Non-cancer Drugs Research Articles

Combined In Silico and In Vitro Evidence Supporting an Aurora A Kinase Inhibitory Role of the Anti-Viral Drug Rilpivirine and an Anti-Proliferative Influence on Cancer Cells.

The global burden of cancer necessitates rapid and ongoing development of effective cancer therapies. One promising approach in this context is the repurposing of existing non-cancer drugs for cancer indications. A key to this approach is selecting the cellular targets against which to identify novel repurposed drugs for pre-clinical analysis. Protein kinases are highly sought-after anticancer drug targets since dysregulation of kinases is the hallmark of cancer. To identify potential kinase-targeted drug candidates from the existing portfolio of non-cancer therapeutics, we used combined in silico and in vitro approaches, including ligand-based 3D screening followed by biochemical and cellular assessments. This strategy revealed that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In view of previous findings implicating Aurora A kinase in abnormal cell cycle regulation, we also examined the influence of rilpivirine on the growth of T47D breast cancer cells. Herein, we detail the identification of rilpivirine as an Aurora A kinase inhibitor, its molecular basis of inhibitory activity towards this kinase, and its Aurora A-mediated anticancer mechanisms in T47D cells. Our results illustrate the value of integrated in silico and in vitro screening strategies in identifying repurposed drug candidates and provide a scientific basis for further exploring the potential anticancer properties of the anti-viral drug rilpivirine.

Drug repurposing as a potential source of innovative therapies in cervical cancer

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...

Drug Repurposing Strategies for Non-cancer to Cancer Therapeutics.

Global efforts invested in the prevention and treatment of cancer need to be repositioned to develop safe, effective, and economic anticancer therapeutics by adopting rational approaches of drug discovery. Drug repurposing is one of the established approaches to reposition old, clinically approved off-patent noncancer drugs with known targets into newer indications. The literature review suggests a key role of drug repurposing in the development of drugs intended for cancer as well as noncancer therapeutics. A wide category of noncancer drugs such as, drugs acting on CNS, anthelmintics, cardiovascular drugs, antimalarial drugs, anti-inflammatory drugs, have come out with interesting outcomes during preclinical and clinical phases. In the present article, a comprehensive overview of the current scenario of drug repurposing for the treatment of cancer has been focused. The details of some successful studies along with examples have been included followed by associated challenges.

Assessment in vitro of interactions between anti-cancer drugs and noncancer drugs commonly used by cancer patients.

Cancer patients often suffer from cancer symptoms, treatment complications and concomitant diseases and are, therefore, often treated with several drugs in addition to anticancer drugs. Whether such drugs, here denoted as 'concomitant drugs', have anticancer effects or interact at the tumor cell level with the anticancer drugs is not very well known. The cytotoxic effects of nine concomitant drugs and their interactions with five anti-cancer drugs commonly used for the treatment of colorectal cancer were screened over broad ranges of drug concentrations in vitro in the human colon cancer cell line HCT116wt. Seven additional tyrosine kinase inhibitors were included to further evaluate key findings as were primary cultures of tumor cells from patients with colorectal cancer. Cytotoxic effects were evaluated using the fluorometric microculture cytotoxicity assay (FMCA) and interaction analysis was based on Bliss independent interaction analysis. Simvastatin and loperamide, included here as an opioid agonists, were found to have cytotoxic effects on their own at reasonably low concentrations whereas betamethasone, enalapril, ibuprofen, metformin, metoclopramide, metoprolol and paracetamol were inactive also at very high concentrations. Drug interactions ranged from antagonistic to synergistic over the concentrations tested with a more homogenous pattern of synergy between simvastatin and protein kinase inhibitors in HCT116wt cells. Commonly used concomitant drugs are mostly neither expected to have anticancer effects nor to interact significantly with anticancer drugs frequently used for the treatment of colorectal cancer.

REPURPOSING DRUGS FOR CANCER THERAPY

Cancer remains a second leading cause of death worldwide. The economic burden of cancer is increasing day by day due to the morbidity, recurrence, and poor prognosis of this disease. Over the last decades, there is an increasing need to discover and development effective and safe therapeutic agents for cancer. Traditionally, the development and approval of new drugs are long term and also costly. Therefore, this has encouraged scientists to repurposing of known drugs for the treatment of cancer. This strategy has been considered as a good way to offer safe, effective and cost-effective new anticancer drugs. Approximately, 300 non-cancer drugs have been shown to exhibit anticancer effect on different cancer cells, thus they are promising anticancer potential and, candidates for development. However, the appropriate and comprehensive research is required in order to define exact mechanism, dosage and toxicity potential of repurposed drugs. A broad range of therapeutic strategies should be used in order to assess the success of repurposed drugs in replacement of conventional cancer therapies or enhancement of chemotherapy. 

A comparative study of cancer drug approvals in india and high-income countries

BackgroundThe new drug approval in every country is closely monitored and regulated by central authorities which regulates drug development, approval, and marketing. In this study, we aim to analyze and compare the approval status of drugs that are approved for medical use in India by the Central Drugs Standard Control Organization (CDSCO) with the drug approval organizations of Western Countries. MethodsWe conducted a retrospective cross-sectional study. We queried the CDSCO website and database for new drugs and anti-cancer drugs that are approved for use in India by CDSCO during 2010–2019. We compared the approval status of those drugs in the FDA (Food and Drug Administration), EMA (European Medicines Agency), and Health Canada (HC) databases. ResultsA total of 257 new drugs (including 47 anti-cancer drugs) are approved for use in India by the CDSCO during the period 2010–2019. Out of these, only 69.6% (n = 179) new drugs were approved by the FDA, 62.65% (n = 161) were approved by EMA and 63.40% were approved by Health Canada (n = 163). Most of the anti-cancer drugs that are approved for use in India are approved by these agencies except 2 drugs that are not approved by FDA and HC. ConclusionMajority of cancer drugs approved for use in India are approved for use in the USA, Europe and Canada. However, a significant number of non-cancer drugs approved for use in India are not approved in these regions. Policy summaryWe recommend a comprehensive assessment of India’s drug regulatory processes and policies to improve patient safety.

Safety verification of a new peripheral intravenous catheter placed in the upper arm vein for administration of drugs with high irritant potential.

Despite the widespread use of peripheral intravenous catheters, unscheduled catheter failure before completion of treatment occurs frequently. If a large vein is selected, catheter failures may be prevented despite administering a highly irritant drug. In this study, we attempted to use a catheter that can be placed in a large upper arm vein. The new catheter was 88 mm long but had no guidewire to reduce contamination risk. This study aimed to evaluate the safety of the first-in-human trial for the new catheter with the administration of highly irritant drugs. This study was conducted at a university hospital in Tokyo, Japan. Eight Japanese adults were hospitalized adults with planned administration of non-cancer drugs with high irritant potential using a peripheral catheter. A trained nurse catheterized with the new catheter in the upper arm using ultrasonography. The catheterization site was monitored by staff and a research nurse once every 24 hours for up to 7 days. No adverse events or catheter failure occurred and the catheter placement success rate was 100%. In two patients, a temporary occlusion alarm of the infusion pump occurred, possibly due to the flexion of the catheter base. The new peripheral intravenous catheter did not interrupt medical treatments as is common after placement, but safety administered the irritant drugs. However, because this catheter may be easily affected by the contraction of the muscle at the fixation position, the position and method of catheter fixation in the upper arm need to be carefully considered.

Review of the Chinese Landscape in Phase 1 Clinical Trials for Noncancer Innovative Drugs Over 2015 to 2020.

In recent years, the research and development (R&D) of innovative drugs in China has been dramatically accelerated. And the early clinical study is crucial for drug R&D. However, little is known involving the change of phase I trials for noncancer drugs. We retrieved the data of phase I clinical trials for noncancer innovative drugs on the Registration and Information Disclosure Platform for Drug Clinical Studies on the Center for Drug Evaluation. The number of clinical trials proliferating in recent years and the average annual growth rates of chemical and biological drugs were 55.5% and 42.1%, respectively. Most trials were distributed in Beijing, Shanghai, and other developed coastal cities. Moreover, the clinical trials of innovative drugs in China were focused on the digestive and endocrine systems, whereas the pediatric and orphan drugs were scarce. Based on the data assessment, this work provided comprehensive analysis and suggestions about Chinese drug R&D. Significant advancement has been made in mainland China with the implementation of available policies and the emergence of advanced technologies. Though shortcomings, including uneven geographic distribution and lack of pediatric and orphan drugs, still exist, we believe progress will continue to be made in mainland China.

Efficacy End Points and Dose Analysis of Food and Drug Administration-Approved Novel Drugs in 2020

During 2020, the Food and Drug Administration approved 53 novel drugs. Biomarkers, surrogate endpoints and dosing regimens used in early and pivotal clinical stages are evaluated. Information on various efficacy end points of 2020 Food and Drug Administration approved novel drugs was gathered from the Drug Approvals and Databases page of the Food and Drug Administration website. Endpoint data from efficacy end points for the 2019 approved novel drugs by Tong and Wang are used as a comparison. Among the 53 drugs approved during 2020, 49 were for treatment of various diseases and 4 were for diagnostics. Twenty-five drug approvals (51%, relative to 49 drugs for treatment of diseases) were based on surrogate end points, consisting of 12 accelerated approvals and 13 regular approvals. There were 19 drug approvals for cancer treatments (39%, relative to 49 drugs for treatment of diseases). During 2019, there were 48 drugs approved. Forty-four were for treatment of various diseases and 4 were for diagnostics. Fourteen drug approvals (32%, relative to 44 drugs for treatment of diseases) were based on surrogate end points, consisting of 9 accelerated approvals and 5 regular approvals. There were 10 drug approvals for cancer treatments (23%, relative to 44 drugs for treatment of diseases).The approved doses were usually much closer to the highest dose tested in clinical trials (about 2-fold lower) compared with the lower dose tested in clinical trials (about 11-fold higher). Large and variable distances between the starting low dose in humans and the final approved doses indicate that finding the optimal dose in clinical trials is still a time-consuming and costly process. Further dose analysis for cancer drugs approved during 2020 showed that the distances between the starting dose in human beings and the final approved doses of cancer drugs were still large and variable, similar to distances in noncancer drugs. Stratification of drugs approved in 2020 by molecular weights shows that small molecular weights (<1000 Daltons) appeared to be smaller and less variable than those for drugs with large molecules (>1000 Daltons). (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX). Surrogate end points with accelerated approval have been widely used for approvals, with an increasing trend from 2019 to 2020 (32% vs. 51%). The approved doses usually were much higher (10-fold) than the lowest tested dose in first-in-human trials, while much closer (2-fold lower) to the highest dose tested in clinical trials.

A Database of Drug Repurposing Clinical Trials in Oncology.

Drug repurposing is a strategy that seeks new medical treatments from existing licensed medications rather than from de novo development of new molecules. The rationale for this approach is predicated in part on the perceived advantages of using existing data on safety and toxicity, the ready availability of such medicines and the potential for lowered drug costs (Pantziarka et al., 2014; Bertolini et al., 2015). In particular, the use of non-cancer drugs as new cancer treatments is becoming an increasingly attractive proposition. While bibliometric data shows an exponential increase in the peer reviewed literature in this area, much of it remains focused on drug candidate identification and pre-clinical studies (Pantziarka et al., 2020). There has been a growth of computational support for candidate identification in recent years, with a focus on algorithms and database support to enhance disease-target-drug analysis (Peyvandipour et al., 2018; Zhu et al., 2018; Tanoli et al., 2021). A notable contribution to the field is the PRISM (profiling relative inhibition simultaneously in mixtures) system from the Broad Institute. This open access resource records the growth inhibitory activity of thousands of compounds against more than 500 cancer cell lines (Corsello et al., 2020). The importance of regulatory approvals, intellectual property rights and other non-clinical factors in repurposing have also been highlighted and discussed, particularly by Verbaanderd et al. (2019) and by Begley et al. (2021). To date there has not been a comprehensive analysis of clinical trials in repurposing in oncology. The answers to key questions regarding the proportion of clinical trials by drug, by phase, by geographic location or cancer indication remain unclear. This work describes the methodology for the creation of a curated database of drug repurposing clinical trials in oncology. The database, which we have called the ReDO_Trials_DB, is available as an online, open access database with basic search, filtering and download functionality. Definitions of drug repurposing, sometimes also called drug repositioning, vary widely and can encompass multiple drug development strategies from the further development of previously shelved compounds to the use of licensed cancer drugs in new cancer types to the exploration of non-cancer drugs as new cancer therapeutics (Pushpakom et al., 2019; Pantziarka et al., 2020). In this work we are focused specifically on the use of licensed non-cancer drugs as potential cancer therapeutics. To this end the list of drugs classed as repurposing candidates is derived from the ReDO_DB (https://www.anticancerfund.org/en/redo-db), our previously published drug repurposing database (Pantziarka et al., 2018). To recap, drugs are included in the ReDO_DB if they meet the following criteria: • Licensed by one or more national/international medicines regulatory agency (e.g., FDA, EMA, MHRA etc) • Are not licensed for a cancer indication, although drugs used for symptomatic or diagnostic uses in cancer can be included (e.g., anti-emetics) if there is evidence of anticancer activity as well • Have published evidence of anti-cancer activity, including in vitro, in vivo, case reports, observational studies or clinical trials In this paper we present the ReDO_Trials_DB, the methodology employed to generate and maintain it and a first description of the number and characteristics of the included trials.

Everything Old Is New Again: Drug Repurposing Approach for Non-Small Cell Lung Cancer Targeting MAPK Signaling Pathway.

Non-small cell lung cancer (NSCLC) is a prominent subtype of lung carcinoma that accounts for the majority of cancer-related deaths globally, and it is responsible for about 80% to 85% of lung cancers. Mitogen-Activated Protein Kinase (MAPK) signaling pathways are a vital aspect of NSCLC, and have aided in the advancement of therapies for this carcinoma. Targeting the Ras/Raf/MEK/ERK pathway is a promising and alternative method in NSCLC treatment, which is highlighted in this review. The introduction of targeted medicines has revolutionized the treatment of patients with this carcinoma. When combined with current systems biology-driven stratagems, repurposing non-cancer drugs into new therapeutic niches presents a cost-effective and efficient technique with enhancing outcomes for discovering novel pharmacological activity. This article highlights the successful cutting-edge techniques while focusing on NSCLC targeted therapies. The ultimate challenge will be integrating these repurposed drugs into the therapeutic regimen of patients affected with NSCLC to potentially increase lung cancer cure rates.

Health technology assessment (HTA) in England, France and Germany: what do matched drug pairs tell us about recommendations by national HTA agencies?

Aims: To explore health technology assessment (HTA) outcomes of matched drug pairs by national agencies in Germany (Gemeinsamer Bundesausschuss, GBA), France (Haute Autorité de Santé, HAS) and England and Wales (NICE). Methods: We considered published GBA decisions, HAS reports and NICE guidance from January 2011 to June 2018. HTAs of matched pairs were compared overall, and for non-cancer and cancer drugs separately. We further analyzed the role of additional attributes related to cancer therapies. Results: Matched pairs show higher concordance for GBA/HAS than for GBA/NICE and HAS/NICE. Overall, NICE evaluated technologies more favorably than GBA and HAS. GBA appraisals ofcancer drugs, however, tended to be more positive than cancer-related recommendations by NICE and HAS. Conclusion: The findings indicate substantial variations in HTAs, although cancer-related outcomes seem to diverge less than non-cancer results.

Use of non-cancer drugs and survival among patients with pancreatic adenocarcinoma: a nationwide registry-based study in Norway

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.

Differential Protein Interactome in Esophageal Squamous Cell Carcinoma Offers Novel Systems Biomarker Candidates with High Diagnostic and Prognostic Performance.

Esophageal squamous cell carcinoma (ESCC) is among the most dangerous cancers with high mortality and lack of robust diagnostics and personalized/precision therapeutics. To achieve a systems-level understanding of tumorigenesis, unraveling of variations in the protein interactome and determination of key proteins exhibiting significant alterations in their interaction patterns during tumorigenesis are crucial. To this end, we have described differential protein-protein interactions and differentially interacting proteins (DIPs) in ESCC by utilizing the human protein interactome and transcriptome. Furthermore, DIP-centered modules were analyzed according to their potential in elucidation of disease mechanisms and improvement of efficient diagnostic, prognostic, and treatment strategies. Seven modules were presented as potential diagnostic, and 16 modules were presented as potential prognostic biomarker candidates. Importantly, our findings also suggest that 30 out of the 53 repurposed drugs were noncancer drugs, which could be used in the treatment of ESCC. Interestingly, 25 of these, proposed as novel drug candidates here, have not been previously associated in a context of esophageal cancer. In this context, risperidone and clozapine were validated for their growth inhibitory potential in three ESCC lines. Our findings offer a high potential for the development of innovative diagnostic, prognostic, and therapeutic strategies for further experimental studies in line with predictive diagnostics, targeted prevention, and personalization of medical services in ESCC specifically, and personalized cancer care broadly.

Repurposing existing therapeutics, its importance in oncology drug development: Kinases as a potential target.

Repurposing the large arsenal of existing non‐cancer drugs is an attractive proposition to expand the clinical pipelines for cancer therapeutics. The earlier successes in repurposing resulted primarily from serendipitous findings, but more recently, drug or target‐centric systematic identification of repurposing opportunities continues to rise. Kinases are one of the most sought‐after anti‐cancer drug targets over the last three decades. There are many non‐cancer approved drugs that can inhibit kinases as “off‐targets” as well as many existing kinase inhibitors that can target new additional kinases in cancer. Identifying cancer‐associated kinase inhibitors through mining commercial drug databases or new kinase targets for existing inhibitors through comprehensive kinome profiling can offer more effective trial‐ready options to rapidly advance drugs for clinical validation. In this review, we argue that drug repurposing is an important approach in modern drug development for cancer therapeutics. We have summarized the advantages of repurposing, the rationale behind this approach together with key barriers and opportunities in cancer drug development. We have also included examples of non‐cancer drugs that inhibit kinases or are associated with kinase signalling as a basis for their anti‐cancer action.

Repurposing of Antimicrobial Agents for Cancer Therapy: What Do We Know?

Simple SummaryDespite the leaps and bounds in the prevention and treatment of cancer, it remains the second leading cause of death worldwide. A significant hurdle during cancer treatment is the occurrence of intrinsic and acquired therapeutic resistance. This latter case emphasizes the need for new drugs to overcome the challenges resulting from the current therapy. Considering that every drug has at least six off-targets, which might be relevant in cancer therapy, makes drug repurposing an excellent mean to speed up access to new therapeutic options. This review aims to thoroughly discuss anti-microbial agents currently in different trials or those evaluated in pre-clinical settings against various types of cancer and provide an overview of the mechanism(s) by which these agents exert their effects. The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.

Repurposing calcium channel blockers: may be sensible combination with erlotinib for non-small cell lung cancer.

Erlotinib is a tyrosine kinase inhibitor that inhibits epidermal growth factor receptor. It is being used for metastatic non-small cell lung cancer patients (NSCLC). Repurposing noncancer drugs for cancer treatment is a current issue and it has many advantages. We planned to reveal the effects of noncancer drugs [calcium channel blockers (CCBs) and others] on erlotinib. We scanned the files of NSCLC patients retrospectively who were applied to Karadeniz Technical University between January 2013 and April 2019 and used erlotinib. There were 63 patients, 9 of them were taking CCB simultaneously for arterial hypertension. We analyzed some parameters of these patients and their effects on overall survival (OS) and progression-free survival (PFS). A χ2 or Fisher's exact test, Kaplan-Meier and Cox regressions were used in the statistical analysis. 12-month OS rates of CCB user and nonuser were 78.3 and 39.7%, respectively, [odds ratio (OR),0.14; 95% confidence interval (CI), 0.27-0.75; P = 0.023]. 24-month PFS rates of CCB user and nonuser were 44.4 and 8.3%, respectively (OR,0.11; 95% CI, 0.02-0.60; P = 0.016). There was 12-month OS and 24-month PFS advantage with simultaneously taking CCBs and erlotinib, they have an additive effect for NSCLC. This study will be inspiring future prospective studies.

Temporal trends in oncology drug revenue among the world’s major pharmaceutical companies: A 2010-2019 cohort study.

6505 Background: In the past decade there has been a 70% increase in the number of clinical trials for cancer drugs. During this time, there has also been a substantial increase in the price of cancer drugs. It is unclear how these trends have changed the revenue landscape of major pharmaceutical companies. In this study we characterize temporal trends in cancer drug revenue relative to non-cancer drugs. Methods: This retrospective cohort study used publicly available global sales data from the 10 pharmaceutical companies with the highest annual revenue in 2019; Abbvie (AB), AstraZeneca (AZ), Bristol Myers Squibb (BMS), GlaxoSmithKline (GSK), Johnson &amp; Johnson (JJ), Merck (M), Novartis (N), Pfizer (P), Roche (R) and Sanofi (S). We quantified the contribution of cancer drugs to net revenue for each company from 2010 – 2019 using consolidated annual financial reports (i.e. 10-K or 20-F forms). Cancer drugs were defined as those with an FDA-approved indication for anti-cancer effect or supportive care. All sales data were converted to USD and adjusted for global inflation. Trends in the percentage of company revenues accounted for by cancer drugs were assessed with the Kendall-Mann test. P-values were adjusted for multiple hypothesis testing using the Benjamini-Hochberg method. Results: During 2010-2019, cumulative annual revenue generated from cancer drugs in our cohort of companies (n = 10) increased by 96%, from $52.8 billion to $103.5 billion. The cumulative revenue from non-oncology drugs decreased by 19%, from $342.5 billion to $276.9 billion. The proportion of total revenue generated from cancer drugs grew over time; from 13% in 2010 to 27% in 2019 (p &lt; 0.001). During 2015-2019, annual revenue for the study cohort grew by 12%: from $339.7 billion to $380.4 billion. During this period non-oncology revenues remained stagnant (mean $278.9 billion, range 276.9 – 281.9), while oncology revenues grew by 66%; from $61.4 billion to $103.5 billion. Six companies (AB, AZ, BMS, JJ, N, and P) saw substantial increases in the proportion of revenue attributable to cancer drugs. R had both the highest net revenue ($23.9 billion), and highest proportion of revenue (57%) from cancer drugs in 2010 among the cohort, similar to 2019 ($27.7 billion, 57%; p = 0.37). While not reaching significance over the total study period, M saw increases in oncology revenue from $1.5 billion in 2015 to $12.3 billion in 2019 (4% to 30% of total revenue); driven almost exclusively by sales of Pembrolizumab. Conclusions: Amongst the world’s largest pharmaceutical companies, sales revenue from cancer drugs have increased by 96% over the past decade, while revenues from non-cancer drugs have decreased by 19%. Revenues from cancer drugs accounted for 27% of company revenues in 2019. Further work is needed to understand if this massive increase in sales revenues has translated into proportional improvements in patient and population outcomes.

Exploring the Efficacy of Generic Drugs in Treating Cancer

Thousands of scientific publications discuss evidence on the efficacy of non-cancer generic drugs being tested for cancer. However, trying to manually identify and extract such evidence is intractable at scale. We introduce a natural language processing pipeline to automate the identification of relevant studies and facilitate the extraction of therapeutic associations between generic drugs and cancers from PubMed abstracts. We annotate datasets of drug-cancer evidence and use them to train models to identify and characterize such evidence at scale. To make this evidence readily consumable, we incorporate the results of the models in a web application that allows users to browse documents and their extracted evidence. Users can provide feedback on the quality of the evidence extracted by our models. This feedback is used to improve our datasets and the corresponding models in a continuous integration system. We describe the natural language processing pipeline in our application and the steps required to deploy services based on the machine learning models.

Drug target ranking for glioblastoma multiforme

BackgroundGlioblastoma Multiforme, an aggressive primary brain tumor, has a poor prognosis and no effective standard of care treatments. Most patients undergoing radiotherapy, along with Temozolomide chemotherapy, develop resistance to the drug, and recurrence of the tumor is a common issue after the treatment. We propose to model the pathways active in Glioblastoma using Boolean network techniques. The network captures the genetic interactions and possible mutations that are involved in the development of the brain tumor. The model is used to predict the theoretical efficacies of drugs for the treatment of cancer.ResultsWe use the Boolean network to rank the critical intervention points in the pathway to predict an effective therapeutic strategy for Glioblastoma. Drug repurposing helps to identify non-cancer drugs that could be effective in cancer treatment. We predict the effectiveness of drug combinations of anti-cancer and non-cancer drugs for Glioblastoma.ConclusionsGiven the genetic profile of a GBM tumor, the Boolean model can predict the most effective targets for treatment. We also identified two-drug combinations that could be more effective in killing GBM cells than conventional chemotherapeutic agents. The non-cancer drug Aspirin could potentially increase the cytotoxicity of TMZ in GBM patients.