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.

Fig. 1

Major cellular pathways for targeted therapy of MCL. Intracellular location of aberrant pathways is shown in the center. Around this, individual pathways are highlighted. Pathway-specific inhibitors (mostly limited to clinical grade inhibitors) are boxed. Activating connections are indicated by arrows, inhibitory effects are depicted by lines.

Fig. 2

Targeting B-cell activation. The B-cell receptor signaling pathway is initiated through phosphorylation of co-receptors Igα (CD79a) and Igβ (CD79b), recruiting the tyrosine kinase SYK. In turn, SYK phosphorylates several downstream kinases including BTK and PI3Kδ. BAFF receptor signaling involves cross-talk with BCR and also results in activation of NFκB. Targeted inhibitors used in clinical trials are shown.

Fig. 3

Targeting the PI3K/AKT/mTOR pathway. PI3 kinases, heterodimers composed of p85 regulatory and p110 catalytic subunits, activate AKT. AKT activation requires both phosphorylation at threonine 308(P*) and at serine 473(P**) in order to activate mTOR-containing complexes mTORC1 and mTORC2 and HDM2 or inhibit FOXO, GSK3β, and BAD. Several small molecules targeting the PI3K/AKT/mTOR pathway at different levels are indicated in blue boxes.

Fig. 4

Targeting the cell cycle. The Cyclin D1-CDK4/6 complex phosphorylates Rb and promotes G1/S phase transition of the cell cycle. Endogenous proteins p15/16 suppress this complex as do the pharmacologic inhibitors shown in blue boxes. Pan-CDK inhibitors regulate transcription through CDK7, 9 and 10 in addition to cell cycle inhibition.

Fig. 5

Targeting DNA Damage Response proteins. Exogenous and endogenous stress can activate the DNA damage sensor ATM, which is frequently mutated or deleted in primary MCL. ATM in turn activates p53, which stops cell cycle progression and activates DNA repair mechanisms. Pharmacologic inhibitors of MDM2, which degrades p53; and PARP, which aids in DNA repair, are shown in blue.

Fig. 6

Targeting BCL-2 family proteins. The BCL-2 proteins BCL-2, BCL-XL, BCL-W, MCL-1, and A1 are anti-apoptotic proteins that sequester the apoptotic effectors BAX and BAK. Pro-apoptotic proteins BIM, BID, PUMA antagonize the function of all BCL-2 proteins. BAD specifically antagonizes BCL-2, BCL-XL and BCL-W whereas NOXA antagonizes MCL-1 and A1. The small molecule BH-3 mimetics GX15-070 and AT-101 are pan-BCL-2 inhibitors, in contrast to ABT-737/ABT-263, which specifically inhibit BCL-2, BCL-XL and BCL-W but not MCL-1 and A1.

Fig. 7

Targeting regulators of protein homeostasis. A) Small ubiquitin-like proteins are sequentially conjugated to protein substrates and affect their localization, function and degradation. E1 enzymes such as the NEDD8-activating enzyme activate small NEDD8 proteins, which are then conjugated and ligated to acceptor proteins by E2 and E3 enzymes, respectively. NEDD8ylation of cullin proteins is essential for function of multi-protein cullin-RING (E3 ubiquitin) ligase complexes. Inhibition of the E1 NEDD8-activating enzyme leads to inhibition of the SCF complex. Inhibition of the E3 ubiquitin ligase HDM2, leads to stabilization of select proteins, e.g., tumor suppressor protein p53. B) HSP90 requires dimerization, mediated through the C-terminal domain, for full chaperone function. Blocking ATP-binding at the N-terminal domain, interferes with HSP90 dimerization and prevents chaperoning of client proteins resulting in their proteasomal degradation. C) Proteins are marked with Lys48-linked ubiquitin chains for proteasomal degradation. Pharmacological inhibition of the enzymatic activity of catalytic proteasome subunits causes a cellular stress response that leads to apoptosis.

Figure 8. Targeting epigenetic modifications

DNA is maintained in a coiled “inactive” state around histones and needs to undergo physical conformational changes to allow access for gene transcription. The biochemical modification of DNA and histones regulates this process and in turn is regulated by opposing groups of enzymes thatcan be inhibited for therapeutic benefit. Inhibitors of enzymes effecting epigenetic changes are shown in blue boxes.