IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation

Li, Shirong; Fu, Jingzhu; Wang, Hui; Ma, Huihui; Xu, Xiaoming; Yang, Yong‐Guang; Deng, Shi‐Xian; Mapara, Markus Y.; Lentzsch, Suzanne

doi:10.1182/bloodadvances.2017010348

Cited by 18 publications

(7 citation statements)

References 42 publications

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“…The most common AE (all grade and grade 3/4) observed with avadomide was neutropenia, which results from Ikaros degradation in myeloid cells, leading to a maturation arrest at a promyelocyte stage. 56 The introduction of an intermittent 5/7-day dosing schedule improved tolerability and reduced the frequency and severity of AEs while maintaining the clinical activity of avadomide. We recently reported that lenalidomide-mediated degradation of Ikaros in an in vitro model of myeloid differentiation results in a reversible arrest in neutrophil maturation, which is released upon removal of the drug, without any loss of cell viability.…”

Section: Discussionmentioning

confidence: 99%

Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier

Carpio¹,

Bouabdallah

Ysebaert

et al. 2020

Blood

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Treatment options for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) are limited with no standard of care; prognosis is poor, with 4- to 6-month median survival. Avadomide (CC-122) is a cereblon-modulating agent with immunomodulatory and direct antitumor activities. This phase 1 dose expansion study assessed safety and clinical activity of avadomide monotherapy in patients with R/R de novo DLBCL and transformed lymphoma. Additionally, a novel gene expression classifier, which identifies tumors with a high immune cell infiltration, was shown to enrich for response to avadomide in R/R DLBCL. Ninety-seven patients with R/R DLBCL, including 12 transformed lymphoma, received 3 to 5 mg of avadomide administered on continuous or intermittent schedules until unacceptable toxicity, disease progression, or withdrawal. Eighty-two patients (85%) experienced ≥1 grade 3/4 treatment-emergent adverse events (AEs), most commonly neutropenia (51%), infections (24%), anemia (12%), and febrile neutropenia (10%). Discontinuations because of AEs occurred in 10% of patients. Introduction of an intermittent 5/7‑day schedule improved tolerability and reduced frequency and severity of neutropenia, febrile neutropenia, and infections. Among 84 patients with de novo R/R DLBCL, overall response rate (ORR) was 29%, including 11% complete response (CR). Responses were cell-of-origin-independent. Classifier-positive DLBCL patients (de novo) had an ORR of 44%, median progression-free survival (mPFS) of 6 months, and 16% CR versus an ORR of 19%, mPFS of 1.5 months, and 5% CR in classifier-negative patients (P = .0096). Avadomide is being evaluated in combination with other antilymphoma agents. This trial was registered at www.clinicaltrials.gov as #NCT01421524.

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Section: Discussionmentioning

confidence: 99%

Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier

Carpio¹,

Bouabdallah

Ysebaert

et al. 2020

Blood

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“…Total RNA was isolated with TRIZOL reagent and cDNA generated with SuperScript III reverse transcriptase (Cat#18080400; Invitrogen, Grand Island, NY), followed by Taqman (Invitrogen) based real-time polymerase chain reaction assays (Cat# 4352042; Invitrogen, Grand Island, NY) performed as described 3 , 7 , 41 . TaqMan® Gene Expression Assay (Cat# 4331182) was used for m-Pd-1h: Mm00472314_m1; m Dc-stamp: Mm04209236_m1; m-beta-actin: Mm00607939_s1.…”

Section: Methodsmentioning

confidence: 99%

The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease

Liu

et al. 2023

Nat Commun

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Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone disease mouse model wherein myeloma cells injected into Pd-1h-/-Rag2-/- results in attenuated bone destruction. Our findings identify a role of PD-1H in bone biology independent of its known immunoregulatory functions and suggest that targeting the MMP-13/PD-1H axis may represent a potential approach for the treatment of myeloma associated osteolysis.

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“…In POMdex treated patients, the incidence of grade 3/4 neutropenia was ~50% [ 40 , 41 ]. Recent studies on molecular mechanisms of IMiD agent-mediated myelosuppression showed LEN and POM reduced PU.1 expression in CD34 + cells, leading to maturation arrest of myeloid precursors, and subsequent neutropenia [ 42 , 43 ]. The PU.1 decreased expression in CD34 + cells following IMiD exposure was found to be Ikaros-mediated and the subsequent maturation arrest at the promyelocyte stage shown to be reversible [ 44 ].…”

Section: Mechanism-driven Adverse Eventsmentioning

confidence: 99%

“…The PU.1 decreased expression in CD34 + cells following IMiD exposure was found to be Ikaros-mediated and the subsequent maturation arrest at the promyelocyte stage shown to be reversible [ 44 ]. In additional myelosuppression studies, the reduction of GATA1 expression by IMiD agents led to arrest in megakaryocyte precursors impacting thrombocytopenia [ 42 , 43 ].…”

Section: Mechanism-driven Adverse Eventsmentioning

confidence: 99%

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma

et al. 2021

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Multiple Myeloma (MM) is an incurable malignancy with current treatment choices primarily comprising combination regimens implemented with a riskadapted approach. Cereblon (CRBN)-targeting immunomodulatory agents (IMiDs ® ) lenalidomide (LEN) and pomalidomide (POM) play a central role in combination regimens due to their pleiotropic antitumor/immunomodulatory mechanisms that synergize with many anti-myeloma approved or developmental agents. Currently, more potent next generation cereblon E3 ligase modulators (CELMoDs ® ) -iberdomide (IBER) and CC-92480 are in clinical development. With an expanding number of active agents/therapeutic modalities and a myriad of combinatorial possibilities, physicians and drug developers share an opportunity and challenge to combine and sequence therapies to maximize long-term patient benefit. Understanding drug mechanisms and their application in combination settings as well as the unique disease biology considerations from newly diagnosed (NDMM), relapsed/refractory (RRMM), and maintenance settings will be vital to guide the development of future MM therapies centered on a backbone of IMiD or CELMoD agents. Key aspects of drug activity are critical to consider while evaluating potential combinations: direct antitumor effects, indirect antitumor cytotoxicity, immune surveillance, and adverse side effects. In addition, the treatment journey from NDMM to early and late MM relapses are connected to genomic and immune changes associated with disease progression and acquisition of resistance mechanisms. Based on the types of combinations used and the goals of therapy, insights into mechanisms of drug activity and resistance may inform treatment decisions for patients with MM. Here we focus on the evolving understanding of the molecular mechanisms of CRBN-binding drugs and how they can be differentiated and suggest a strategic framework to optimize efficacy and safety of combinations using these agents. LEARNINGS FROM THE BENCHIMiD/CELMoD compounds bind CRBN, a substrate receptor of the Cul4A/DDB1/Roc1 (Cul4A CRBN ) E3 ligase complex, and trigger recruitment, polyubiquitination and subsequent degradation of substrate proteins. A simple framework (Figure 1) underscores critical parameters that capture the diversity of the downstream biochemical or biological effects of these drugs in target cell types, via key common molecular steps. Chemically, IMiD and CELMoD agents share glutarimide rings for binding to the tri-tryptophan pocket of cereblon, and isoindolinone rings that interact with cereblon and substrates (e.g. ikaros, aiolos, etc.). However, CELMoD structures are extended relative to those of IMiDs, containing additional phenyl and morpholino moieties enabling enhanced interactions with cereblon or substrates [1,2]. While both LEN and POM bind CRBN with similar affinity (K d~1 .0-1.5 uM)

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IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation

Cited by 18 publications

References 42 publications

Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier

Avadomide monotherapy in relapsed/refractory DLBCL: safety, efficacy, and a predictive gene classifier

The checkpoint inhibitor PD-1H/VISTA controls osteoclast-mediated multiple myeloma bone disease

Developing next generation immunomodulatory drugs and their combinations in multiple myeloma

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