Opinion
The Valley of Death in anticancer drug development: a reassessment

https://doi.org/10.1016/j.tips.2012.02.001Get rights and content

The past decade has seen an explosion in our understanding of cancer biology and with it many new potential disease targets. Nonetheless, our ability to translate these advances into therapies is poor, with a failure rate approaching 90%. Much discussion has been devoted to this so-called ‘Valley of Death’ in anticancer drug development, but the problem persists. Could we have overlooked some straightforward explanations to this highly complex problem? Important aspects of tumor physiology, drug pharmacokinetics, preclinical models, drug delivery, and clinical translation are not often emphasized, but could be crucial. This perspective summarizes current views on the problem and suggests feasible alternatives.

Section snippets

The Valley of Death

Failure to translate our rapidly expanding knowledge of cell biology into effective therapeutics has been a topic of lively and ongoing debate in the scientific community 1, 2, 3, 4, 5, 6, 7, 8, 9 as well as popular press 10, 11, 12, 13, which has been particularly critical. The issue is urgent for anticancer drug development where the late-stage attrition rate for oncology drugs is as high as 70% in Phase II and 59% in Phase III trials [14]. Commentators have delineated numerous underlying

The tumor microenvironment

The rise of molecular biology and the emergence of the genomics era have led to major progress in our understanding of cancer cell biology. However, this focus has also overshadowed knowledge of cancer at the tissue level. A prime example is the prevalence of hypoxic and acidic microenvironments in human solid tumors. Although hypoxia is recognized as an important target for cancer therapy [15], the concept is not routinely incorporated into preclinical models. A central issue is the definition

The impact of exposure time

Typically, the initial stage in drug discovery and development is target-to-hit in which a large number of compounds from combinatorial/parallel chemistry are subjected to high-throughput screening against an isolated molecular target in a cell-free assay. The endpoint is potency measured as the concentration that produces half-maximal response (IC50, ED50). Potency remains the primary endpoint when screening progresses to cell-based assays, despite the various biological barriers between drug

Choice of preclinical model

3D primary tumor models have been demonstrated to provide more clinically relevant results than the typical monolayer cell-line models [47]. Because these models are necessarily low-throughput, they have been overshadowed by high-throughput technologies that can rapidly generate large databases of information for biostatistical analyses that yield the now familiar pathway or heat maps of drug response. Whether this will be a superior approach given its inherent limitations remains to be seen.

Drug delivery to tumors

The emergence of biomarker-driven drug development is an important step toward the goal of personalized medicine. However, correlation of molecular biomarker data to tumor response with parallel measurement of active drug in tumor target tissue is rare and is required for accurate interpretation. Comparatively little effort has been devoted to tumor pharmacokinetics because we continue to use plasma pharmacokinetics as a surrogate (the property of kinetic homogeneity), despite considerable

Changing clinical practice

The previous categories all reflect missed connections on the ‘bench’ side of the bridge across the Valley of Death. There are similar issues on the ‘bedside’ of the bridge. For example, consider the concept of pharmacokinetically-guided dosing. Although there is consensus that such individualized dosing of cancer chemotherapeutics is of value, particularly for reducing toxicity, methotrexate is the only oncology drug in which therapeutic drug monitoring (TDM) for dose adjustment is standard

Some paths forward

The Valley of Death in anticancer drug development is a highly complex problem with numerous driving forces. The need for solutions is urgent as illustrated by recent financial reports. Of the twelve pharmaceutical companies that spent the most on R&D, return on investment fell 3.4 percentage points in 2010, a 29% decline, while the cost of bringing a new molecular entity (NME) to market rose from $830 million to $1.05 billion [74].

The pharmacological audit trail (PhAT) of Workman and

Concluding remarks

In summary, given the continuing and probably increasing restrictions on resources to support bringing new therapies to cancer patients, it is worth taking stock of our current processes and re-thinking our assumptions. The current emphasis on genetic molecular approaches has certainly paid dividends. However, advances in understanding and modeling tumor physiology and in drug delivery and monitoring also have important roles to play. Multidisciplinary approaches to both translational and

Acknowledgments

This work was supported in part by Small Business Innovation Research Grant CA125871 from the National Cancer Institute. The author acknowledges the invaluable scientific contributions and mentorship in anticancer drug development of Drs O. Michael Colvin, David Rizzieri, and Mark Dewhirst from Duke University, Durham, NC; Drs Mansukh Wani and Govindarajan Manikumar from Research Triangle Institute International, Research Triangle Park, NC and Dr Lee Roy Morgan from DEKK-TEC, Inc., New Orleans,

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