Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B‐cell acute lymphoblastic leukemia

Zinngrebe, Julia; Schlichtig, Ferdinand; Kraus, Johann M.; Meyer, Malcolm; Boldrin, Elena; Kestler, Hans A.; Meyer, Lüder Hinrich; Fischer‐Posovszky, Pamela; Debatin, Klaus‐Michael

doi:10.1002/ijc.32799

Cited by 8 publications

(9 citation statements)

References 45 publications

(142 reference statements)

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“…In a recent study, Zinngrebe et al reported the identification of gene expression markers that could help in stratifying patients that were particularly sensitive to SMs. This was done in B-cell acute lymphoblastic leukemia (BCP-ALL) and found four commonly predictive genes, which were TSPAN7, DIPK1C, MTX2 and TNFRSF1A, the latter encoding TNFR1 (Zinngrebe, et al, 2020).…”

Section: Biomarkers For Treatment Response To Smac Mimeticsmentioning

confidence: 99%

The Multiple Roles of the IAP Super-family in cancer

Kumar

Fairmichael

Longley

et al. 2020

Pharmacology & Therapeutics

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The Inhibitor of Apoptosis proteins (IAPs) are a family of proteins that are mainly known for their anti-apoptotic activity and ability to directly bind and inhibit caspases. Recent research has however revealed that they have extensive roles in governing numerous other cellular processes.IAPs are known to modulate ubiquitin (Ub)-dependent signaling pathways through their E3 ligase activity and influence activation of nuclear factor B (NFB). In this review, we discuss the involvement of IAPs in individual hallmarks of cancer and the current status of therapies targeting these critical proteins.

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Section: Biomarkers For Treatment Response To Smac Mimeticsmentioning

confidence: 99%

The Multiple Roles of the IAP Super-family in cancer

Kumar

Fairmichael

Longley

et al. 2020

Pharmacology & Therapeutics

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“…One of the main challenges is to identify and develop biomarkers of response to birinapant. Several studies have assessed and demonstrated that IAP levels do not correlate with sensitivity to birinapant ( 48 , 49 ). Zinngrebe et al demonstrated that protein expression levels of cIAP1 and XIAP were similar in SMAC mimetic-sensitive and SMAC mimetic-insensitive primary B-cell acute lymphoblastic leukemia samples ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have assessed and demonstrated that IAP levels do not correlate with sensitivity to birinapant ( 48 , 49 ). Zinngrebe et al demonstrated that protein expression levels of cIAP1 and XIAP were similar in SMAC mimetic-sensitive and SMAC mimetic-insensitive primary B-cell acute lymphoblastic leukemia samples ( 48 ). McCann et al also reported that expression of IAP proteins alone could not be correlated to birinapant sensitivity in a panel of colorectal cancer cell lines ( 49 ).…”

Section: Discussionmentioning

confidence: 99%

“…In an attempt to characterize predictive biomarkers of response to birinapant, a recent study has identified a 12-protein signature consisting of apoptotic proteins that could segregate responders and non-responders to birinapant and chemotherapy combinations in colorectal cancer ( 49 ). Another study identified a biomarker set of 4 genes including TNFRSF1A , TSPAN7 , DIPK1C and MTX2 for prediction of response to SMAC mimetics in pediatric precursor-cell acute lymphoblastic leukemia ( 48 ). Although these studies have paved the way for personalized treatment of cancer using SMAC mimetics, their successful clinical implementation across different cancers requires further evaluation in clinical trials.…”

Section: Discussionmentioning

confidence: 99%

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Efficacy of birinapant in combination with carboplatin in targeting platinum‑resistant epithelial ovarian cancers

et al. 2022

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Patients diagnosed with epithelial ovarian cancers (EOCs) often suffer from disease relapse associated with the emergence of resistance to standard platinum-based chemotherapy. Treatment of patients with chemo-resistant disease remains a clinical challenge. One mechanism of chemoresistance includes overexpression of pro-survival proteins called inhibitors of apoptosis (IAP) which enable cancer cells to evade apoptosis. Due to their anti-apoptotic activity, association with poor prognosis, and correlation with therapy resistance in multiple malignancies, IAP proteins have become an attractive target for development of anticancer therapeutics. Second mitochondrial activator of caspase (SMAC) mimetics are the most widely used IAP antagonists currently being tested in clinical trials as a monotherapy and in combination with different chemotherapeutic drugs to target different types of cancer. In the present study, the antitumor efficacy of combination therapy with birinapant, a bivalent SMAC mimetic compound, and carboplatin to target platinum-resistant EOC cells was investigated. A 3D organoid bioassay was utilized to test the efficacy of the combination therapy in a panel of 7 EOC cell lines and 10 platinum-resistant primary patient tumor samples. Findings from the in vitro studies demonstrated that the birinapant and carboplatin combination was effective in targeting a subset of ovarian cancer cell lines and platinum-resistant primary patient tumor samples. This combination therapy was also effective in vitro and in vivo in targeting a platinum-resistant patient-derived xenograft (PDX) model established from one of the patient tumors tested. Overall, our study demonstrated that birinapant and carboplatin combination could target a subset of platinum-resistant ovarian cancers and also highlights the potential of the 3D organoid bioassay as a preclinical tool to assess the response to chemotherapy or targeted therapies in ovarian cancer.

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“…14,15 Therapeutic targeting of members of the IAP superfamily was investigated in patients with advanced solid tumors 16,17 and hematologic malignancies. [18][19][20][21][22][23][24][25] Infante et al were the first to investigate the oral, monovalent, SMAC mimetic LCL161, in a first-in-human, large phase 1, dose-escalation clinical trial in patients with advanced solid tumors, demonstrating overall safety and feasibility of administering this once-weekly, oral medication. Furthermore, upon correlative study in this clinical trial, LCL161 showed downmodulation of cellular IAP1 (cIAP1), demonstrating, as hypothesized, an on-target effect of this novel agent.…”

Section: Strikingly Survival Outcomesmentioning

confidence: 99%

Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis

Pemmaraju¹,

Carter²,

Bose³

et al. 2021

Blood Advances

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Outcomes in patients with high-risk and treatment-resistant myelofibrosis (MF) post-JAK inhibitor therapy remain poor, with no approved drug therapies beyond the JAK inhibitor class. In certain clinical situations, such as severe thrombocytopenia, administration of most JAK inhibitors are contraindicated. Thus, there is an unmet medical need for the development of novel agents for patients with MF. SMAC mimetics [or inhibitor of apoptosis (IAP) antagonists] induce apoptosis in cancer cells. Because these agents are hypothesized to have increased activity in a tumor necrosis factor-α cytokine-rich microenvironment, as is the case with MF, we conducted a single-center, investigator-initiated phase 2 clinical trial, with a monovalent SMAC mimetic LCL161 (oral, starting dose, 1500 mg per week) in patients with intermediate to high-risk MF. In an older group, 66% with ≥2 prior therapies and a median baseline platelet count of 52 × 103/μL and 28% with ASXL1 mutations, we observed a 30% objective response by Revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) 2013 criteria. Notably, 6 responding patients achieved clinical improvement of anemia: 4, hemoglobin response; 2, transfusion independence. Median OS was 34 months (range, 2.2-60.1+). Reductions of cIAPs were observed in all responders. The most common toxicity was nausea/vomiting (N/V) in 64% (mostly grade 1/2); fatigue in 46%; and dizziness/vertigo in 30%. There were 4 grade 3/4 adverse events (2, syncope; 1, N/V; 1, skin eruption/pruritis). There were 2 deaths during the study period, both unrelated to the study drug. SMAC mimetics may represent an option for older patients with thrombocytopenia or for those in whom prior JAK inhibitors has failed. This trial was registered at www.clinicaltrials.gov as #NCT02098161.

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Biomarker profile for prediction of response to SMAC mimetic monotherapy in pediatric precursor B‐cell acute lymphoblastic leukemia

Cited by 8 publications

References 45 publications

The Multiple Roles of the IAP Super-family in cancer

The Multiple Roles of the IAP Super-family in cancer

Efficacy of birinapant in combination with carboplatin in targeting platinum‑resistant epithelial ovarian cancers

Final results of a phase 2 clinical trial of LCL161, an oral SMAC mimetic for patients with myelofibrosis

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