Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) - Volume 14, Issue 2, 2016

Background: Many drugs when conjugated with DNA by covalent or noncovalent interaction form highly reactive, site specific delivery species called drug-DNA adduct. Objective: The objective of the present review is to highlight the importance and utility of DNA – drug conjugates for site-specific delivery in anti-cancer therapy. Results: Drugs, such as doxorubicin, cisplatin, ellipticine, melphalan, tamoxifen, etc. were reacted with endosomal formaldehyde to form an intermediate Schiff base. The Schiff base can successfully interact with the exocyclic amino group of guanine nucleotides, resulting in drug-DNA adducts through the aminal linkage. This mechanism has been extended to in vitro adduct formation of anthracycline drugs with deoxyguanosine group of DNA, which is highly stable at low temperature and in physiological pH. Conclusion: The adduct would gradually release the drug at a physiological temperature and is thus well suited for site-specific targeted drug delivery with reduced side effects.

Background: Genomic basis of drug response is the main objective of Pharmacogenomic studies. The classical paradigm of clinical treatment focused in the disease is becoming a new approach, the Personalized Medicine (PM) based on the individual patient. One important challenge of PM application is the availability of adequate and validated genetic information. Objective: In this review, we will focus on the impact of new technologies on Pharmacogenomics, the most recent advances to be applied to Personalized Medicine and how they contribute to face arising challenges related to quality aspects, clinical validation, cost and education. Method: Current situation of new methodologies such as single cell sequencing, long fragment reads or nanopore systems is reviewed using Pubmed in order to explore the scientific literature and to assess their contribution to boost the translation from basic pharmacogenomics to clinical practice. Results: An overview of the most recent technological advances to be applied to pharmacogenomics is provided, including a discussion about advantages and disadvantages of the different approaches. Conclusion: The great development of new technologies can open promising insight on pharmacogenomics, allowing to study genes involved in pharmacokinetics and pharmacodynamics and providing holistic information of drug toxicity and efficacy. The understanding of therapeutic effects, adverse events and drugs interaction is still limited by incomplete knowledge of cellular pathways, therefore inferring interacting biological molecules involved in drug response is required.

Background: A typical feature of acute myeloid leukemia (AML) consists in the blockade of the cell differentiation process. Many experimental studies have shown that some chemical compounds induce the selective differentiation of hematopoietic cell lines, thus supporting the rationale of using these agents to treat AML by forcing these cells to undergo a process of terminal differentiation. From these studies emerged the potential of all-trans retinoic acid (ATRA) to induce the differentiation of acute promyelocytic cells (APLs) and to treat these patients. The introduction of ATRA in the therapy of these patients improved the treatment of APLs, providing evidence that ATRA, combined with standard chemotherapy or arsenic trioxide (ATO) gives a curative effect in most of these patients. Attempts to emulate the effects of ATRA using other differentiation agents have failed. Results: The recent identification of new AML subsets classified according to specific molecular abnormalities and the development of agents selectively targeting these leukemia biomarkers led to a renewed interest for the differentiation therapy. It was shown that inhibition of mutant FLT3 or of mutant IDH1/2 exerts a significant anti-leukemia effect in part mediated by induction of cell differentiation. Preclinical studies strongly support the use of these inhibitors in combination with ATRA. On the other hand, recent observations indicate that various modulators of the epigenetic response (such as DNMT3A or LSD1 inhibitors) restore the sensitivity of non-APL AML blasts to the differentiative effect of ATRA. Conclusion: These observations suggest new successful developments of AML differentiation therapy in the near future.

Background: MicroRNAs are non-coding RNAs which regulate gene expression by binding to 3’ UTR site on mRNA. These small RNAs repress gene expression by interfering with the process of translation or by degrading the target mRNA. Abnormal expression of miRNAs has been implicated in a wide spectrum of human diseases like atherosclerosis, cancers and diabetes. Traditionally, pharmacogenomics focuses on single nucleotide polymorphisms and copy number variants of genes implicated in pharmacokinetics and pharmacodynamics. Recently, drug response has been proposed to be regulated by microRNAs. Mutations involving miRNAs can contribute to disease pathogenesis and modulation of drug response. Objective: The main objective of this review is to highlight the role of miRNAs in biological processes leading to disease states as well as in the field of drug action and pharmacogenomics. Method: A literature review was performed incorporating the latest insights in the field of miRNA therapeutics, diagnostics and pharmacogenomics. Results: Altered expression of miRNAs is seen in diabetes, vascular inflammation, atherosclerosis, infection and cancers. In the field of miRNA- pharmacogenomics, maximum work has been done studying the resistance to anticancer drugs. Some examples of microRNAs regulating drug response are miR-24 influencing the response to methotrexate, miR-125b affecting the action of calcitriol and miR-27b regulating the expression of CYP3A4. Among miRNAs currently being targeted in therapeutics are miR-122, miR- 33, miR-21, let-7 and miR-34. Conclusion: A significant fraction of all mRNAs transcribed in a cell are regulated by miRNAs. miRNAs implicated in a given disease may interfere with drug action and metabolism. Further research is needed to understand the association between miRNA, mRNAs, diseases and pharmacokinetics and dynamics.

Background: By using exome sequencing, we envisioned that certain single nucleotide variants (SNVs), predictive of sensitivity to platinum treatment, could be discovered. Methods: Twenty-two Platinum-Sensitive (Pt-S) and 6 Platinum-Resistant (Pt-R) ovarian cancer patients were tested. Platinum sensitivity was defined as disease free survival greater than 6 months. Next-generation sequencing of exomes was used to compare Pt-S and Pt-R patients. SNVs associated with platinum sensitivity were identified using Ingenuity Variant Analysis. Results: No SNV was significantly associated with sensitivity to platinum treatment after correcting for multiple comparison, however, three genes included a significantly higher number of SNVs previously shown to have pharmacogenetics associations (pSNV) in Pt-S patients when compared to Pt-R patients. Insulin-like growth factor 1 receptor (IGF1R) contained pSNVs in 59% of Pt-S and 0% of Pt-R (14 variants, p=1.25 E-2). Liproteinrelated protein 2 (LRP2) contained pSNVs in 54% of Pt-S and 0% of Pt-R (12 variants, p=3.20 E-2), and non-SMC condensin I complex subunit D2 (NCAPD2) contained pSNVs in 50% of Pt-S and 0% of Pt-R (7 variants, p=4.71 E-2). Three genes included a significantly higher number of pSNVs in Pt-R when compared to Pt-S patients. AF4/FMR2 family member 1 (AFF1) contained pSNVs in 50% of Pt-R and 0% of Pt-S (3 variants, p=3.20 E-3), breast cancer type 2 susceptibility protein (BRCA2) contained pSNVs in 50% Pt-R and 0% of Pt-S (3 variants, p=2.40 E-3), and DNA-dependent protein kinase (PRKDC) contained pSNVs in 50% of Pt-R and 0% of Pt-S (3 variants, p=2.90 E-3). Conclusion: pSNVs load in certain genes may be predictive of sensitivity to platinum in ovarian cancer. With validation of these findings, it is possible that a new marker predictive of patient response may be identified.