Trends in Pharmacological Sciences
OpinionThe Valley of Death in anticancer drug development: a reassessment
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,
References (117)
- et al.
The altered metabolism of tumors: HIF-1 and its role in the Warburg effect
Advances in Enzyme Regulation
(2010) Requirement of caspase-3(-like) protease-mediated hydrogen peroxide production for apoptosis induced by various anticancer drugs
J. Biol. Chem.
(1998)Role of pH in tumor-trapping of the anticancer drug 5-fluorouracil
Adv. Enzyme Regul.
(2000)Tumor acidity, ion trapping and chemotherapeutics I. pH-dependent partition coefficients predict importance of ion trapping on pharmacokinetics of weakly basic chemotherapeutic agents
Biochem. Pharmacol.
(2003)Causes and consequences of acidic pH in tumors: a magnetic resonance study
Adv. Enzyme Regul.
(1999)Concordance of the toxicity of pharmaceuticals in humans and in animals
Regul. Toxicol. Pharmacol.
(2000)The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents
Cancer Treat. Rev.
(2011)F-19-MRS studies of fluorinated drugs in humans
Adv. Drug Del. Rev.
(2000)The observed variance between predicted and measured radiation dose in breast and prostate patients utilizing an in vivo dosimeter
Int. J. Radiat. Oncol. Biol. Phys.
(2008)Who is in charge of assessing therapeutic drug monitoring? The case of imatinib
Lancet Oncol.
(2011)
Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors
Adv. Enzyme Regul.
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial
Lancet
Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial
Lancet
Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study
Lancet Oncol.
Identification of selective inhibitors of cancer stem cells by high-throughput screening
Cell
Salinomycin-induced apoptosis of human prostate cancer cells due to accumulated reactive oxygen species and mitochondrial membrane depolarization
Biochem. Biophys. Res. Commun.
Salinomycin inhibits osteosarcoma by targeting its tumor stem cells
Cancer Lett.
Combination of salinomycin and gemcitabine eliminates pancreatic cancer cells
Cancer Lett.
Salinomycin can effectively kill ALDH(high) stem-like cells on gastric cancer
Biomed. Pharmacother.
Tumor-homing multifunctional nanoparticles for cancer theragnosis: Simultaneous diagnosis, drug delivery, and therapeutic monitoring
J. Control. Release
Carbonic anhydrase 9 in clear cell renal cell carcinoma: A marker for diagnosis, prognosis and treatment
Eur. J. Cancer
The productivity crisis in pharmaceutical R&D
Nat. Rev. Drug Discov.
Anticancer drug development: the grand challenges
Nat. Rev. Drug Discov.
How to improve R&D productivity: the pharmaceutical industry's grand challenge
Nat. Rev. Drug Discov.
Opinion. Assessing the translatability of drug projects: what needs to be scored to predict success?
Nat. Rev. Drug Discov.
Translational research: crossing the valley of death
Nature
Traversing the Valley of Death: a guide to assessing prospects for translational success
Sci. Transl. Med.
Overcoming the ‘valley of death’: Mouse models to accelerate translational research
Diabetes Technol. Ther.
NCATS could mitigate pharma Valley of Death
Genet. Eng. Biotechnol. News
Why we’re losing the war on cancer and how to win it
Fortune
Desperately seeking cures
Newsweek
We fought cancer... and cancer won
Newsweek
Can the pharmaceutical industry reduce attrition rates?
Nat. Rev. Drug Discov.
Targeting hypoxia in cancer therapy
Nat. Rev. Cancer
Culturing at atmospheric oxygen levels impacts lymphocyte function
Proc. Natl. Acad. Sci. U.S.A.
Hypoxia or in situ normoxia: the stem cell paradigm
J. Cell. Physiol.
Detection and characterization of tumor hypoxia using pO2 histography
Antioxid. Redox Signal.
Understanding the tumor metabolic phenotype in the genomic era
Curr. Mol. Med.
Topotecan inhibits vascular endothelial growth factor production and angiogenic activity induced by hypoxia in human neuroblastoma by targeting hypoxia-inducible factor-1 alpha and -2 alpha
Mol. Cancer Ther.
Antiangiogenic effects of camptothecin analogues 9-amino-20(S)camptothecin, topotecan, and CPT-11 studied in the mouse cornea model
Clin. Cancer Res.
Anti-angiogenic effects of SN38 (active metabolite of irinotecan): inhibition of hypoxia-inducible factor 1 alpha (HIF-1 alpha)/vascular endothelial growth factor (VEGF) expression of glioma and growth of endothelial cells
J. Cancer Res. Clin. Oncol.
Marked activity of irinotecan and rapamycin combination toward colon cancer cells in vivo and in vitro is mediated through cooperative modulation of the mammalian target of rapamycin/hypoxia-inducible factor-1 alpha axis
Clin. Cancer Res.
Acute oxidant damage promoted on cancer cells by amitriptyline in comparison with some common chemotherapeutic drugs
Anti-Cancer Drugs
Camptothecin and Fas receptor agonists synergistically induce medulloblastoma cell death: ROS-dependent mechanisms
Anti-Cancer Drugs
The effect of Topotecan on oxidative stress in MCF-7 human breast cancer cell line
Acta Biochim. Pol.
The hematopoietic stem cell niche: low in oxygen but a nice place to be
J. Cell. Physiol.
Camptothecin analogs with enhanced activity against human breast cancer cells. II. Impact of the tumor pH gradient
Cancer Chemother. Pharmacol.
Cellular pH gradient in tumor versus normal tissue: Potential exploitation for the treatment of cancer
Cancer Res.
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