Novel treatment approaches in MCL in clinical development
| Drug class . | Drugs . | Mechanism of action and effects on MCL biology . | Clinical development and results . |
|---|---|---|---|
| Proteasome inhibitors | Bortezomib (CT-L),48-50 NPI-0052 (CT-L, T-L, C-L),59 PR-171 (CT-L),60 MLN9708 (CT-L)61 | Reversible or irreversible inhibition of ≥ 1 proteasome activities; cell-cycle arrest and induction of apoptosis through oxidative and ER stress–mediated up-regulation of NOX | Bortezomib (phase 2): ORR 33%-58% in relapsed/refractory MCL; NPI-0052 and PR-171 (phase 1); MLN9708 (phase 1) |
| CDK inhibitors | Flavopiridol (pan-CDK),63 PD0332991 (CDK4/6)62 | Flavopiridol: pan-CDK inhibitor, decreased RNA stability; PD0332991: blocks cyclin D1/CDK4, leading to cell-cycle arrest | Flavopiridol (phase 1, 2): minimal responses as a single agent, modified dosing schedules may be more effective; PD0332991(phase 1) |
| Serine/threonine and tyrosine kinase inhibitors | Enzastaurin (PKC-β ΙΙ),66 fostamatinib (SYK),65 PCI-32765 (BTK)67 | Inhibition of BCR signal transduction cascade | Mostly stable disease for fostamatinib and enzastaurin; objective responses in phase 1 study of PCI-32765 |
| PI3K/AKT inhibitors | CAL-101 (PI3Kδ),73,131 ON1910.Na (multikinase /PI3Kα),72 perifosine (AKT)75 | Inactivation of AKT and mTOR; cell-cycle arrest, cyclin D1 down-regulation; activation of p53 and BAD-mediated apoptosis | CAL-101 (oral agent, phase 1): PRs in MCL and CLL; ON-01910.Na (phase 1); Perifosine (phase 1) |
| mTOR inhibitors (rapalogs) | Rapamycin, temsirolimus (CCI-779),79-81 everolimus (RAD001),83,132 deforolimus (AP23573)78 | Partial allosteric TORC1 inhibition; cell-cycle arrest; inconsistent effects on expression of cell-cycle regulators (cyclin D1, p21, p27); may induce autophagy but not apoptosis | Temsirolimus (phase 2 and 3): ORR 30%-40% in relapsed patients, mostly PRs of rapid onset (median, 1 mo), median duration of response of 6.9 mos; everolimus (phase 1 and 2): some objective responses; deferolimus (phase 2): 30% PR and 40% SD |
| BH3 mimetics | *ABT-263,103 AT-101,104 obatoclax (GX15-070)105 | Inhibition of antiapoptotic members of BCL-2 family, BCL-2, BCL-XL; GX 15-070 inhibits also MCL-1; mitochondrial depolarization through release of BH-3–only proteins and BAX/BAK activation | Obatoclax (phase 1 and 2) with or without bortezomib; AT-101 (phase 2); ABT-737 (phase 1 and 2) |
| IMIDs | Lenalidomide,113,114 thalidomide115 | Modulation of immune response; microenvironment or direct effect on tumor cells | Lenalidomide (phase 2): ORR 42%-53%, CR 20%, PFS 5.6 mos in relapsed MCL |
| HDAC inhibitor | Vorinostat (SAHA)119,120 | Cyclin D1 down-regulation, p21 and p27 up-regulation, and cell-cycle arrest; up-regulation of the BH3-only proteins BIM and BMF | SAHA (phase 1 and 2) with or without bortezomib |
| HSP90 inhibitors122 | Ansamycins: 17-AAG, 17-DMAG: IPI-504; synthetic: SNX-5422, KW-2478 | Degradation of client proteins, including cyclin D1, CDK4, IKKβ, AKT, c-MYC, and c-RAF133 ; cell-cycle arrest; activation of the mitochondrial apoptotic pathway | 17-AAG (phase 2): mostly disease stabilization, with or without bortezomib; 17-DMAG clinical development stopped; IPI-504: water-soluble 17-AAG derivative; synthetic inhibitors: entering early stage testing |
| Drug class . | Drugs . | Mechanism of action and effects on MCL biology . | Clinical development and results . |
|---|---|---|---|
| Proteasome inhibitors | Bortezomib (CT-L),48-50 NPI-0052 (CT-L, T-L, C-L),59 PR-171 (CT-L),60 MLN9708 (CT-L)61 | Reversible or irreversible inhibition of ≥ 1 proteasome activities; cell-cycle arrest and induction of apoptosis through oxidative and ER stress–mediated up-regulation of NOX | Bortezomib (phase 2): ORR 33%-58% in relapsed/refractory MCL; NPI-0052 and PR-171 (phase 1); MLN9708 (phase 1) |
| CDK inhibitors | Flavopiridol (pan-CDK),63 PD0332991 (CDK4/6)62 | Flavopiridol: pan-CDK inhibitor, decreased RNA stability; PD0332991: blocks cyclin D1/CDK4, leading to cell-cycle arrest | Flavopiridol (phase 1, 2): minimal responses as a single agent, modified dosing schedules may be more effective; PD0332991(phase 1) |
| Serine/threonine and tyrosine kinase inhibitors | Enzastaurin (PKC-β ΙΙ),66 fostamatinib (SYK),65 PCI-32765 (BTK)67 | Inhibition of BCR signal transduction cascade | Mostly stable disease for fostamatinib and enzastaurin; objective responses in phase 1 study of PCI-32765 |
| PI3K/AKT inhibitors | CAL-101 (PI3Kδ),73,131 ON1910.Na (multikinase /PI3Kα),72 perifosine (AKT)75 | Inactivation of AKT and mTOR; cell-cycle arrest, cyclin D1 down-regulation; activation of p53 and BAD-mediated apoptosis | CAL-101 (oral agent, phase 1): PRs in MCL and CLL; ON-01910.Na (phase 1); Perifosine (phase 1) |
| mTOR inhibitors (rapalogs) | Rapamycin, temsirolimus (CCI-779),79-81 everolimus (RAD001),83,132 deforolimus (AP23573)78 | Partial allosteric TORC1 inhibition; cell-cycle arrest; inconsistent effects on expression of cell-cycle regulators (cyclin D1, p21, p27); may induce autophagy but not apoptosis | Temsirolimus (phase 2 and 3): ORR 30%-40% in relapsed patients, mostly PRs of rapid onset (median, 1 mo), median duration of response of 6.9 mos; everolimus (phase 1 and 2): some objective responses; deferolimus (phase 2): 30% PR and 40% SD |
| BH3 mimetics | *ABT-263,103 AT-101,104 obatoclax (GX15-070)105 | Inhibition of antiapoptotic members of BCL-2 family, BCL-2, BCL-XL; GX 15-070 inhibits also MCL-1; mitochondrial depolarization through release of BH-3–only proteins and BAX/BAK activation | Obatoclax (phase 1 and 2) with or without bortezomib; AT-101 (phase 2); ABT-737 (phase 1 and 2) |
| IMIDs | Lenalidomide,113,114 thalidomide115 | Modulation of immune response; microenvironment or direct effect on tumor cells | Lenalidomide (phase 2): ORR 42%-53%, CR 20%, PFS 5.6 mos in relapsed MCL |
| HDAC inhibitor | Vorinostat (SAHA)119,120 | Cyclin D1 down-regulation, p21 and p27 up-regulation, and cell-cycle arrest; up-regulation of the BH3-only proteins BIM and BMF | SAHA (phase 1 and 2) with or without bortezomib |
| HSP90 inhibitors122 | Ansamycins: 17-AAG, 17-DMAG: IPI-504; synthetic: SNX-5422, KW-2478 | Degradation of client proteins, including cyclin D1, CDK4, IKKβ, AKT, c-MYC, and c-RAF133 ; cell-cycle arrest; activation of the mitochondrial apoptotic pathway | 17-AAG (phase 2): mostly disease stabilization, with or without bortezomib; 17-DMAG clinical development stopped; IPI-504: water-soluble 17-AAG derivative; synthetic inhibitors: entering early stage testing |
Information on ongoing clinical trials at is available at http://www.clinicaltrials.gov.
CT-L indicates chymotrypsin-like; T-L, trypsin-like; C-L, caspase-like; ORR, overall response rate; ER, endoplasmic reticulum; PR, partial response; SD, stable disease; CR, complete response; and PFS, progression-free survival.
ABT-263 is the oral formulation of the compound used in clinical trials; ABT-737 is the equivalent compound typically used in preclinical studies.