Precision medicine for cancer with next-generation functional diagnostics

Friedman, Adam; Letaï, Anthony; Fisher, David E.; Flaherty, Keith T.

doi:10.1038/nrc4015

Cited by 471 publications

(350 citation statements)

References 107 publications

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“…For example, the application of human induced pluripotent stem cells (iPSCs), which could store personalized big data, could be an important component in personalized medicine—a patient's personalized database 50, 51. With the tremendous advances in “next‐generation” diagnostic techniques, thousands of mutations have been found and the origin of many diseases understood in greater depth 128. In addition, over the past few years, the arrival of liquid biopsy technology has made the acquisition of a database of tumors much easier, including DNA/chromatin mutations, methylation changes, and even information concerning C‐EVs 129, 130…”

Section: Outlook For Personalized and Precision Medicinementioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native‐source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the “modular design” of EV components. One high‐yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized “modular design” components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine.

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Section: Outlook For Personalized and Precision Medicinementioning

confidence: 99%

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

2018

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“…The noted genotyping methods have already become routine practice, while the phenotyping methods are currently used only for research and clinical trials purposes. 110 However, recognizing the significant involvement of dysfunctional p53 in AML will eventually prompt future implementation of p53 functional diagnostics into clinical workup as part of a comprehensive diagnostic approach aiming to improve personalized therapeutic decisions. Accordingly, the following suggested therapies merely represent a conceptual model for future potential therapeutic strategies.…”

Section: Targeting Dysfunctional Wtp53 In Amlmentioning

confidence: 99%

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Prokocimer

Molchadsky

Rotter

2017

Blood

135

111

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The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis. While in human solid tumors TP53 is mutated in more than half of cases, TP53 mutations occur in less than one tenth of de novo AML cases. Nevertheless, wild-type (wt) p53 dysfunction due to nonmutational p53 abnormalities appears to be rather frequent in various AML entities, bearing, presumably, a greater impact than is currently appreciated. Hereby, we advocate assessment of adult AML with respect to coexisting p53 alterations. Accordingly, we focus not only on the effects of mutant p53 oncogenic gain of function but also on the mechanisms underlying nonmutational wtp53 inactivation, which might be of therapeutic relevance. Patient-specific TP53 genotyping with functional evaluation of p53 protein may contribute significantly to the precise assessment of p53 status in AML, thus leading to the tailoring of a rationalized and precision p53-based therapy. The resolution of the mechanisms underlying p53 dysfunction will better address the p53-targeted therapies that are currently considered for AML. Additionally, a suggested novel algorithm for p53-based diagnostic workup in AML is presented, aiming at facilitating the p53-based therapeutic choices. (Blood. 2017; 130(6):699-712)

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“…A further hindrance to the clinical utility of mutation status is a lack of drug therapies that selectively target cancer-associated mutations, with effective Food and Drug Administration (FDA)-approved drugs existing for only a subset of the genes currently known to underlie tumorigenesis (1). These limitations invite a complementary strategy that assesses drug sensitivities obtained with targeted agents designed to inhibit discrete cellular processes as a means of identifying phenotypic indications for specific cancers (2). Associating phenotypic responses with particular genetic alterations may then beget precision-based therapies.…”

mentioning

confidence: 99%

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Kurtz

Eide

Kaempf

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

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Precision medicine for cancer with next-generation functional diagnostics

Cited by 471 publications

References 107 publications

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

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