Preclinical evidence for an effective therapeutic activity of FL118, a novel survivin inhibitor, in patients with relapsed/refractory multiple myeloma

Holthof, Lisa C.; Horst, Hilma J. van der; Veen, Susan E. van Hal-van; Ruiter, Ruud; Li, Fengzhi; Buijze, Marijke; Andersen, Morten Nørgaard; Yuan, Huipin; Bruijn, Joost D. de; Donk, Niels W.C.J. van de; Lokhorst, Henk M.; Groen, Richard W.J.; Mutis, Tuna

doi:10.3324/haematol.2018.213314

Cited by 12 publications

(16 citation statements)

References 14 publications

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“…In more recent studies we used another novel small molecule, FL118, which inhibits multiple anti-apoptotic proteins including Survivin, MCL-1, and XIAP [101]. This small molecule, which is effective against multiple drug-resistant solid tumors, also demonstrates potent single agent anti-MM activity and was able to abrogate MSC-mediated drug resistance in our recent preclinical studies [102][103][104][105][106]. In our preliminary studies, FL118 is also able to largely abrogate the MSC-mediated immune resistance against HLA-restricted T-cells, CAR T-cells, Daratumumab and DR5 antibodies, without showing toxicity for immune cells [100] (manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

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Section: Discussionmentioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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“…Along with the versatile and unique features of FL118 summarized above, FL118 has shown striking antitumor activity in human tumor animal models [63,68,78,80,95,96]. FL118 exhibited significantly superior antitumor activity when compared with FDA-approved anticancer drugs commonly used in clinical practice (irinotecan, topotecan, doxorubicin, 5-FU, gemcitabine, docetaxel, oxaliplatin, cytoxan and cisplatin) [63].…”

Section: Fl118mentioning

confidence: 99%

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Aljahdali

Ling

2019

J Exp Clin Cancer Res

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Survivin (also named BIRC5) is a well-known cancer therapeutic target. Since its discovery more than two decades ago, the use of survivin as a target for cancer therapeutics has remained a central goal of survivin studies in the cancer field. Many studies have provided intriguing insight into survivin's functional role in cancers, thus providing promise for survivin as a cancer therapeutic target. Despite this, moving survivin-targeting agents into and through the clinic remains a challenge. In order to address this challenge, we may need to rethink current strategies in order to develop a new mindset for targeting survivin. In this Review, we will first summarize the current survivin mechanistic studies, and then review the status of survivin cancer therapeutics, which is classified into five categories: (i) survivin-partner protein interaction inhibitors, (ii) survivin homodimerization inhibitors, (iii) survivin gene transcription inhibitors, (iv) survivin mRNA inhibitors and (v) survivin immunotherapy. We will then provide our opinions on cancer therapeutics using survivin as a target, with the goal of stimulating discussion that might facilitate translational research for discovering improved strategies and/or more effective anticancer agents that target survivin for cancer therapy.

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“…On the other hand, a small molecule FL118 was discovered via HTS [ 42 ]. FL118 was found to exhibit high antitumor efficacy by targeting multiple antiapoptotic proteins, including survivin, Mcl-1, XIAP, cIAP2, and MdmX [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. However, the direct target of FL118 is unknown.…”

Section: Molecular Glues For Cancer Treatmentmentioning

confidence: 99%

Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

Aljahdali

Ling

2022

IJMS

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Molecular glue (MG) compounds are a type of unique small molecule that can change the protein–protein interactions (PPIs) and interactomes by degrading, stabilizing, or activating the target protein after their binging. These small-molecule MGs are gradually being recognized for their potential application in treating human diseases, including cancer. Evidence suggests that small-molecule MG compounds could essentially target any proteins, which play critical roles in human disease etiology, where many of these protein targets were previously considered undruggable. Intriguingly, most MG compounds with high efficacy for cancer treatment can glue on and control multiple key protein targets. On the other hand, a single key protein target can also be glued by multiple MG compounds with distinct chemical structures. The high flexibility of MG–protein interaction profiles provides rich soil for the growth and development of small-molecule MG compounds that can be used as molecular tools to assist in unraveling disease mechanisms, and they can also facilitate drug development for the treatment of human disease, especially human cancer. In this review, we elucidate this concept by using various types of small-molecule MG compounds and their corresponding protein targets that have been documented in the literature.

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Preclinical evidence for an effective therapeutic activity of FL118, a novel survivin inhibitor, in patients with relapsed/refractory multiple myeloma

Cited by 12 publications

References 14 publications

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Cancer therapeutics using survivin BIRC5 as a target: what can we do after over two decades of study?

Molecular Glues: Capable Protein-Binding Small Molecules That Can Change Protein–Protein Interactions and Interactomes for the Potential Treatment of Human Cancer and Neurodegenerative Diseases

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