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Abstract
Cellular plasticity and the ability to avoid terminal differentiation are hallmarks
of cancer. Here, we review the evidence that tumor cells themselves can take on properties
of neurons of the central nervous system, which can regulate tumor growth and metastasis.
We discuss recent evidence that axon guidance molecules and regulators of electrical
activity and synaptic transmission, such as ion channels and neurotransmitters, can
drive the oncogenic and invasive properties of tumor cells from a range of cancers.
We also review how FDA-approved treatments for neurological disorders are being tested
in pre-clinical models and clinical trials for repurposing as anti-cancer agents,
offering the potential for new therapies for cancer patients that can be accessed
more quickly.
The hallmarks of cancer conceptualization is a heuristic tool for distilling the vast complexity of cancer phenotypes and genotypes into a provisional set of underlying principles. As knowledge of cancer mechanisms has progressed, other facets of the disease have emerged as potential refinements. Herein, the prospect is raised that phenotypic plasticity and disrupted differentiation is a discrete hallmark capability, and that nonmutational epigenetic reprogramming and polymorphic microbiomes both constitute distinctive enabling characteristics that facilitate the acquisition of hallmark capabilities. Additionally, senescent cells, of varying origins, may be added to the roster of functionally important cell types in the tumor microenvironment. SIGNIFICANCE: Cancer is daunting in the breadth and scope of its diversity, spanning genetics, cell and tissue biology, pathology, and response to therapy. Ever more powerful experimental and computational tools and technologies are providing an avalanche of "big data" about the myriad manifestations of the diseases that cancer encompasses. The integrative concept embodied in the hallmarks of cancer is helping to distill this complexity into an increasingly logical science, and the provisional new dimensions presented in this perspective may add value to that endeavor, to more fully understand mechanisms of cancer development and malignant progression, and apply that knowledge to cancer medicine.
Similar to embryonic development, changes in cell phenotypes defined as an epithelial to mesenchymal transition (EMT) have been shown to play a role in the tumorigenic process. Although the first description of EMT in cancer was in cell cultures, evidence for its role in vivo is now widely reported but also actively debated. Moreover, current research has exemplified just how complex this phenomenon is in cancer, leaving many exciting, open questions for researchers to answer in the future. With these points in mind, we asked four scientists for their opinions on the role of EMT in cancer and the challenges faced by scientists working in this fast-moving field.
How much do drug companies spend on research and development to bring a new medicine to market? In this study, which included 63 of 355 new therapeutic drugs and biologic agents approved by the US Food and Drug Administration between 2009 and 2018, the estimated median capitalized research and development cost per product was $985 million, counting expenditures on failed trials. Data were mainly accessible for smaller firms, products in certain therapeutic areas, orphan drugs, first-in-class drugs, therapeutic agents that received accelerated approval, and products approved between 2014 and 2018. This study provides an estimate of research and development costs for new therapeutic agents based on publicly available data; differences from previous studies may reflect the spectrum of products analyzed and the restricted availability of data in the public domain. The mean cost of developing a new drug has been the subject of debate, with recent estimates ranging from $314 million to $2.8 billion. To estimate the research and development investment required to bring a new therapeutic agent to market, using publicly available data. Data were analyzed on new therapeutic agents approved by the US Food and Drug Administration (FDA) between 2009 and 2018 to estimate the research and development expenditure required to bring a new medicine to market. Data were accessed from the US Securities and Exchange Commission, Drugs@FDA database, and ClinicalTrials.gov, alongside published data on clinical trial success rates. Conduct of preclinical and clinical studies of new therapeutic agents. Median and mean research and development spending on new therapeutic agents approved by the FDA, capitalized at a real cost of capital rate (the required rate of return for an investor) of 10.5% per year, with bootstrapped CIs. All amounts were reported in 2018 US dollars. The FDA approved 355 new drugs and biologics over the study period. Research and development expenditures were available for 63 (18%) products, developed by 47 different companies. After accounting for the costs of failed trials, the median capitalized research and development investment to bring a new drug to market was estimated at $985.3 million (95% CI, $683.6 million-$1228.9 million), and the mean investment was estimated at $1335.9 million (95% CI, $1042.5 million-$1637.5 million) in the base case analysis. Median estimates by therapeutic area (for areas with ≥5 drugs) ranged from $765.9 million (95% CI, $323.0 million-$1473.5 million) for nervous system agents to $2771.6 million (95% CI, $2051.8 million-$5366.2 million) for antineoplastic and immunomodulating agents. Data were mainly accessible for smaller firms, orphan drugs, products in certain therapeutic areas, first-in-class drugs, therapeutic agents that received accelerated approval, and products approved between 2014 and 2018. Results varied in sensitivity analyses using different estimates of clinical trial success rates, preclinical expenditures, and cost of capital. This study provides an estimate of research and development costs for new therapeutic agents based on publicly available data. Differences from previous studies may reflect the spectrum of products analyzed, the restricted availability of data in the public domain, and differences in underlying assumptions in the cost calculations. This study uses publicly available data to analyze research and development spending to win FDA approval and bring new drugs to market between 2009 and 2018.
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History
Date
received
: 21
October
2024
Date
accepted
: 2
February
2025
Funding
Funded by: NIH
Award ID: DP2CA271387
Award ID: DP2CA271387
Award ID: DP2CA271387
Award ID: DP2CA271387
Award Recipient
:
Hanan BloomerHaley B. DameSavannah R. ParkerMadeleine J. Oudin
Funded by: G. Harold and Leila Y. Mathers Foundation
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