The concept of the pre-cancerous niche applies the ‘seed and soil’ theory of metastasis to the in... more The concept of the pre-cancerous niche applies the ‘seed and soil’ theory of metastasis to the initial process of carcinogenesis. TP53 is at the nexus of this process and, in the context of Li-Fraumeni Syndrome (LFS), is a key determinant of the conditions in which cancers are formed and progress. Important factors in the creation of the pre-cancerous niche include disrupted tissue homeostasis, cellular metabolism and chronic inflammation. While druggability of TP53 remains a challenge, there is evidence that drug re-purposing may be able to address aspects of pre-cancerous niche formation and thereby reduce the risk of cancer in individuals with LFS.
Background The prognosis of pancreatic cancer is poor and new treatment strategies are urgently n... more 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 (...
A global, comprehensive and open access listing of approved anticancer drugs does not currently e... more A global, comprehensive and open access listing of approved anticancer drugs does not currently exist. Partial information is available from multiple sources, including regulatory authorities, national formularies and scientific agencies. Many such data sources include drugs used in oncology for supportive care, diagnostic or other non-antineoplastic uses. We describe a methodology to combine and cleanse relevant data from multiple sources to produce an open access database of drugs licensed specifically for therapeutic antineoplastic purposes. The resulting list is provided as an open access database, (http://www.redo-project.org/cancer-drugs-db/), so that it may be used by researchers as input for further research projects, for example literature-based text mining for drug repurposing.
This work would not be as extensive as it is without the contribution of multiple collaborators w... more This work would not be as extensive as it is without the contribution of multiple collaborators who share our interest in drug repurposing. Though we cannot list them all, a special thank goes to Vidula Sukhatme, Vikas Sukhatme, Richard Kast & all colleagues at the Anticancer Fund.
Background. A number of recent high-profile cases have focused attention on scientific misconduct... more 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.
Vaccines used to prevent infections have long been known to stimulate immune responses to cancer ... more Vaccines used to prevent infections 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-tumor responses with existing infectious diseases vaccines used as such, either alone or in combination with immune checkpoint inhibitors. Here, we have reviewed and summarized research activities using approved vaccines to treat cancer. Data supporting a cancer therapeutic use was found for 16 vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus, 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 ...
Despite five decades of clinical investigations, there is currently no effective treatment for ch... more 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-ap...
Background: The global pandemic caused by SARS-CoV-2 virus has prompted an unprecedented internat... more Background: The 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. Methods: Using 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/. Results: Descriptive statistics of the database from April...
trial design • drug development • drug registration • patient benefit • risks of bias Pivotal cli... more trial design • drug development • drug registration • patient benefit • risks of bias Pivotal clinical trials: biased? A recent study by Naci et al. examined the design characteristics, risks of bias and reporting adequacies of pivotal randomized controlled trials of cancer drugs approved by the EMA in the period 2014-2016 [1]. During this period, 32 new cancer drugs were approved by the EMA on the basis of 54 pivotal trials-of these, 41 (76%) were randomized controlled trials and 13 (24%) were non-randomized or single arm trials. The study reported that 49% of trials were judged to be at high risk of bias based on aspects of their design, conduct or analysis. Furthermore, only 10 (26%) randomized controlled trials measured overall survival as a primary end point, with the majority of trials evaluating surrogate metrics such as progression free survival or response rates. Furthermore, there were also discrepancies between scientific publications and regulatory documentation, thereby raising concerns of reporting inadequacies and risks of bias in both sources of information. These findings raise serious questions regarding clinical trial design and the drug registration process, particularly with regards to patient benefits. The problem is not restricted to Europe alone; previous studies have also raised concerns with US FDA approvals. For example, a study that assessed all FDA approvals of novel drugs, across all areas of medicine in the period 2005-2012, reported wide disparities in pivotal trial characteristics across different therapeutic areas [2]. While overall 219 of 448 (48.9%) pivotal trials included a surrogate end point, for cancer it was 46 of 55 (83.6%). Pivotal trials in cancer were also less likely to be randomized, double-blinded or to not include a placebo or active comparator. Another notable finding was that most cancer approvals were on the basis of a single pivotal trial, whereas for other therapeutic areas, approvals were based on two to four pivotal trials. A different study examining FDA cancer drug approvals based on response rate showed that many cancer drugs are approved based on low or modest response rates, typically tested in single-arm studies [3]. It could be argued that the surrogate end points used in such pivotal trials are acceptable as they correlate to overall survival and/or quality of life in the long term [4]. However, the data to support such an argument is lacking [5]. A recent systematic review of the association between surrogate end points and overall survival in oncology showed that the vast majority (82%) are low or moderate in strength [6]. A study of FDA approvals of cancer drugs during 2008-2012, a period in which 67% of approvals were made on the basis of a surrogate end point, assessed whether subsequent data emerged to show an increase in overall survival [7]. With a median follow-up of 4.4 years, the study reported that of 36 drugs approved with surrogate end points, only five subsequently reported improved overall survival in a randomized controlled trial, 18 had been shown to not improve overall survival in subsequent trials and 13 had not been tested or had not reported overall survival in subsequent trials. Similar results have also been reported for EMA approvals for drugs approved without a survival or quality of life end point [8]. Indeed, equally concerning is the fact that, in many cases, even the surrogate end points in pivotal trials are not subsequently replicated in post-approval studies [9].
The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing... more The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.
NEATG is a simple non-physiological tumour growth model which displays emergent properties which ... more NEATG is a simple non-physiological tumour growth model which displays emergent properties which are analogous to a number of characteristics common to physical tumour growth. NEATG employs a novel dual-scale evolutionary algorithm which models both cell-autonomous and non-cell autonomous behaviours. The components of the model are outlined briefly, with reference to the core algorithm and data structures. Experimental results are presented which illustrate the behaviour of the model under different evolutionary scenarios, including homeostasis, tumour growth and a number of anti-tumour interventions. In particular the system is used to explore the impact of cytotoxic interventions, (analogous to high-dose chemotherapy), with respect to adaptive responses and evolutionary change. Finally, a number of avenues for further development of the system are discussed.
While there have been enormous advances in our understanding of the genetic drivers and molecular... more 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 suggest...
The concept of the pre-cancerous niche applies the ‘seed and soil’ theory of metastasis to the in... more The concept of the pre-cancerous niche applies the ‘seed and soil’ theory of metastasis to the initial process of carcinogenesis. TP53 is at the nexus of this process and, in the context of Li-Fraumeni Syndrome (LFS), is a key determinant of the conditions in which cancers are formed and progress. Important factors in the creation of the pre-cancerous niche include disrupted tissue homeostasis, cellular metabolism and chronic inflammation. While druggability of TP53 remains a challenge, there is evidence that drug re-purposing may be able to address aspects of pre-cancerous niche formation and thereby reduce the risk of cancer in individuals with LFS.
Background The prognosis of pancreatic cancer is poor and new treatment strategies are urgently n... more 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 (...
A global, comprehensive and open access listing of approved anticancer drugs does not currently e... more A global, comprehensive and open access listing of approved anticancer drugs does not currently exist. Partial information is available from multiple sources, including regulatory authorities, national formularies and scientific agencies. Many such data sources include drugs used in oncology for supportive care, diagnostic or other non-antineoplastic uses. We describe a methodology to combine and cleanse relevant data from multiple sources to produce an open access database of drugs licensed specifically for therapeutic antineoplastic purposes. The resulting list is provided as an open access database, (http://www.redo-project.org/cancer-drugs-db/), so that it may be used by researchers as input for further research projects, for example literature-based text mining for drug repurposing.
This work would not be as extensive as it is without the contribution of multiple collaborators w... more This work would not be as extensive as it is without the contribution of multiple collaborators who share our interest in drug repurposing. Though we cannot list them all, a special thank goes to Vidula Sukhatme, Vikas Sukhatme, Richard Kast & all colleagues at the Anticancer Fund.
Background. A number of recent high-profile cases have focused attention on scientific misconduct... more 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.
Vaccines used to prevent infections have long been known to stimulate immune responses to cancer ... more Vaccines used to prevent infections 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-tumor responses with existing infectious diseases vaccines used as such, either alone or in combination with immune checkpoint inhibitors. Here, we have reviewed and summarized research activities using approved vaccines to treat cancer. Data supporting a cancer therapeutic use was found for 16 vaccines. For 10 (BCG, diphtheria, tetanus, human papillomavirus, 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 ...
Despite five decades of clinical investigations, there is currently no effective treatment for ch... more 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-ap...
Background: The global pandemic caused by SARS-CoV-2 virus has prompted an unprecedented internat... more Background: The 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. Methods: Using 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/. Results: Descriptive statistics of the database from April...
trial design • drug development • drug registration • patient benefit • risks of bias Pivotal cli... more trial design • drug development • drug registration • patient benefit • risks of bias Pivotal clinical trials: biased? A recent study by Naci et al. examined the design characteristics, risks of bias and reporting adequacies of pivotal randomized controlled trials of cancer drugs approved by the EMA in the period 2014-2016 [1]. During this period, 32 new cancer drugs were approved by the EMA on the basis of 54 pivotal trials-of these, 41 (76%) were randomized controlled trials and 13 (24%) were non-randomized or single arm trials. The study reported that 49% of trials were judged to be at high risk of bias based on aspects of their design, conduct or analysis. Furthermore, only 10 (26%) randomized controlled trials measured overall survival as a primary end point, with the majority of trials evaluating surrogate metrics such as progression free survival or response rates. Furthermore, there were also discrepancies between scientific publications and regulatory documentation, thereby raising concerns of reporting inadequacies and risks of bias in both sources of information. These findings raise serious questions regarding clinical trial design and the drug registration process, particularly with regards to patient benefits. The problem is not restricted to Europe alone; previous studies have also raised concerns with US FDA approvals. For example, a study that assessed all FDA approvals of novel drugs, across all areas of medicine in the period 2005-2012, reported wide disparities in pivotal trial characteristics across different therapeutic areas [2]. While overall 219 of 448 (48.9%) pivotal trials included a surrogate end point, for cancer it was 46 of 55 (83.6%). Pivotal trials in cancer were also less likely to be randomized, double-blinded or to not include a placebo or active comparator. Another notable finding was that most cancer approvals were on the basis of a single pivotal trial, whereas for other therapeutic areas, approvals were based on two to four pivotal trials. A different study examining FDA cancer drug approvals based on response rate showed that many cancer drugs are approved based on low or modest response rates, typically tested in single-arm studies [3]. It could be argued that the surrogate end points used in such pivotal trials are acceptable as they correlate to overall survival and/or quality of life in the long term [4]. However, the data to support such an argument is lacking [5]. A recent systematic review of the association between surrogate end points and overall survival in oncology showed that the vast majority (82%) are low or moderate in strength [6]. A study of FDA approvals of cancer drugs during 2008-2012, a period in which 67% of approvals were made on the basis of a surrogate end point, assessed whether subsequent data emerged to show an increase in overall survival [7]. With a median follow-up of 4.4 years, the study reported that of 36 drugs approved with surrogate end points, only five subsequently reported improved overall survival in a randomized controlled trial, 18 had been shown to not improve overall survival in subsequent trials and 13 had not been tested or had not reported overall survival in subsequent trials. Similar results have also been reported for EMA approvals for drugs approved without a survival or quality of life end point [8]. Indeed, equally concerning is the fact that, in many cases, even the surrogate end points in pivotal trials are not subsequently replicated in post-approval studies [9].
The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing... more The current approach to systemic therapy for metastatic cancer is aimed predominantly at inducing apoptosis of cancer cells by blocking tumor-promoting signaling pathways or by eradicating cell compartments within the tumor. In contrast, a systems view of therapy primarily considers the communication protocols that exist at multiple levels within the tumor complex, and the role of key regulators of such systems. Such regulators may have far-reaching influence on tumor response to therapy and therefore patient survival. This implies that neoplasia may be considered as a cell non-autonomous disease. The multi-scale activity ranges from intra-tumor cell compartments, to the tumor, to the tumor-harboring organ to the organism. In contrast to molecularly targeted therapies, a systems approach that identifies the complex communications networks driving tumor growth offers the prospect of disrupting or "normalizing" such aberrant communicative behaviors and therefore attenuating tumor growth. Communicative reprogramming, a treatment strategy referred to as anakoinosis, requires novel therapeutic instruments, so-called master modifiers to deliver concerted tumor growth-attenuating action. The diversity of biological outcomes following pro-anakoinotic tumor therapy, such as differentiation, trans-differentiation, control of tumor-associated inflammation, etc. demonstrates that long-term tumor control may occur in multiple forms, inducing even continuous complete remission. Accordingly, pro-anakoinotic therapies dramatically extend the repertoire for achieving tumor control and may activate apoptosis pathways for controlling resistant metastatic tumor disease and hematologic neoplasia.
NEATG is a simple non-physiological tumour growth model which displays emergent properties which ... more NEATG is a simple non-physiological tumour growth model which displays emergent properties which are analogous to a number of characteristics common to physical tumour growth. NEATG employs a novel dual-scale evolutionary algorithm which models both cell-autonomous and non-cell autonomous behaviours. The components of the model are outlined briefly, with reference to the core algorithm and data structures. Experimental results are presented which illustrate the behaviour of the model under different evolutionary scenarios, including homeostasis, tumour growth and a number of anti-tumour interventions. In particular the system is used to explore the impact of cytotoxic interventions, (analogous to high-dose chemotherapy), with respect to adaptive responses and evolutionary change. Finally, a number of avenues for further development of the system are discussed.
While there have been enormous advances in our understanding of the genetic drivers and molecular... more 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 suggest...
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