Has Drug Repurposing Fulfilled Its Promise in Acute Myeloid Leukaemia?

Valli, Debora; Gruszka-Westwood, Alicja M.; Alcalay, Myriam

doi:10.3390/jcm9061892

Cited by 11 publications

(8 citation statements)

References 165 publications

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“…Repositioning approved drugs for other indications is an interesting subject for clinical trials by cooperating study groups ( 137 ). Even though glucocorticoids have received little attention in AML, the evidence in this review provides a basis for clinical assessment of whether glucocorticoids such as dexamethasone can one day be included in the AML treatment armamentarium.…”

Section: Discussionmentioning

confidence: 99%

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Récher

2021

Front. Oncol.

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Recent advances in the description of the tumor microenvironment of acute myeloid leukemia, including the comprehensive analysis of the leukemic stem cell niche and clonal evolution, indicate that inflammation may play a major role in many aspects of acute myeloid leukemia (AML) such as disease progression, chemoresistance, and myelosuppression. Studies on the mechanisms of resistance to chemotherapy or tyrosine kinase inhibitors along with high-throughput drug screening have underpinned the potential role of glucocorticoids in this disease classically described as steroid-resistant in contrast to acute lymphoblastic leukemia. Moreover, some mutated oncogenes such as RUNX1, NPM1, or SRSF2 transcriptionally modulate cell state in a manner that primes leukemic cells for glucocorticoid sensitivity. In clinical practice, inflammatory markers such as serum ferritin or IL-6 have a strong prognostic impact and may directly affect disease progression, whereas interesting preliminary data suggested that dexamethasone may improve the outcome for AML patients with a high white blood cell count, which paves the way to develop prospective clinical trials that evaluate the role of glucocorticoids in AML.

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Section: Discussionmentioning

confidence: 99%

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Récher

2021

Front. Oncol.

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“…A recent comprehensive review of the time and cost expenditures of drug repurposing clinical trials in acute myeloid leukemia (AML) debunked the common dogmas associated with drug repurposing, namely (1) drug repurposing saves time, (2) phase I clinical trials can be skipped, and (3) repurposed drugs are safe as their toxicity profile is known [126]. However, the realities are much more complex, and in particular the toxicities of drug combinations can be unexpected, and should not be underestimated.…”

Section: Expert Opinionmentioning

confidence: 99%

“…However, the realities are much more complex, and in particular the toxicities of drug combinations can be unexpected, and should not be underestimated. For example, combination with cholesterol medication pravastatin with idarubicin and cytarabine resulted in multi-organ failure in AML patients [126]. Thus, it remains vital to develop better AI and ML models to predict combinatorial toxicities.…”

Section: Expert Opinionmentioning

confidence: 99%

Artificial intelligence, machine learning, and drug repurposing in cancer

Tanoli

Vähä‐Koskela

Aittokallio

2021

Expert Opinion on Drug Discovery

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Introduction: Drug repurposing provides a cost-effective strategy to re-use approved drugs for new medical indications. Several machine learning (ML) and artificial intelligence (AI) approaches have been developed for systematic identification of drug repurposing leads based on big data resources, hence further accelerating and de-risking the drug development process by computational means. Areas covered: The authors focus on supervised ML and AI methods that make use of publicly available databases and information resources. While most of the example applications are in the field of anticancer drug therapies, the methods and resources reviewed are widely applicable also to other indications including COVID-19 treatment. A particular emphasis is placed on the use of comprehensive target activity profiles that enable a systematic repurposing process by extending the target profile of drugs to include potent off-targets with therapeutic potential for a new indication. Expert opinion: The scarcity of clinical patient data and the current focus on genetic aberrations as primary drug targets may limit the performance of anticancer drug repurposing approaches that rely solely on genomics-based information. Functional testing of cancer patient cells exposed to a large number of targeted therapies and their combinations provides an additional source of repurposing information for tissue-aware AI approaches.

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“…Drug repurposing as an alternative method offers multiple advantages; compounds already in clinical use will typically have a known safety and toxicity profile, leading to accelerated timelines and reduced costs [ 19 ]. The unaffordable prices of traditionally developed compounds combined with an unmet clinical need to improve OS in AML have encouraged the exploration of repurposing as a feasible strategy [ 42 ]. Several examples of drug repurposing in AML have been identified in the literature [ 43 , 44 ]; most often, these arise serendipitously through observed side effects, as evidenced by thalidomide [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Multiplex Screening for Interacting Compounds in Paediatric Acute Myeloid Leukaemia

Cairns

Lappin

Mutch

et al. 2021

IJMS

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Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.

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Has Drug Repurposing Fulfilled Its Promise in Acute Myeloid Leukaemia?

Cited by 11 publications

References 165 publications

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Clinical Implications of Inflammation in Acute Myeloid Leukemia

Artificial intelligence, machine learning, and drug repurposing in cancer

Multiplex Screening for Interacting Compounds in Paediatric Acute Myeloid Leukaemia

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