New molecular targets in mantle cell lymphoma

Abstract

Mantle cell lymphoma (MCL) is a malignancy of mature B cells characterized by aberrant expression of cyclin D1 due to the translocation t(11;14). Epigenomic and genomic lesions in pathways regulating B-cell activation, cell cycle progression, protein homeostasis, DNA damage response, cell proliferation and apoptosis contribute to its pathogenesis. While patients typically respond to first-line chemotherapy, relapse is the rule resulting in a median survival of 5–7 years. The PI3K/AKT/mTOR appears as a key pathway in the pathogenesis and can be targeted with small molecules. Most experience is with mTOR inhibitors of the rapamycin class. Second-generation mTOR inhibitors and the PI3K inhibitor CAL-101 are novel options to more effectively target this pathway. Bruton’s tyrosine kinase inhibition by PCI-32765 has promising activity and indicates immunoreceptor signaling as a novel therapeutic target. Up to 50% of relapsed patients respond to the proteasome inhibitor bortezomib suggesting that MCL may be particularly sensitive to disruption of protein homeostasis and/or induction of oxidative stress. Recent work has focused on elucidating the mechanism of bortezomib-induced cytotoxicity and the development of second-generation proteasome inhibitors. DNA hypomethylating agents and histone deacetylase inhibitors effect epigenetic de-repression of aberrantly silenced genes. These epigenetic pharmaceuticals and HSP90 inhibitors can synergize with proteasome inhibitors. Finally, BH3 mimetics are emerging as tools to sensitize tumor cells to chemotherapy. Participation in clinical trials offers patients a chance to benefit from these advances and is essential to maintain the momentum of progress. Innovative trial designs may be needed to expedite the clinical development of these targeted agents.

Molecular pathogenesis of mantle cell lymphoma

“…A second generation of proteasome inhibitors, including NPI-0052 (salinosporamide A), PR-171 (carfilzomib), and MLN9708, are now entering the clinic. Efficacy has also been reported for proteasome inhibitors in combination with other cytotoxic agents and targeted therapies such as histone deacetylase inhibitors and HSP90 inhibitors (78,82). Several proteins central to MCL, including cyclin D1, CDK4, AKT, and p53, bind to the molecular chaperone HSP90, suggesting that HSP90 inhibitors may be a suitable therapeutic target (83).…”

“…Several proteins central to MCL, including cyclin D1, CDK4, AKT, and p53, bind to the molecular chaperone HSP90, suggesting that HSP90 inhibitors may be a suitable therapeutic target (83). However, HSP90 inhibitors as well as histone deacetylase inhibitors have demonstrated only moderate clinical antitumor activity when used alone (78,82,84). mTOR is another attractive target for new therapies (85).…”

“…The PI3K-δ inhibitor CAL101 has shown an overall response rate of 62% in relapsed and refractory MCL cases (95). In addition, several ongoing clinical trials are using MK2206, an allosteric inhibitor of AKT, and OSI-027, a dual mTORC1 and mTORC2 inhibitor (82,96).…”

“…Promising results are being obtained with drugs targeting the DNA repair pathway (25,101), such as the poly(ADPribose) polymerase 1 (PARP) inhibitor AG014699 (102)(103)(104). The use of proapoptotic molecules that mimic the activity of BH3-only proteins (105) has shown promising Results in preclinical models (106)(107)(108) but no responses or only modest activity in clinical studies (82,109). However, these compounds may sensitize cells to the effect of other therapeutic agents.…”

Whole transcriptome sequencing reveals recurrent NOTCH1 mutations in mantle cell lymphoma

“…6 On the other hand, indolent MCL may be identified by a non-nodal presentation and low expression of the transcription factor SOX11. 7 Although targeted therapies are emerging in MCL, 8 we currently lack reliable markers that identify those patients with aggressive disease who might benefit from novel treatment approaches and, alternatively, patients with indolent disease who might be best initially observed without intervention.…”