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Medicinal Polypharmacology in the Clinic - Translating the Polypharmacolome into Therapeutic Benefit.

ABSTRACT: Drugs with multiple targets, often annotated as 'unselective', 'promiscuous', 'multitarget', or 'polypharmacological', are widely considered in both academic and industrial research as a high risk due to the likelihood of adverse effects. However, retrospective analyses have shown that particularly approved drugs bear rich polypharmacological profiles. This raises the question whether our perception of the specificity paradigm ('one drug-one target concept') is correct - and if specifically multitarget drugs should be developed instead of being rejected. These questions provoke a paradigm shift - regarding the development of polypharmacological drugs not as a 'waste of investment', but acknowledging the existence of a 'lack of investment'. This perspective provides an insight into modern drug development highlighting latest drug candidates that have not been assessed in a broader polypharmacology-based context elsewhere embedded in a historic framework of classical and modern approved multitarget drugs. The article shall be an inspiration to the scientific community to re-consider current standards, and more, to evolve to a better understanding of polypharmacology from a challenge to an opportunity.

SUBMITTER: Rafehi M

PROVIDER: S-EPMC10927880 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Medicinal Polypharmacology in the Clinic - Translating the Polypharmacolome into Therapeutic Benefit.

Rafehi Muhammad M Möller Marius M Ismail Al-Khalil Wouroud W Stefan Sven Marcel SM

Pharmaceutical research 20240216 3

Drugs with multiple targets, often annotated as 'unselective', 'promiscuous', 'multitarget', or 'polypharmacological', are widely considered in both academic and industrial research as a high risk due to the likelihood of adverse effects. However, retrospective analyses have shown that particularly approved drugs bear rich polypharmacological profiles. This raises the question whether our perception of the specificity paradigm ('one drug-one target concept') is correct - and if specifically mult ...[more]

PMID: 38366233

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Project description:Background & aimsThe progress toward clinical translation of imaging biomarkers for mass-forming intrahepatic cholangiocarcinoma (MICC) is slower than anticipated. Questions remain on the biologic behaviour underlying imaging traits. We developed and validated imaging-based prognostic systems for resected MICCs with an appraisal of the tumour immune microenvironment (TIME) underpinning patient-specific imaging traits.MethodsBetween January 2009 and December 2019, a total of 322 patients who underwent dynamic computed tomography/magnetic resonance imaging and curative-intent resection for MICC at three hepatobiliary institutions were retrospectively recruited, divided into training (n = 193) and validation (n = 129) datasets. Two radiological and clinical scoring (RACS) systems, one integrating preoperative variables and one integrating preoperative and postoperative variables, were developed using Cox regression analysis. We then prospectively analysed the TIME of tissue samples from 20 patients who met study criteria from January 2021 to December 2021 using multiplexed immunofluorescence.ResultsPreoperative and postoperative MICC-RACS systems built on carbohydrate antigen 19-9, albumin, tumour number, radiological/pathological nodal status, pathological necrosis, and three radiological traits (arterial enhancement pattern, tumour boundary, and capsular retraction) demonstrated good performance in predicting disease-specific (C-statistic >0.80) and disease-free (C-statistic >0.75) survival that outperformed rival models and staging systems across study cohorts (P <0.05 for all). Patients with MICC-RACS score of 0-2 (low risk), 3-5 (medium risk), and ≥6 (high risk) had incrementally worse prognosis after surgery. Significant differences in spatial distribution and infiltration level of immune cells were identified between arterial enhancement patterns. Enhanced infiltration of immunosuppressive regulatory T cells and M2-like macrophages at the invasive margin were noted in tumours with distinct boundary and capsular retraction, respectively.ConclusionsOur MICC-RACS systems are simple but powerful prognostic tools that may facilitate the understanding of spatially distinct TIMEs and patient-tailored immunotherapy approach.Impact and implicationsThe progress toward clinical translation of imaging biomarkers for mass-forming intrahepatic cholangiocarcinoma (MICC) is slower than anticipated. Questions remain on the biologic behaviour of MICC underlying imaging traits. In this study, we proposed novel and easy-to-use tools, built on radiological and clinical features, that demonstrated good performance in predicting the prognosis either before or after surgery and outperformed rival models/systems across major imaging modalities. The characteristic radiological traits integrated into prognostic systems (arterial enhancement pattern, tumour boundary, and capsular retraction) were highly correlated with heterogeneous tumour-immune microenvironments, thereby renovating treatment paradigms for this difficult-to-treat disease.

Dataset Information

Medicinal Polypharmacology in the Clinic - Translating the Polypharmacolome into Therapeutic Benefit.

Publications

Medicinal Polypharmacology in the Clinic - Translating the Polypharmacolome into Therapeutic Benefit.

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