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ObjectiveDrug repurposing is an alternative development pathway that utilizes the properties of drugs approved for other diseases and builds on available safety and pharmacological data to develop the drug as a potential treatment for other diseases. A literature-based approach was performed to identify drug repurposing opportunities in cervical cancer to inform future research and trials.MethodsWe queried PubMed for each drug included in two databases (ReDO_DB and CDcervix_DB, which include 300+ non-cancer drugs and 200+ cancer drugs not used in cervical cancer, respectively) and manually assessed all abstracts for relevance and activity in cervix cancer, and type of evidence. Subsequently, we also performed a search of clinical trial databases where we generated a list of registered trials in cervical cancer with all drugs from our databases.ResultsOf the 534 drugs from both databases, 174 (33%) had at least one relevant abstract or registered trial in cervical cancer. 94 (18%) drugs had at least human data available, and 52 (10%) drugs were evaluated in registered trials. To prioritize drugs to consider for future trials, all 174 drugs were further assessed for strength of scientific rationale, feasibility for integration in cervical cancer standard of care, evidence of radiosensitization, and potential mechanism of action. Out of the 174 drugs, 38 (22%) potential drug candidates were selected.ConclusionThis study resulted in a list of candidate drugs for potential evaluation in cervical cancer. Many drugs might warrant additional (pre)clinical investigation, which could be done in a coordinated manner using platform trials.

Background The prognosis of pancreatic cancer is poor and new treatment strategies are urgently needed. To identify non-cancer drugs that could be re-purposed for cancer, we investigated the association between the use of selected drugs and cancer-specific mortality in a nationwide cohort of pancreatic cancer patients. Material and methods The study is based on linkage between the Cancer Registry of Norway and the Norwegian Prescription Database, comprising 2614 pancreatic cancer patients diagnosed between 2007 and 2014. We evaluated the association between use at diagnosis of a pre-defined list of non-cancer drugs, including metformin, antihypertensives, and statins, and pancreatic cancer-specific mortality, using Cox regression. Patients were defined as users of a particular drug if it was prescribed before diagnosis, and the prescription covered the date of diagnosis. Results In total, 2096 (80.2%) patients died from pancreatic cancer; median survival was 6 months. Statin users (n = 621) had lower mortality (hazard ratio (HR): 0.86; 95% confidence interval (CI) 0.76-0.97) compared to non-users (n = 1993). This association was more pronounced (P-heterogeneity 0.062) in users of hydrophilic (n = 37, HR: 0.61; 95% CI 0.42-0.90) than lipophilic (n = 587, HR: 0.87; 95% CI 0.78-0.98) statins. An indication for lower mortality (HR: 0.85; 95% CI 0.69-1.05) was observed in users of non-selective beta-blockers (n = 113) compared to non-users (n = 2501). Notably, when compared to users of other antihypertensives (n = 643), users of non-selective beta-blockers (n = 40) had lower mortality (HR 0.67; 95% CI 0.47-0.96). The use of other drugs, including selective beta-blockers and metformin, was not associated with mortality. Conclusion The findings suggest an association between the use of statins and non-selective beta-blockers and reduced pancreatic cancer mortality, and add to the literature supporting the design of randomised clinical trials to evaluate those drugs in the management of pancreatic cancer.

ispartof: FUTURE ONCOLOGY vol:16 issue:3 pages:4419-4423 ispartof: location:England status: published

Aims Reducing the rate of recurrence after curative-intent surgical resection is an attractive strategy for improving long-term survival in cancer. Perioperative therapies administered in the period immediately prior to, during, or after surgery therefore hold the potential to improve overall survival. Drug repurposing is a source of therapeutic candidates for further clinical investigation. We aimed to identify noncancer drugs with the potential to be repurposed as perioperative therapies. Methods The Repurposing Drugs in Oncology repurposing database and PubMed were used for a literature-based search of publications related to perioperative treatment of cancer. Three clinical trials registries were also searched to identify relevant clinical trials with survival endpoints. Both the literature and trial screens were supplemented with additional data known to the authors. Results Fifty-two drugs were identified as potential perioperative therapies, with 67% having supporting human data. There are few clinical trials with survival endpoints, mainly in breast and colorectal cancers. Discussion The perioperative setting is not as well established as the neoadjuvant and adjuvant settings, making identification of relevant research and clinical trials difficult. Despite the potential benefits of such interventions, there is a need for more well-designed clinical trials, additional research, and biomarkers of response.

Despite five decades of clinical investigations, there is currently no effective treatment for children diagnosed with Diffuse Intrinsic Pontine Glioma (DIPG). We now understand that DIPGs share the same histone 3 mutation and fatal prognosis as other diffuse midline gliomas (DMGs), which led to the introduction of a new entity referred to as DMG, H3 K27M mutant. Indeed, therapeutics indicated for other brain neoplasms have proven ineffective for DIPGs. We posit that by using a polypharmacological approach to determine drug combinations that target distinct mechanistic pathways of DIPG, it is more likely that an efficacious treatment will be developed. We predict monodrug therapies using a link prediction model trained on various embeddings of a drug-disease regulatory network and physicochemical properties of small molecules and proteins. We validate the in silico predictions by performing cell viability assays on patient-derived cell cultures for notable therapeutics. Using FDA-approved drugs as a proxy for viability of a drug pair for combinatorial use, we develop a model to predict the synergism of the relationship between drug pairs. Finally, we calculate the transitive probability that a drug pair contains drugs that individually regulate DIPG, are blood-brain barrier penetrant, and the drug pair are suitable for combined use. We find only moderate agreement between computational predictions and experimental results for both monodrug and multidrug therapies, we believe due to the heterogeneity of the disease, the difficulties of modelling brain permeability, and an inherent literature bias in the knowledge graph. Such challenges need to be overcome to develop an efficacious therapy for this disease.

BackgroundThe global pandemic caused by SARS-CoV-2 virus has prompted an unprecedented international effort to seek medicines for prevention and treatment of infection. Drug repurposing has played a key part in this response. The rapid increase in trial activity has raised questions about efficiency and lack of coordination. Our objective was to develop a user-friendly, open access database to monitor and rapidly identify trials of medicinal products.MethodsUsing the US clinicaltrials.gov (NCT) registry, the EU Clinical Trials Register (EUCTR) and the WHO International Clinical Trials Registry Platform (WHO ICTRP), we identified all COVID-19 trials of medicinal products. Trials that were out of scope and duplicates were excluded. A manual encoding was performed to ascertain key information (e.g. trial aim, type of intervention etc). The database, Covid19db, is published online at: http://www.redo-project.org/covid19db/.ResultsDescriptive statistics of the database from April 4th 2020 through to August 18th show an increase from 186 to 1618 trials, or an average of 10.5 new trials registered per day. Over this period, the proportion of trials including a repurposing arm decreased slightly (from a maximum of 75% to 64% at the end of the covered period) as did the proportion of trials aiming to prevent infection (from a maximum of 16% to 13%). The most popular trial intervention is hydroxychloroquine (212 trials), followed by azithromycin (64 trials), tocilizumab, favipiravir and chloroquine (145 trials). Total planned enrolment is 1064556 participants as of 18th August 2020.Conclusionswe have developed an open access and regularly updated tool to monitor clinical trials of medicinal products to prevent or treat infection by SARS-CoV-2 globally. Our analysis shows a high number of ‘me-too’ trials, in particular for some repurposed drugs, such as hydroxychloroquine, azithromycin and tocilizumab, substantiating calls for better coordination and better use of trial resources.

Repurposing is a drug development strategy that seeks new medical treatments using existing licensed drugs rather than from new molecular entities. There has been increasing interest in the use of this approach to develop innovative treatments in oncology, particularly with respect to the use of noncancer medications as anticancer therapeutics. The review briefly outlines the rationale for such an approach and discusses the process of selecting potential repurposing candidates and the steps necessary to develop them clinically. The challenges of clinical adoption, including regulatory issues, are also explored. Finally, the future prospects of drug repurposing in oncology are touched upon.

Breast cancer (BC) is the most frequent cancer among women in the world and it remains a leading cause of cancer death in women globally. Among BCs, triple negative breast cancer (TNBC) is the most aggressive, and for its histochemical and molecular characteristics is also the one whose therapeutic opportunities are most limited. The REpurposing Drugs in Oncology (ReDO) project investigates the potential use of off patent non-cancer drugs as sources of new cancer therapies. Repurposing of old non-cancer drugs, clinically approved, off patent and with known targets into oncological indications, offers potentially cheaper effective and safe drugs. In line with this project, this article describes a comprehensive overview of preclinical or clinical evidence of drugs included in the ReDO database and/or PubMed for repurposing as anticancer drugs into TNBC therapeutic treatments.

Introduction: Despite the relatively high prevalence of rare cancers as a collective group, the low incidence for individual rare and ultrarare cancers continues to act as an impediment to the deve...

e14564 Background: Vaccines used to prevent infection have long been known to stimulate immune responses to cancer as illustrated by the approval of the Bacillus Calmette–Guérin (BCG) vaccine to treat bladder cancer since the 1970s. The recent approval of immunotherapies has rejuvenated this research area with reports of anti-tumour responses with existing infectious diseases vaccines used as such, either alone or in combination with approved immune checkpoint inhibitors. This prompted us to review recent research activities using approved vaccines to treat cancer. Methods: PubMed and clinicaltrials.gov databases were queried for all 31 infectious diseases having at least one preventive vaccine approved, and all hits were reviewed for relevance. Only articles and trial registrations about infectious diseases vaccines used in an unmodified form as treatment for cancer, were included. The search was restricted in time, capturing articles from the year 2000 until November 2020. Results: A total of 1,754 PubMed abstracts and 549 trial registrations were screened. Data supporting a cancer therapeutic use was found for 16 of the 31 infectious diseases vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus (HPV), influenza, measles, pneumococcus, smallpox, typhoid and varicella-zoster), clinical trials have been conducted or are ongoing. Within the remaining 6, preclinical evidence supports further evaluation of the rotavirus, yellow fever and pertussis vaccine in carefully designed clinical trials. The mechanistic evidence for the cholera vaccine, combined with the observational data in colorectal cancer, is also supportive of clinical translation. There is limited data for the hepatitis B vaccine and for the mumps vaccine alone. Four findings are worth highlighting: first, the superiority of intra-vesical typhoid vaccine instillations over BCG instillations in a preclinical bladder cancer model, which is now the subject of a phase I trial; second, the perioperative use of the influenza vaccine to limit and prevent the NK cell dysfunction induced by cancer surgery; third, objective responses following intra-tumoral injections of the measles vaccine in cutaneous T-cell lymphoma; fourth, objective responses induced by the HPV vaccine in skin squamous cell carcinoma. Conclusions: Sixteen infectious diseases vaccines have been or are currently being explored for repurposing in oncology. All vaccines are intended to induce or improve an anti-tumour (immune) response. Next to biological and immunological mechanisms, that are very different from one vaccine to another, also the mode of administration and combinations and sequence with other (immuno-)therapies deserve more attention in future research.

The repurposing of existing non-cancer drugs is a potential source of new treatment options for cancer patients with high unmet medical needs. While scientific research is progressing rapidly in the field of drug repurposing, the implementation of drug repurposing still faces important financial and regulatory hurdles that should be addressed to optimise clinical adoption.

Drug repurposing is a strategy that aims to develop novel cancer treatments through the reuse of existing medicines developed in other disease areas. Such a strategy includes the identification of candidate drugs, clinical development, drug licensing, reimbursement and clinical implementation. This review outlines a literature-based approach to candidate selection with illustrative examples in osteosarcoma, pancreatic cancer and perioperative therapies. Key issues related to the development of clinical trials, drug licensing/approval and clinical adoption are explored to highlight some of the obstacles that must be overcome to successfully repurpose a drug as a new therapeutic option. ispartof: SEMINARS IN CANCER BIOLOGY vol:68 pages:186-191 ispartof: location:England status: published

Anakoinosis is a new cancer treatment paradigm that posits a key role for communicative reprogramming within tumor systems. To date no mathematical or computational models of anakoinosis have been developed. Here we outline the NEATG_A system, a first computational model of communicative reprogramming. The model recapitulates key features of real tumor systems and responses to both traditional cytotoxic treatments and biomodulatory/anakoinotic treatments. Results are presented and discussed, particularly with respect to the implications for future cancer treatment protocols.

Background. A number of recent high-profile cases have focused attention on scientific misconduct and other problematic issues with the peer review process. The retraction of journal publications is an important part of the scientific publishing process that serves to remove flawed articles, (including, but not limited to, fraudulent results), from the literature. To date there have been few formal studies of journal retractions in the area of oncology. Methods. This article outlines the results of a bibliometric study of journal retractions from 1983 to 2018. Results. Analysis shows that article lifetime – that is the time period from initial publication to ultimate retraction – has decreased in recent years. It also shows that retraction rate has also increased over the same period. The causes and context of these trends are discussed and reference made to the dangers of scientific misconduct in oncology.

Repurposing is a drug development strategy that seeks to use existing medications for new indications. In oncology, there is an increased level of activity looking at the use of non-cancer drugs as possible cancer treatments. The Repurposing Drugs in Oncology (ReDO) project has used a literature-based approach to identify licensed non-cancer drugs with published evidence of anticancer activity. Data from 268 drugs have been included in a database (ReDO_DB) developed by the ReDO project. Summary results are outlined and an assessment of clinical trial activity also described. The database has been made available as an online open-access resource (http://www.redo-project.org/db/). ispartof: ECANCERMEDICALSCIENCE vol:12 ispartof: location:England status: published

The non-selective beta-blocker propranolol is a leading candidate for repurposing as a novel anti-cancer agent. Emerging evidence, including human data, suggests that there are multiple mechanisms of action particularly relevant to breast cancer. This editorial reviews a number of recent studies that show it has anti-metastatic activity that warrants clinical investigation, including investigation as a potential perioperative therapy in breast cancer.

Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of cancers. In particular, evidence is presented that these drugs have potent immunomodulatory activity that warrants clinical study in combination with check-point inhibition.

Selective phosphodiesterase 5 inhibitors, including sildenafil, tadalafil and vardenafil, are widely-used in the treatment of erectile dysfunction and pulmonary arterial hypertension. They are also well-known as examples of successful drug repurposing in that they were initially developed for angina and only later developed for erectile dysfunction. However, these drugs may also be effective cancer treatments. A range of evidentiary sources are assessed in this paper and the case made that there is pre-clinical and clinical evidence that these drugs may offer clinical benefit in a range of cancers. In particular, evidence is presented that these drugs have potent immunomodulatory activity that warrants clinical study in combination with check-point inhibition.

Among the various measures proposed to combat the challenge of financial toxicity in cancer care, an important strategy is the use of lower-priced drugs instead of expensive alternatives. However, the oncology community seems to either ignore or more readily reject cheaper drugs in cancer care compared to more expensive alternatives. In this commentary, we present three examples of lower-priced drugs rejected or ignored by the oncology community and contrast this with three expensive drugs where persistent optimism remained despite negative clinical trial results. We argue that all drugs be held to the same rigorous standards - this not only includes skepticism in the absence of sound evidence, but also the suspension of premature judgement as has happened in the cases of repurposed drugs.

BackgroundDrug repurposing can speed up access to new therapeutic options for cancer patients. With more than 2000 drugs approved worldwide and 6 relevant targets per drug on average, the potential is quantitatively important. In this paper, we have attempted to quantify the number of non-cancer drugs supported by either preclinical or clinical cancer data.MethodsA PubMed search was performed to identify non-cancer drugs which could be repurposed in one or more cancer types. Drugs needed at least one peer-reviewed article showing an anticancer effect in vitro, in vivo or in humans.ResultsA total of 235 eligible non-cancer drugs were identified (Table 1). Main charateirstics of the drugs are summarized in Table 2. 67 (29%) are on the WHO list of essential medicines and 176 (75%) are off-patent. 133 (57%) had human data in cancer patient(s). Four were listed in clinical guidelines, namely thalidomide, all-trans retinoic acid, zoledronic acid and non-steroidal anti-inflammatory drugs (NSAID). Several drugs have shown a survival benefit in randomized trials such as cimetidine (colorectal cancer), progesterone (breast cancer) or itraconazole (lung cancer). Several other drugs induced responses in rare tumours, like clarithromycin, timolol or propranolol.ConclusionWe have found that the number of off-patent repurposing opportunities is large and increasing. Joint non-commercial clinical development (academics, governments, charities) may bring new therapeutic options to patients at low cost, especially in indications for which the industry has no incentive to invest in.

Surgical resection remains the major modality for modern curative treatment for solid tumours. However, post-surgical recurrence, even following clear-margin resection and adjuvant treatment, remains common in many types of cancer. Reducing recurrence rates, therefore, offers the potential to increase cure rates and increase overall survival. Perioperative therapies, simple interventions during the perioperative period, are designed to address some of the factors which influence post-surgical recurrence. A range of perioperative therapies are introduced and the rationale for further clinical investigation outlined.

International audience; The 5th Biennial Metronomic and Anti-angiogenic Therapy Meeting was held on 6th – 8th May in the Indian city of Mumbai. The meeting brought together a wide range of clinicians and researchers interested in metronomic chemotherapy, anti-angiogenics, drug repurposing and combinations thereof. Clinical experiences, including many from India, were reported and discussed in three symposia covering breast cancer, head and neck cancers and paediatrics. On the pre-clinical side research into putative mechanisms of action, and the interactions between low dose metronomic chemotherapy and angiogenesis and immune responses, were discussed in a number of presentations. Drug repurposing was discussed both in terms of clinical results, particularly with respect to angiosarcoma and high-risk neuroblastoma, and in pre-clinical settings, particularly the potential for peri-operative interventions. However, it was clear that there remain a number of key areas of challenge, particularly in terms of definitions, perceptions in the wider oncological community, mechanisms of action and pre- dictive biomarkers. While the potential for metronomics and drug repurposing in low and middle income countries remains a key theme, it is clear that there is also considerable potential for clinically relevant improvements in patient outcomes even in high income economies.

Propranolol (PRO) is a well-known and widely used non-selective beta-adrenergic receptor antagonist (beta-blocker), with a range of actions which are of interest in an oncological context. PRO displays effects on cellular proliferation and invasion, on the immune system, on the angiogenic cascade, and on tumour cell sensitivity to existing treatments. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. In particular there is evidence that PRO is effective at multiple points in the metastatic cascade, particularly in the context of the post-surgical wound response. Based on this evidence the case is made for further clinical investigation of the anticancer effects of PRO, particularly in combination with other agents. A number of trials are on-going, in different treatment settings for various cancers.

While there have been enormous advances in our understanding of the genetic drivers and molecular pathways involved in cancer in recent decades, there also remain key areas of dispute with respect to fundamental theories of cancer. The accumulation of vast new datasets from genomics and other fields, in addition to detailed descriptions of molecular pathways, cloud the issues and lead to ever greater complexity. One strategy in dealing with such complexity is to develop thought experiments which selectively focus on different levels of abstraction in order to build models to replicate salient features of the system and therefore to build hypotheses which reflect on the real system. NEATG is a simple non-physiological tumour growth model which displays emergent behaviours that correspond to a number of clinically relevant phenomena including tumour growth, intra-tumour heterogeneity, growth arrest and accelerated repopulation following cytotoxic insult. Analysis of model data suggests that the processes of cell competition and apoptosis are key drivers of these emergent behaviours. Questions are raised as to the role of cell competition and cell death in physical cancer growth and the relevance these have to cancer research in general is discussed.

Diclofenac (DCF) is a well-known and widely used non-steroidal anti-inflammatory drug (NSAID), with a range of actions which are of interest in an oncological context. While there has long been an interest in the use of NSAIDs in chemoprevention, there is now emerging evidence that such drugs may have activity in a treatment setting. DCF, which is a potent inhibitor of COX-2 and prostaglandin E2 synthesis, displays a range of effects on the immune system, the angiogenic cascade, chemo- and radio-sensitivity and tumour metabolism. Both pre-clinical and clinical evidence of these effects, in multiple cancer types, is assessed and summarised and relevant mechanisms of action outlined. Based on this evidence the case is made for further clinical investigation of the anticancer effects of DCF, particularly in combination with other agents - with a range of possible multi-drug and multi-modality combinations outlined in the supplementary materials accompanying the main paper.

Scientific Advice meetings are a mechanism to improve communications between drug developers and regulators during the drug-development process. While standard practice for industry, the benefits provided by these meetings are under-utilised by academia. In the context of drug repurposing, can scientific advice, as part of a proposed new R&D tax credits scheme, help to unblock some of the obstacles in the way to clinical adoption?