Mantle Cell Lymphoma
Mantle Cell Lymphoma
Several drugs currently being explored in phase I and II studies are showing exquisite promise in MCL. One particularly promising approach has focused on disruption of B-cell receptor downstream signaling. Two agents are notable in this regard: PCI37625 and CAL-101. Administration of PCI37625 leads to targeted inhibition of Bruton's tyrosine kinase and so far is showing an overall response rate of 67%. CAL-101 is targeted to the specific isoform of phosphatidylinositol 3-kinase delta and has shown an overall response rate of 62%. Interestingly, both agents are associated with lymphocytosis, suggesting that inhibition of this pathway may be associated with disruption of microenvironment, perhaps via secondary influences on CXCR4 signaling. The failure of temsirolimus to produce dramatic responses has fostered further preclinical study showing that MCL may escape MTORC1 inhibition via increasing signaling through MTORC2 and phopshorylation of AKT, a survival pathway. This has led to the development of several dual MTORC inhibitors, including OSI-027 and PP242, both of which are currently in phase I clinical testing.
Given that overexpression cyclin D1 is central to pathogenesis of MCL, current studies are also under-way to inhibit this molecule. Interestingly, targeted disruption of cyclin D1 was associated with increased signaling via cyclin D2 and cyclin D3 in preclinical models. Therefore, research has been focused on inhibiting downstream targets of cyclin D1. One such novel agent is PD0332991, which targets cyclin-dependent kinases 4 and 6 to effectively inhibit proliferation in MCL. Clinical studies using this as a single agent have shown an overall response rate of 18% in relapsed cases. Although this response rate was lower than expected, subsequent pharmacodynamic studies demonstrated significant inhibition of cell cycling. This has fueled an alternative approach, currently under study, in which PD0332991 is administered to coordinate cell cycling in order to facilitate enhanced sensitivity to the agent bortezomib.
Emerging Agents
Several drugs currently being explored in phase I and II studies are showing exquisite promise in MCL. One particularly promising approach has focused on disruption of B-cell receptor downstream signaling. Two agents are notable in this regard: PCI37625 and CAL-101. Administration of PCI37625 leads to targeted inhibition of Bruton's tyrosine kinase and so far is showing an overall response rate of 67%. CAL-101 is targeted to the specific isoform of phosphatidylinositol 3-kinase delta and has shown an overall response rate of 62%. Interestingly, both agents are associated with lymphocytosis, suggesting that inhibition of this pathway may be associated with disruption of microenvironment, perhaps via secondary influences on CXCR4 signaling. The failure of temsirolimus to produce dramatic responses has fostered further preclinical study showing that MCL may escape MTORC1 inhibition via increasing signaling through MTORC2 and phopshorylation of AKT, a survival pathway. This has led to the development of several dual MTORC inhibitors, including OSI-027 and PP242, both of which are currently in phase I clinical testing.
Given that overexpression cyclin D1 is central to pathogenesis of MCL, current studies are also under-way to inhibit this molecule. Interestingly, targeted disruption of cyclin D1 was associated with increased signaling via cyclin D2 and cyclin D3 in preclinical models. Therefore, research has been focused on inhibiting downstream targets of cyclin D1. One such novel agent is PD0332991, which targets cyclin-dependent kinases 4 and 6 to effectively inhibit proliferation in MCL. Clinical studies using this as a single agent have shown an overall response rate of 18% in relapsed cases. Although this response rate was lower than expected, subsequent pharmacodynamic studies demonstrated significant inhibition of cell cycling. This has fueled an alternative approach, currently under study, in which PD0332991 is administered to coordinate cell cycling in order to facilitate enhanced sensitivity to the agent bortezomib.
Source...