Page 119 - Hematology_ Basic Principles and Practice ( PDFDrive )

90 Part I Molecular and Cellular Basis of Hematology

in vitro. The in vitro results with the TK, JAK2, and ALK inhibitors chemistry-based approaches to biologic pathway perturbations are
were confirmed in mouse xenograft models, when patient-derived likely to accelerate the discovery of pharmacogenomics mechanisms.
Ph-like ALL cells were exposed to respective inhibitors based on the The outputs of such studies will advance understanding of the phar-
genetic profile of the leukemia cells. 28 macology of existing medications and will help to identify genes
In summary, this provides evidence that kinase-activating genetic and pathways involved in drug resistance and novel therapeutic
alterations are biologically relevant drivers in Ph-like ALL, and that targets.
the genetic signature can help to select drugs such as TKIs, JAK2 One important consideration in modern medicine is that clinically
or ALK inhibitors. However, rapid molecular profiling is needed to useful approaches must also be cost effective. About a decade ago,
identify potentially actionable mutations in patients with Ph-like the cost for the first full human genome sequence was approximately
ALL, and additional prospective trials are needed to establish their US$3 billion; this cost is now (2015) about US$1000. The markedly
benefit in the clinical setting. In contrast to children, outcomes in lower cost for robust genotyping points to an exciting future for
ALL have not improved significantly during recent decades in the genomics and pharmacogenomics research and translation, suggesting
AYA cohort; and as Ph-like ALL is the most common subtype in that the current approach to selecting medications (often “trial and
AYAs, the introduction of signaling pathway inhibitors may be an error”) will continue to evolve into more scientific-based methods for
attractive strategy to improve outcome in these patients who have selecting the optimal medications and doses for individual patients—
been therapeutically neglected for too long. with genomics playing an increasing role in such therapeutic
decisions. As pharmacoggenomics research expands the number of
robust associations between genome variation and drug response,
FUTURE DIRECTIONS the challenges of successful clinical translation and implementation
will be hurdle that will need to be overcome for precision medicine
Pharmacogenomics has already proven to be an important approach is to become a reality. 31
to improve drug therapy, and as of March 2015 the FDA has included
information on pharmacogenomic biomarkers in the labels of more
than 130 medications. A full list of these medications and further REFERENCES
details are available on the FDA’s website (see Table 8.1). There is,
however, a relatively slow pace of translating pharmacogenomics into 1. Evans WE, Relling MV: Moving towards individualized medicine with
clinical practice. Laboratory tests (e.g., liver and kidney function pharmacogenomics. Nature 429(6990):464–468, 2004.
tests) are widely used to adjust drug dosages, but even though tech- 2. Chhibber A, Kroetz DL, Tantisira KG, et al: Genomic architecture
nology for testing relevant pharmacogenomic biomarkers is widely of pharmacological efficacy and adverse events. Pharmacogenomics
available, simple, robust, and inexpensive genotyping tests are rarely 15(16):2025–2048, 2014.
used to optimize drug therapy. As of 2015 only five institutions in 3. Ivanov M, Barragan I, Inglman-Sundberg M: Epigenetic mechanisms
the United States are routinely performing “preemptive genotyping” of importance for drug treatment. Trends Pharmacol Sci 35(8):384–396,
for pharmacogenomic traits to guide the optimal selection of medica- 2014.
tions and their dosage. Because genotyping at the time of prescribing 4. Hunt RC, Simhadri VL, Indoli M, et al: Exposing synonymous muta-
is compromised by the relatively long delay until genotype results tions. Trends Genet 30(7):308–321, 2014.
are available, prospective genotyping early in a person’s life or at the 5. Diouf B, Crews C, Lew G, et al: Association of an inherited genetic
time of initial illness is a more efficient and cost-effective approach. variant with vincristine-related peripheral neuropathy in children with
In addition, because a person’s germline genotype does not change acute lymphoblastic leukemia. JAMA 313(8):815–823, 2015.
over a lifetime, it only needs to be done once. As genotyping becomes 6. Rukov JL, Wilentzik R, Jaffe I, et al: Pharmaco-miR: linking microRNAs
faster and cheaper, it is anticipated that this issue may no longer be and drug effects. Brief Bioinform 15(4):648–659, 2014.
an obstacle. In addition, educative and legislative initiatives, and the 7. He Y, Hoskins JM, McLeod HL: Copy number variants in pharmaco-
implementation of user-friendly decision-support systems (e.g., as genetic genes. Trends Mol Med 17(5):244–251, 2011.
realized in the “Clinical implementation of pharmacogenomics— 8. Diouf B, Cheng Q, Krynetskaia N, et al: Somatic deletions of genes
29
PG4KDS protocol” at St. Jude Children’s Research Hospital) will regulating MSH2 protein stability cause DNA mismatch repair
help to make pharmacogenomic biomarkers a routine part of clinical deficiency and drug resistance in human leukemia cells. Nat Med
care. 17(10):1298–1303, 2011.
The recent unprecedented gain of insights into the human genome 9. Manalio TA: Bringing genome-wide association findings into clinical use.
and genomic variations among individuals has already changed Nature Rev Genet 14:549–558, 2013.
the practice of medicine. High-throughput technologies, such as 10. Relling MV, Gardner EE, Sandborn WJ, et al: Clinical Pharmacogenetics
hybridization-based microarray approaches and next-generation Implementation Consortium guidelines for thiopurine methyltransferase
sequencing technologies, are available for genome-wide analyses genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther
of genomic variants, gene expression patterns, epigenetic patterns, 93(4):324–325, 2013.
and proteomic and metabonomic profiles. Moreover, sophisticated 11. Yang SK, Hong M, Baek J, et al: A common missense variant in
methods have been developed to integrate these data in order to NUDT15 confers susceptibility to thiopurine-induced leucopenia. Nat
uncover genotype–phenotype interactions, and some of the most Genet 46(9):1017–1020, 2014.
30
important methods are metadimensional and multistaged analyses. 12. Yang JJ, Landier W, Yang W, et al: Inherited NUDT15 variant is a
The recent application of these genome-wide tools has already yielded genetic determinant of mercaptopurin intolerance in children with
novel insights into drug actions and led to important drug discoveries. acute lymphoblastic leukemia. J Clin Oncol 2015. doi: 10.1200/
Moreover, these tools are being used to elucidate differences JCO.2014.59.4671.
between genomes of normal cells and cancer cells (e.g., the Pediatric 13. Tzoneva G, Perez-Garcia A, Carpenter Z, et al: Activating mutations in
Cancer Genome Project; see Table 8.1), and this knowledge has the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed
the potential to illuminate paths toward novel prognostic markers ALL. Nat Med 19(3):368–371, 2013.
(those that can be used for risk stratification in clinical trials) and/ 14. Meyer JA, Wang J, Hogan LE, et al: Relapse specific mutations in NT5C2
or novel therapeutic targets (those that can be used to discover new in childhood acute lymphoblastic leukemia. Nat Genet 45(3):290–294,
medications). 2013.
Once novel candidate genes have been identified via GWA 15. Pirmohamed M, Kamali F, Daly AK, et al: Oral anticoagulation: a
studies, functional investigations such as systematic mutagenesis, critique of recent advances and controversies. Trends Pharmacol Sci
RNA interference, and genome-wide CRISPR/Cas9 knockouts 36(2):153–163, 2015.
or enhancement of gene expression, use of overexpression systems 16. Nigam SK: What do drug transporters really do? Nat Rev Drug Discov
(cDNA, open-reading frame and miRNA expression libraries), and 14:29–44, 2015.