TABLE 2.
Pathway-based oncogenic biomarkers and their therapeutic applications in lymphomas
| Oncogenic Biomarker |
Therapeutics | Agent | Involved Lymphomas | Phase | Trial Registration or Reference |
|---|---|---|---|---|---|
| BTK | Btk inhibitor | Ibrutinib (PCI-32765) | Recurrent B-cell lymphoma, CLL/SLL, R/R MCL, ABC-DLBCL, FL, MZL, T-cell lymphoma | Phase 1/2 | NCT00849654; NCT01325701; NCT02169180; NCT01109069 |
| Btk inhibitor | BGB-3111 | R/R B-cell malignancies | Phase 1 | NCT02343120 | |
| Btk inhibitor | AVL-292 (cc-292) | R/R B-Cell NHL, CLL/SLL, WM | Phase 1 | NCT01351935 | |
| Btk inhibitor | M7583 | R/R B-cell malignancies, MCL, ABC-DLBCL | Phase 1/2 | NCT02825836 | |
| Btk inhibitor | Acalabrutinib (ACP-196) | R/R ABC-DLBCL, CLL/SLL, MCL | Phase 1/2 | NCT02112526; NCT02337829; NCT02029443; NCT02213926 | |
| SYK | Syk inhibitor | Fostamatinib (R788) (R406) | CLL/SLL, DLBCL, MCL, FL, T-cell lymphoma | Phase 1/2 | NCT00446095; NCT00798096 |
| Syk inhibitor | Cerdulatinib (PRT062070) | CLL/SLL, FL, NHL,T-cell lymphoma | Phase 1/2 | NCT01994382 | |
| Syk inhibitor | Entospletinib (GS-9973) | R/R CLL/SLL, MCL, DLBCL, FL; indolent NHL; MZL | Phase 2 | NCT01799889 | |
| PI3Ks | PI3Kδ inhibitor | Idelalisib (CAL-101, GS-1101) | R/R MCL, FL, SLL, LPL, MZL | Phase 1/2 | NCT00710528; NCT01282424 |
| PI3Kδ inhibitor | AMG 319 | Lymphoid malignancies | Phase 1 | NCT01300026 | |
| PI3Kδ/γ inhibitor | Duvelisib (IPI-145, INK1197) | R/R NHL, advanced hematologic malignancies | Phase 1/2 | NCT02598570; NCT01882803; NCT01476657 | |
| PI3Kδ inhibitor | Acalisib (GS-9820) (CAL-120) | R/R lymphoid malignancy | Phase 1 | NCT01705847 | |
| PI3Kγ inhibitor | Buparlisib (BKM120) | PCNSL, SCNSL, CLL/SLL | Phase 2 | NCT02301364; NCT02340780 | |
| PI3K inhibitor | SAR 245408 (XL147) | Lymphomas | Phase 1 | NCT00486135 | |
| AKT | Akt inhibitor | Perifosine (KRX-0401) | Hematologic malignancies, Lymphomas | Phase 1/2 | NCT00019656; NCT00389077 |
| Akt1/2/3 inhibitor | MK-2206 | Relapsed lymphoma, R/R DLBCL | Phase 2 | NCT01258998; NCT01481129 | |
| Akt inhibitor | GSK690693 | Lymphoma and solid tumor | Phase 1 | NCT00493818 | |
| mTOR | mTOR inhibitor | Ridaforolimus (AP23573, MK-8669) | Lymphoma, multiple myeloma, hematologic malignancies | Phase 2 | NCT00060632; NCT00060645; NCT00086125 |
| mTOR inhibitor | Temsirolimus (CCI-779) | R/R HL, R/R PCNSL, FL, CLL/SLL, R/R MCL | Phase 1/2/4 | NCT00838955; NCT00942747; NCT00033267; NCT01180049 | |
| mTOR inhibitor | Rapamycin (Sirolimus) | R/R Acute Lymphoblastic Leukemia/Lymphoma | Terminated | NCT01658007 | |
| mTORC1/mTORC2 inhibitor | Everolimus (RAD001) | R/R NHL, R/R MCL, R/R cutaneous T-cell lymphoma | Phase 1/2 | NCT00622258; NCT00516412; NCT01637090 | |
| mTORC1/mTORC2 inhibitor | AZD2014 | R/R non-GCB DLBCL | Phase 1 | NCT02780830 | |
| BCL2 | Bcl-2, Bcl-xl, Bcl-w inhibitor | Navitoclax (ABT263) | R/R lymphoid malignancy | Phase 2 | NCT00406809; NCT01557777 |
| BCL2 inhibitor | Venetoclax (ABT199) | NHL, CLL/SLL, MM, R/R NHL | Phase 1/2/3 | NCT01969695; NCT01328626; NCT02756611; NCT02966756 | |
| BCL2 inhibitor | Obatoclax Mesylate (GX15-070MS) | R/R HL | Phase 2 | NCT00359892 | |
| p53 | MDM2 inhibitor | APG-115 | Advanced solid tumors or lymphomas | Phase 1 | NCT02935907 |
| MDM2 inhibitor | DS-3032 | Advanced solid tumors or lymphomas | Phase 1 | NCT01877382 | |
| P53-MDM2 blockade | ALRN-6924 | Advanced solid tumors or lymphomas | Phase 1/2 | NCT02264613 | |
| MYC | BET inhibitor | CPI-0610 | Progressive lymphomas | Phase 1 | NCT01949883; NCT02158858 |
| BET/BRD4 inhibitor | AZD5153 | Hematologic malignancies | Preclinical | Reference 86 | |
| c-Myc-Max dimerization inhibitor | 10058-F4 | BL | Preclinical | Reference 81 | |
| Aurora A inhibitor | Alisertib | Myc-positive aggressive B-cell lymphomas | Phase 1 | NCT02700022 | |
| Small inhibitory RNA oligonucleotide targeting MYC | DCR-MYC | NHL, MM, solid tumors | Phase 1 | NCT02110563 | |
| BET inhibitor | JQ1 | Hematologic malignancies | Preclinical | Reference 82-84 | |
| JAKs | JAK3 inhibitor | Tofacitinib (CP-690550) | EBV-related NK/T-cell lymphoma | Preclinical | Reference 132 |
| JAK2 inhibitor | Pacritinib (SB1518) | R/R cHL, FL, MCL, and DLBCL | Phase 1/2 | NCT00741871; NCT01263899 | |
| JAK2 inhibitor | Ruxolitinib (INCB018424) | R/R T-cell or NK-cell lymphoma, R/R HL and PMBL | Phase 2 | NCT02974647; NCT01965119; NCT01877005 | |
| STAT3 | STAT3 inhibitor | Pyrimethamine | Relapsed CLL/SLL | Phase 1/2 | NCT01066663 |
| STAT3 inhibitor | IONIS-STAT3Rx (ISIS 481464) | DLBCL, lymphoma, advanced cancer | Phase 1/2 | NCT01563302 | |
| IL-6 | IL-6 inhibitor | Siltuximab (CNTO-328) | B-cell NHL, MM, or Castleman’s disease | Phase 1 | NCT00412321 |
| PD-1 | Anti-PD-1 antibody | MEDI0680 (AMP-514) | R/R aggressive B-cell lymphomas; advanced malignancies | Phase 1/2 | NCT02271945; NCT02013804 |
| Anti-PD-1 antibody | Pidilizumab (CT-011) | DLBCL and PMBL after ASCT; stage III–IV DLBCL; | Phase 2 | NCT00532259; NCT02530125 | |
| Anti-PD-1 antibody | Nivolumab (BMS-936558, MDX-1106, ONO-4538) | R/R DLBCL, PCNSL, PTL, FL, PTCL | Phase 2 | NCT02038933; NCT02857426; NCT02038946; NCT03075553 | |
| Anti-PD-1 antibody | Pembrolizumab (lambrolizumab, MK-3475) | R/R FL; HL, DLBCL and T-NHL after ASCT; T-cell or NK-cell lymphomas; R/R HL; recurrent PCNSL; R/R PMBL | Phase 2 | NCT02446457; NCT02362997; NCT03021057; NCT02453594; NCT02779101; NCT02576990 | |
| PD-L1 | Anti-PD-L1 antibody | Durvalumab (MEDI4736) | R/R lymphoma, solid tumor | Phase 1 | NCT02793466 |
| Anti-PD-L1 antibody | Avelumab (MSB0010718C) | Advanced cHL; R/R PTCL | Phase 1/2 | NCT02603419; NCT03046953 | |
| Anti-PD-L1 antibody | Atezolizumab (MPDL3280A) (RG7446) | Locally advanced or metastatic solid tumors or hematologic malignancies; R/R FL and DLBCL; R/R HL | Phase 1/2 | NCT01375842; NCT02220842; NCT02862275; NCT03120676 | |
| MYD88 | TLRs ligands inhibitor | IMO-8400 | R/R ABC-DLBCL with MYD88 L256 mutation | Phase 1/2 | NCT02252146 |
| IRAK4 inhibitor | ND-2158, ND-2110 | ABC-DLBCL, or other malignancies harboring aberrant MYD88 | Preclinical | Reference 138 | |
| IkBa | IkBa inhibitor | Bortezomib (Velcade, PS341) | MALT, R/R FL, DLBCL, R/R B-cell lymphomas | Phase 2 | NCT00210327; NCT00136591; NCT01226849; NCT00038571 |
| IkBa inhibitor | MLN4924 | ABC-DLBCL, MCL, hematologic malignancies | Phase 1 | NCT00722488 |
ABC, active B-cell; AKT, v-akt murine thymoma viral oncogene homolog1; ASCT, autologous stem cell transplantation; ATLL, Adult T-cell leukemia/lymphoma; BET, bromodomain and extra-terminal proteins; BRD4, bromodomain containing protein 4; BL, Burkitt lymphoma; BTK, bruton tyrosine kinase; cHL, classical Hodgkin lymphoma; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; HL, Hodgkin lymphoma; IL-6, interleukin 6; JAK, Janus kinase; LPL, lymphoplasmacytic lymphoma; MALT, mucosa associated lymphoid tissue lymphoma; MCL, mantle cell lymphoma; MDM2, mouse double-minute 2 protein; MM, multiple myeloma; mTOR, mechanistic target of Rapamycin; mTORC, mTOR complex; MYC, v-Myc avian myelocytomatosis viral oncogene homolog; MYD88, myeloid differentiation primary response 88; MZL, marginal zone lymphoma; NHL, non-Hodgkin’s lymphoma; PCNSL, primary central nervous system lymphoma; PD-1, programmed death-1; PD-Ls, programmed death-ligands; PI3K, phosphoinositide-3-kinase; PMBL, primary mediastinal B-cell lymphoma; PTCL, peripheral T-cell lymphoma; PTL, primary testicular lymphoma; R/R, refractory and relapsed; SCNSL, secondary central nervous system lymphoma; SLL, small lymphocytic lymphoma; STAT, signal transducer and activator of transcription; SYK, spleen-associated tyrosine kinase; WM, Waldenstrom’s macroglobulinem.