively (Fig. 1B). Dual PI3K/mTOR inhibitors may overcome this effect by directly inhibiting mTOR and preventing over-activation of AKT via simultaneous inhibition of PI3K. mTOR can also be activated by MAPK mediated signalling, therefore the inhibition of PI3K in combination with inhibition of mTOR may lead to greater suppression of this pro-survival pathway than PI3K inhibition alone. This is demonstrated by a disconnect between PI3K/AKT activity and phosphorylation of the mTOR target 4E-BP1 in CLL [22], which indicates that inhibition of PI3K alone would not achieve maximal inhibition of mTOR mediated signalling. Indeed, CLL cells treated in vitro with the dual PI3K/mTOR inhibitor PF-04691502 or idelalisib plus mTOR inhibitor everolimus, underwent significantly greater apoptosis compared to PI3Kδ or mTOR inhibition alone [23]. PF-04691502 also inhibited chemotaxis, reduced BCR stimulated signalling/survival and significantly prolonged survival in a murine model of CLL [23]. Various PI3K/mTOR inhibitors are progressing through clinical trials for a number of different cancers and may therefore provide a promising novel treatment strategy for CLL and other B cell malignancies.
Conclusion
Contributions
Introduction Multiple myeloma (MM) is the second most common hematologic malignancy and presents primarily in elderly patients, with a median age at manifestation of approximately 72 years in Europe [1,2]. The number of older patients with this disease is expected to rise over time as a consequence of the increased life expectancy of the normal population. In recent years, the introduction of novel agents such as thalidomide, lenalidomide, and the proteasome inhibitor bortezomib has changed the management of elderly myeloma patients and extended overall survival (OS) times in all age categories supporting the use of modern anti-myeloma therapy independent of age [3,4]. Despite this improvement in OS, MM remains incurable and the majority of patients ultimately relapses and require further therapy. Thus, knowledge of relapse patterns and management of relapsed disease is a critical aspect of MM treatment and an important area of ongoing research [5]. Moreover, the optimal sequence or combination of post relapse therapeutic strategies remains unclear, and information is needed on the efficacy of each treatment, especially in the second-line setting. In this regard, previous reports focused on patients relapsing after conventional chemotherapy or autologous stem cell transplantation [6–8], and such data on elderly patients in the era of novel therapies is limited.