EORTC-related new drug discovery and development activities: role of the Pharmacology and Molecular Mechanisms Group

Peters, Godefridus J.; Chatelut, Étienne; Larsen, Annette K.; Zaffaroni, Nadia

doi:10.1016/s1359-6349(12)70022-8

Cited by 3 publications

(4 citation statements)

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“…However, it was discontinued due to lack of in vivo activity, possibly because of poor pharmacokinetics. Guidelines developed by the Joint Formulation Working party of the Screening and Pharmacology Group (SPG) which was continued as a PAMM sub-committee and renamed into: Drug Discovery Committee (DDC) [11] A completely different compound, NSC-625492 was selected for its unique molecular structure being a bismuth analogue (Figure 4). The GI50 was low (0.3 µM) with activity in many tumour types (colon, ovarian, non-small cell lung cancer and leukaemia; Figure 2).…”

Section: Examples Of Selected Compoundsmentioning

confidence: 99%

“…The authors thank all members of the European NCI compounds group [10,11], consisting of investigators from the former EORTC-SPG and PTMG groups, the NCI, CRC and CRUK and the current EORTC-PAMM group and its DDC group.…”

Section: Acknowledgementsmentioning

confidence: 99%

“…In order to speed up the backlog in this development and since many compounds came from Europe, an international academic collaboration between both sides of the Atlantic was initiated in 1993, between the EORTC Research Branch, the Cancer Research Campaign (CRC, now CRUK) and the NCI, the so-called European NCI compounds initiative, which focused on compounds synthesised in Europe and showing interesting data in the NCI screen. CRC and EORTC set up a review committee to select European compounds for further development [10,11]. About 2,000 compounds were evaluated by the CRC-EORTC review committee in >20 years and 95 were selected for further evaluation.…”

Section: Introductionmentioning

confidence: 99%

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The role of pharmacology in anticancer drug development

Peters

Govaerts

Hendriks³

et al. 2018

ADMET DMPK

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Section: Examples Of Selected Compoundsmentioning

confidence: 99%

Section: Acknowledgementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of pharmacology in anticancer drug development

Peters

Govaerts

Hendriks³

et al. 2018

ADMET DMPK

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“…Currently most combinations are established using various in vitro assays either focusing on the interaction of drugs on a specific target in a cell-free system, or using a pharmacological assay as summarized previously (7)(8)(9). However, an often observed mistake is the lack of proper controls (simply testing the effect of the single agent and combined effect over the whole tested concentration range on cells).…”

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confidence: 99%

To Combine or Not Combine: Drug Interactions and Tools for Their Analysis. Reflections from the EORTC-PAMM Course on Preclinical and Early-phase Clinical Pharmacology

et al. 2019

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Combination therapies are used in the clinic to achieve cure, better efficacy and to circumvent resistant disease in patients. Initial assessment of the effect of such combinations, usually of two agents, is frequently performed using in vitro assays. In this review, we give a short summary of the types of analyses that were presented during the Preclinical and Early-phase Clinical Pharmacology Course of the Pharmacology and Molecular Mechanisms Group, European Organization for Research and Treatment on Cancer, that can be used to determine the efficacy of drug combinations. The effect of a combination treatment can be calculated using mathematical equations based on either the Loewe additivity or Bliss independence model, or a combination of both, such as Chou and Talalay's mediandrug effect model. Interactions can be additive, synergistic (more than additive), or antagonistic (less than additive). Software packages CalcuSyn (also available as CompuSyn) and Combenefit are designed to calculate the extent of the combined effects. Interestingly, the application of machinelearning methods in the prediction of combination treatments, which can include pharmacogenomic, genetic, metabolomic and proteomic profiles, might contribute to further refinement of combination regimens. However, more research is needed to apply appropriate rules of machine learning methods to ensure correct predictive models.Even as early as the 1960s, the majority of clinical treatments consisted of combination regimens. Combinations such as mechlorethamine, vincristine, procarbazine and prednisone (MOPP), and cyclophosphamide, hydroxydaunorubicin and oncovin with prednisone (CHOP) represented a breakthrough in the cure of lymphoma, while other combinations led to a high curation rate in childhood leukaemia (1). Depending on the type of combination used, the treatment rationale is to i) increase the efficacy of each separate drug without increasing toxicity, ii) add a drug which offers protection against toxicity, iii) bypass resistance development, or iv) target different subpopulations in a heterogeneous tumour. The initial clinical rationale was to achieve a better therapeutic effect (e.g. a complete response) than accomplished by each drug separately (e.g. only a partial response) (2). Historically, the selection of drugs to apply in combination therapies was based on the observation that each of the drugs showed antitumor activity against a certain tumour type, preferably with different toxicities of the two drugs. Doses and schedules were determined by trial and error. Soon thereafter, a complementary scientific approach was used to select combinations based on the mechanisms of action of each drug (3). An excellent example is the gemcitabine-cisplatin combination, which was initially developed by our group (4) (with the aim of preventing repair of DNA-platinum adducts) and is now standard therapy for tumours such as non-small cell lung cancer and bladder cancer. Another combination is 3303

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Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative

Hendriks¹,

Govaerts

Fichtner

et al. 2017

Br J Cancer

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Background:The European NCI compounds programme, a joint initiative of the EORTC Research Branch, Cancer Research Campaign and the US National Cancer Institute, was initiated in 1993. The objective was to help the NCI in reducing the backlog of in vivo testing of potential anticancer compounds, synthesised in Europe that emerged from the NCI in vitro 60-cell screen.Methods:Over a period of more than twenty years the EORTC—Cancer Research Campaign panel reviewed ∼2000 compounds of which 95 were selected for further evaluation. Selected compounds were stepwise developed with clear go/no go decision points using a pharmacologically directed programme.Results:This approach eliminated quickly compounds with unsuitable pharmacological properties. A few compounds went into Phase I clinical evaluation. The lessons learned and many of the principles outlined in the paper can easily be applied to current and future drug discovery and development programmes.Conclusions:Changes in the review panel, restrictions regarding numbers and types of compounds tested in the NCI in vitro screen and the appearance of targeted agents led to the discontinuation of the European NCI programme in 2017 and its transformation into an academic platform of excellence for anticancer drug discovery and development within the EORTC-PAMM group. This group remains open for advice and collaboration with interested parties in the field of cancer pharmacology.

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EORTC-related new drug discovery and development activities: role of the Pharmacology and Molecular Mechanisms Group

Cited by 3 publications

References 61 publications

The role of pharmacology in anticancer drug development

The role of pharmacology in anticancer drug development

To Combine or Not Combine: Drug Interactions and Tools for Their Analysis. Reflections from the EORTC-PAMM Course on Preclinical and Early-phase Clinical Pharmacology

Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative

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