Evaluating the Utility of a ‘N-of-1' Precision Cancer Medicine Strategy: The Case for ‘Time-to-Subsequent-Disease Progression'

Markman, Maurie; Krämer, Kim; Álvarez, Ricardo H.; Weiss, Glen J.; Ahn, Eugene; Daneker, George W.

doi:10.1159/000450682

Cited by 5 publications

(6 citation statements)

References 8 publications

(13 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was a marked shift from earlier cell-based assays where modulation of specific targets did not occur, but instead relevant cellular phenotypic responses were measured [19, 20]. Significant effort has been expended to mimic these physiologically relevant cell-based systems with a significantly higher throughput [21] and advances have been made using a variety of these and subsequently deployed in cancer drug discovery in particular [22–24] as well as being expanded to areas such as predictive toxicology [25]. …”

Section: Assay Development High Throughput and High Content Screeninmentioning

confidence: 99%

Epigenetic assays for chemical biology and drug discovery

Gul

2017

Clin Epigenet

View full text Add to dashboard Cite

The implication of epigenetic abnormalities in many diseases and the approval of a number of compounds that modulate specific epigenetic targets in a therapeutically relevant manner in cancer specifically confirms that some of these targets are druggable by small molecules. Furthermore, a number of compounds are currently in clinical trials for other diseases including cardiovascular, neurological and metabolic disorders. Despite these advances, the approved treatments for cancer only extend progression-free survival for a relatively short time and being associated with significant side effects. The current clinical trials involving the next generation of epigenetic drugs may address the disadvantages of the currently approved epigenetic drugs.The identification of chemical starting points of many drugs often makes use of screening in vitro assays against libraries of synthetic or natural products. These assays can be biochemical (using purified protein) or cell-based (using for example, genetically modified, cancer cell lines or primary cells) and performed in microtiter plates, thus enabling a large number of samples to be tested. A considerable number of such assays are available to monitor epigenetic target activity, and this review provides an overview of drug discovery and chemical biology and describes assays that monitor activities of histone deacetylase, lysine-specific demethylase, histone methyltransferase, histone acetyltransferase and bromodomain. It is of critical importance that an appropriate assay is developed and comprehensively validated for a given drug target prior to screening in order to improve the probability of the compound progressing in the drug discovery value chain.

show abstract

Section: Assay Development High Throughput and High Content Screeninmentioning

confidence: 99%

Epigenetic assays for chemical biology and drug discovery

Gul

2017

Clin Epigenet

View full text Add to dashboard Cite

show abstract

“…Because risk and molecular profiles of AD vary widely by person, grouping individuals into single entities (placebo vs treatment arm) may mix “super‐responders” with “nonresponders,” washing out treatment effects that only become apparent in post hoc analyses . Instead, comparing time‐to‐disease progression of an individual using a novel therapeutic approach to the time‐to‐disease progression for that same individuals for the immediately preceding treatment paradigm may be preferable . N‐of‐1 trials may be less bound by threats to generalizability of large RCTs due to recruitment delays and challenges to translate significant p‐values in large treatment groups to the care of an individual, which is the ultimate goal of clinical practice.…”

Section: Precision Medicine Approaches To Preventionmentioning

confidence: 99%

“…Longitudinal follow‐up is needed to monitor adherence to recommendations and for evidence of improvement in outcomes. Such a trial could provide a direct estimate of individual treatment effects, fine‐tune personalized care plans, enhance precision of future treatment decisions, improve person‐centered outcomes, and if successful, reduce long‐term healthcare costs …”

Section: Example Of a Personalized Medicine Approach To Dementia Prevmentioning

confidence: 99%

“…24 Instead, comparing time-to-disease progression of an individual using a novel therapeutic approach to the time-to-disease progression for that same individuals for the immediately preceding treatment paradigm may be preferable. 25 N-of-1 trials may be less bound by threats to generalizability of large RCTs due to recruitment delays and challenges to translate significant p-values in large treatment groups to the care of an individual, which is the ultimate goal of clinical practice. In a metaanalyses of 70 N-of-1 trials, 50 of 57 completed trials provided definitive clinical or statistical answers, with 39% prompting physicians to change the plan of care.…”

Section: Precision Medicine Approaches To Preventionmentioning

confidence: 99%

See 1 more Smart Citation

Prevention of Alzheimer's Disease: Lessons Learned and Applied

Galvin

2017

J American Geriatrics Society

View full text Add to dashboard Cite

Alzheimer’s disease (AD) affects over 5 million Americans with substantial consequences to patients, families and society that will only continue to be a significant cause of morbidity, mortality, and healthcare costs. With disease-modifying treatment trials unsuccessful at the present time and only symptomatic medications available, an emerging approach is the creation of prevention trials. Advances in diagnostic criteria, biomarker development and improved understanding of the biophysiological basis of AD make these initiatives feasible. Ongoing pharmacological trials using anti-amyloid therapies are underway in sporadic and genetic forms of AD. However, a large number of modifiable risk factors for AD have been identified in observational studies, many of which do not appear to exert effects via amyloid or tau. This suggests that prevention studies focusing on risk reduction and lifestyle modification may offer additional benefits. Rather than relying solely on large sample, long duration randomized clinical trial designs; a precision medicine approach using N-of-1 trials may provide more rapid results on whether personalized prevention plans can improve patient-centered outcomes. As there appear to be multiple pathways to develop AD, there may also be multiple ways to prevent or delay the onset of AD. Even if these precision approaches alone are not successful in preventing AD, they may greatly improve the likelihood of amyloid- or tau-specific therapies to reach their endpoints by reducing co-morbidities. Keeping this in mind, dementia may be as a disorder that develops over a lifetime, with individualized ways to build a better brain as we age.

show abstract

“…1 ) [ 32 ]. The option we propose is to compare the time-to-disease progression of an individual cancer patient following treatment with a novel therapy to the time-to-disease progression for the same patient on his/her immediately previous treatment [ 33 ]. In other words, in N-of-1 trials the same patient will be the tester of a new therapy and its control arm.…”

Section: N-of-1 Trials As a Tool To Implement “Liquid Dynamic Medicinmentioning

confidence: 99%

Liquid dynamic medicine and N-of-1 clinical trials: a change of perspective in oncology research

Silvestris

Ciliberto

Paoli

et al. 2017

J Exp Clin Cancer Res

View full text Add to dashboard Cite

The increasing use of genomics to define the pattern of actionable mutations and to test and validate new therapies for individual cancer patients, and the growing application of liquid biopsy to dynamically track tumor evolution and to adapt molecularly targeted therapy according to the emergence of tumor clonal variants is shaping modern medical oncology., In order to better describe this new therapeutic paradigm we propose the term “Liquid dynamic medicine” in the place of “Personalized or Precision medicine”. Clinical validation of the “Liquid dynamic medicine” approach is best captured by N-of-1 trials where each patient acts as tester and control of truly personalized therapies.

show abstract

Evaluating the Utility of a ‘N-of-1' Precision Cancer Medicine Strategy: The Case for ‘Time-to-Subsequent-Disease Progression'

Cited by 5 publications

References 8 publications

Epigenetic assays for chemical biology and drug discovery

Epigenetic assays for chemical biology and drug discovery

Prevention of Alzheimer's Disease: Lessons Learned and Applied

Liquid dynamic medicine and N-of-1 clinical trials: a change of perspective in oncology research

Contact Info

Product

Resources

About