Optimising translational oncology in clinical practice: Strategies to accelerate progress in drug development

Stahel, Rolf A.; Bogaerts, Jan; Ciardiello, Fortunato; Ruysscher, Dirk De; Dubsky, Peter; Ducreux, Michel; Finn, Stephen P.; Laurent‐Puig, Pierre; Peters, Solange; Piccart, Martine; Smit, Egbert F.; Sotiriou, Christos; Tejpar, Sabine; Cutsem, Éric Van; Tabernero, Josep

doi:10.1016/j.ctrv.2014.12.004

Cited by 16 publications

(9 citation statements)

References 35 publications

(44 reference statements)

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“…221 and there is a very high attrition rate of drugs passing from preclinical development to clinical implementation. 222 There are many therapies that struggle to balance preclinical promise with clinical realities, and the clinical development pipeline is often challenged by ensuring optimal clinical trial design, as illustrated by PARP inhibitors and antiangiogenesis therapies [223][224][225][226][227] that, although approved by the US Food and Drug Administration, have required further reanalyses to define optimal efficacy. 228,229 Therefore, it is possible that vitamin D-centered chemotherapies will fall to a similar fate.…”

Section: Human Epidemiologic Findings and Clinical Trialsmentioning

confidence: 99%

Vitamin D Receptor Signaling and Cancer

Campbell

Trump

2017

Endocrinology and Metabolism Clinics of North America

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The primary biological action of the secosteroid hormone vitamin D (1,25(OH) 2 D 3 ) is to bind to the vitamin D receptor (NR1I1/VDR) and to regulate serum calcium levels. As a downstream consequence, the actions of the receptor control bone formation and maintenance. The first clinical manifestation of insufficient VDR endocrine signaling, rickets, was discovered by Daniel Whistler in the Netherlands in the 17th century; 300 years later, the VDR gene was cloned by Bert O'Malley and coworkers. 1 Between these dates, research into vitamin D was at the forefront of areas of public health, chemistry and biochemistry including the light catalyzed synthesis of vitamin D 3 by Adolf Windaus. For this work, he received the Nobel Prize in Chemistry (1928). Work in the 1960s and 1970s led to analyses of vitamin D endocrine metabolism and led to remarkable strides describing biochemical synthesis of 1,25(OH) 2 D 3 and the diverse biology in which VDR participates.The precursor of 1,25(OH) 2 D 3 , cholecalciferol or vitamin D 3 , is produced in the skin and converted in the liver to 25-hydroxyvitamin D 3 , (25(OH)D 3 ); circulating levels of 25(OH)D 3 serve as a useful index of vitamin D total body stores. A further hydroxylation occurs in the principally in the kidney at the carbon 1 position by 25-hydroxyvitamin D-1α-hydroxylase (encoded by CYP27B1) to produce the biologically active hormone, 1,25(OH) 2 D 3 . A second mitochondrial cytochrome P450 enzyme, the 24-hydroxylase (encoded by CYP24A1), can use both 25(OH)D and 1,25(OH) 2 D 3 as substrates, and is the first step in the inactivation pathway for these metabolites. Because of the direct role 1,25(OH) 2 D 3 plays in control of serum calcium levels, elevated levels of 1,25(OH) 2 D 3 block its synthesis and induce inactivation and accelerate catabolism 2 via induction of CYP24A1, in a classical negative feedback loop.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). The first report that VDR actions could control cancer cell growth were discovered partly through serendipity, and partly through logical extension of other studies. Reports in the 1970s identified purified cell fractions that bound 1,25(OH) 2 D 3 with high affinity, 14 and encouraged investigators to begin to consider what were the molecular actions of the VDR in the classic tissues involved in calcium homeostasis, for example, skin, bone, intestine, and kidney. 15 In 1981, Kay Colston and coworkers 16 were first to demonstrate that 1α,25(OH) 2 D 3 at nanomolar concentrations inhibited human melanoma cell proliferation in vitro. That the workers used a cancer cell model was serendipitous; cancer cell models are more readily available to study in cell culture experiments than nonmalignant counterparts, and in this case 16 the cells chosen were available in an adjacent laboratory. Campbell and Trump In parallel, it was also known that retinoids, which are also small lipophilic molecules that target NRs, could drive cell differentiation, for exa...

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Section: Human Epidemiologic Findings and Clinical Trialsmentioning

confidence: 99%

Vitamin D Receptor Signaling and Cancer

Campbell

Trump

2017

Endocrinology and Metabolism Clinics of North America

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“…Networks have been progressively structured based on scientific collaborations and on synergy between research sites, sharing standard operating procedures and research tools to better reach common objectives. Among medical specialties, oncology is probably the most advanced in networking since most of RCTs are delivered through structured networks [38]. This approach makes trial process and delivery much more efficient and faster.…”

Section: Main Textmentioning

confidence: 99%

Perspective on optimizing clinical trials in critical care: how to puzzle out recurrent failures

et al. 2016

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BackgroundCritical care is a complex field of medicine, especially because of its diversity and unpredictability. Mortality rates of the diseases are usually high and patients are critically ill, admitted in emergency, and often have several overlapping diseases. This makes research in critical care also complex because of patients’ conditions and because of the numerous ethical and regulatory requirements and increasing global competition. Many clinical trials in critical care have thus failed and almost no drug has yet been developed to treat intensive care unit (ICU) patients. Learning from the failures, clinical trials must now be optimized.Main bodySeveral aspects can be improved, beginning with the design of studies that should take into account patients’ diversity in the ICU. At the site level, selection should reflect more accurately the potential of recruitment. Management of all players that can be involved in the research at a site level should be a priority. Moreover, training should be offered to all staff members, including the youngest. National and international networks are also part of the future as they create a collective synergy potentially improving the efficacy of sites. Finally, computerization is another area that must be further developed with the appropriate tools.ConclusionClinical research in the ICU is thus a discipline in its own right that still requires tailored approaches. Changes have to be initiated by the investigators themselves as they know all the specificities of the field.

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“…In particular, EGFR, ALK, K-RAS, BRAF, AKT1, PIK3CA and HER2 pathways have been extensively evaluated [20][21][22][23][24][25][26]. Furthermore, deregulation in cancer cell receptors of systemic regulatory peptides has also been suggested as a further mechanism of aggressiveness of lung cancer [27][28][29][30].…”

Section: Page 5 Of 27mentioning

confidence: 99%