Polymorphisms in Pharmacogenetics of Personalized Cancer Therapy

Abstract

Therapy process of personalized cancer management covers surgery, chemotherapy, radiation therapy and targeted therapies. The choice of cancer chemotherapeutic agents and doses depends upon the location and stage of tumor, as well as the general state of the patient. On the chemotherapy, radiotherapy, and targeted therapy processes, pharmacogenetics offers customized solutions according to the personal genetic information. Especially for clinicians, genetic information obtained from polymorphism-based pharmacogenetic tests is highly crucial for the better prediction ability of drug response and life-threatening toxic reactions due to the narrow therapeutic index of cancer chemotherapeutic agents. Pharmacogenotyping utilizes different examination strategies, such as single nucleotide polymorphism analysis, somatic/germline mutation analysis and partial/full genome sequencing. The promising effect of pharmacogenetics on the solving of the individual variability in drug response and toxic reactions is being observed with the accumulation of the information that unravel the human genomic variations from large-scale population and multi-parameter-based pharmacogenetic studies of the postgenomic era. Polymorphisms contribute wide variations in human genome and may define how individuals respond to medications, either by changing the pharmacokinetics and pharmacodynamics of drugs or by altering the cellular response to therapeutic agents. To define the effect of polymorphisms on the targets of chemotherapeutics is necessary for the prediction of altered pharmacokinetics of therapeutic agents.

Cytogenetics, Molecular Genetics and Epigenetics and Their Impact on The Management of Acute Lymphoblastic Leukemia

“…Current therapeutic regimens that are used in the treatment of ALL patients are mostly non-targeted and most of the chemotherapeutic agents included in these regimens have a narrow therapeutic index that frequently causes life-threatening toxicities and even deaths [124,125]. Even targeted therapies have their own toxicities that may be severe [125]. Hence, new treatments that are tailored to patient-specific tumor vulnerabilities are required to further improve treatment outcomes and limit toxicities [124].…”

“…Mutation in a gene is a change in DNA sequence away from normal allele and forms an abnormal variant. Polymorphism analysis, mutational analysis and genome sequencing are the backbone of "discipline of pharmacogenetics" [125]. Molecular-based diagnostic tests in patients with HMs can be classified into 3 main categories: (1) detection of individual mutations in oncogenes.…”

“…PCR for antigen receptor rearrangements (PARR) assays are used in 2 settings: (1) providing lineage and other clinically useful information in resolving ambiguous cases of leukemia or lymphoma, and (2) as a research tool to better understand the biology of HMs [138]. Polymorphism term is used to describe multiple forms of a single gene that exists in a population [125]. Genetic polymorphisms are one of the most important factors that may contribute to ethnic sensitivity of a drug.…”

“…Therefore, epigenetic targeted therapies may look particularly appealing in the post-remission setting in order to target specific sub-clones that may be resistant to standard cytotoxic chemotherapy [123]. Current therapeutic regimens that are used in the treatment of ALL patients are mostly non-targeted and most of the chemotherapeutic agents included in these regimens have a narrow therapeutic index that frequently causes life-threatening toxicities and even deaths [124,125]. Even targeted therapies have their own toxicities that may be severe [125].…”

“…Precision or personalized medicine refers to the use of specific characteristics of an individual patient, based on his/her molecular and genetic profiles to tailor therapies during all stages of care accordingly and this implies: (1) provision of the right patient with the right drug at the right dose and at the right time, and (2) optimizing therapeutic benefits while limiting toxicities of the drugs used [123,125]. The recent findings have several implications on precision medicine approaches in ALL that include: (1) different disease subtypes have distinct associations with relapse risk, hence the intensity of treatment will be tailored accordingly, (2) several ALL subtypes have genetic alterations making them candidates for genomic studies and individualized targeted therapies, (3) identification of several genes and genetic pathways that are selectively mutated at relapse including epigenetic regulators and these require local and targeted therapeutic interventions, and (4) genomic sequencing is being utilized to develop highly sensitive approaches to detect and track responses to treatments [124].…”