Alkylating agents represent an important class of anticancer drugs. The occurrence and emergence of tumor resistance to the treatment with alkylating agents denotes a severe problem in the clinics. A detailed understanding of the mechanisms of activity of alkylating drugs is essential in order to overcome drug resistance. In particular, the role of non-coding microRNAs concerning alkylating drug activity and resistance in various cancers is highlighted in this review. Both synthetic and natural alkylating agents, which are approved for cancer therapy, are discussed concerning their interplay with microRNAs.
Cancer pharmacogenetics implies a complex combination of germline variants from the patient and somatic mutations in tumor cells. Somatic mutations meanwhile have become drugable targets or biomarkers, whereas germline mutations potentially predict adverse drug effects or drug response. Here, we evaluate hereditary variants in biotransforming enzymes and drug transporters, such as thiopurine S-methyltransferase, UDP-glucuronosyltransferase (UGT1A1), dihydropyrimidine dehydrogenase (DPD), as well as ABC transporters (ABCB1, ABCG2 and ABCC subfamily) with respect to cytostatics and targeted therapies. Furthermore, gene expression regulation with regards to epigenetics and posttranscriptional modification are discussed.
Chemotherapy remains a primary treatment modality for various malignancies. However, resistance to chemotherapeutic drugs is a major obstacle to curative cancer therapy. Lysosomes are acidic organelles that participate in cellular digestion. However, there is rising interest in lysosomes because of their involvement with cancer. For example, extracellular secretion of lysosomal enzymes promote tumorigenesis; cytosolic leakage of lysosomal hydrolases promote apoptosis; and weak chemotherapeutic bases diffuse across the lysosomal membrane and become entrapped in lysosomes in their cationic state. Lysosomal drug sequestration lowers the cytotoxic potential of chemotherapeutics, reduces drug availability to sites of action, and contributes to cancer resistance. This review examines various mechanisms of lysosomal drug sequestration and their consequences on cancer multidrug resistance. Strategies for overcoming drug resistance by exploiting lysosomes as subcellular targets to reverse drug sequestration and drug resistance are also discussed.
Cancer drug development is a time and resources consuming process. Around 90% of drugs entering clinical trials fail due to lack of efficacy and/or safety issues, more often after conspicuous research and economic efforts. Part of the discarded drugs might be beneficial only in a subgroup of the study patients, and some adverse events might be prevented by identifying those patients more vulnerable to toxicities. The implementation of pharmacogenomic biomarkers allows the categorization of patients, to predict efficacy and toxicity and to optimize the drug development process. Around seventy FDA approved drugs currently present one or more genetic biomarker to keep in consideration, and with the progress of Precision Medicine tailoring therapies on individuals’ genomic landscape promises to become a new standard of cancer care. In the current article we review the role of pharmacogenomics in cancer drug development, underlying the advantages and challenges of their implementation.
The aim of this work was to supply an overview of the germline Pharmacogenetics that can be already implemented in the oncology clinical practice. An explanation of the three pillars considered necessary for determining which genetic polymorphisms should be used has been provided. These are PharmGKB single nucleotide polymorphism (SNP)-Drug Clinical Annotations with levels of evidence 1 or 2; the genetic information provided in the drug labels by the drug regulatory main agencies (Food and Drug Administration and European Medicines Agency, mainly); and the guidelines elaborated by international expert consortia (mainly Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group). A summary of the relevant SNPs and the recommendations on how to apply their results has also been compiled.
Pharmacogenetics is the study of therapeutic and adverse responses to drugs based on an individual’s genetic background. Monoclonal antibodies (mAbs) are a rapidly evolving field in cancer therapy, however a number of newly developed and highly effective mAbs (e.g., anti-CTLA-4 and anti-PD-1) possess pharmacogenomic profiles that remain largely undefined. Since the first chemotherapeutic mAb Rituximab was approved in 1997 by the US Food and Drug Administration for cancer treatment, a broad number of other mAbs have been successfully developed and implemented into oncological practice. Nowadays, mAbs are considered as one of the most promising new approaches for cancer treatment. The efficacy of mAb treatment can however be significantly affected by genetic background, where genes responsible for antibody presentation and metabolism, for example, can seriously affect patient outcome. This review will focus on current anticancer mAb treatments, patient genetics that shape their efficacy, and the molecular pathways that bridge the two.
This review describes the mechanism of action - inhibition of microtubules - and the most important mechanisms of resistance for vinca alkaloids, taxanes and epothilones. Resistance is a major problem in vinca and taxane chemotherapy and arises in most cases from overexpression of efflux pumps that transport the drugs out of the cancer cells and from modifications of the target, the microtubules, by overexpression of tubulin isotypes or by attachment of proteins to the ends of the microtubules so that the target is no longer recognized by the drugs. In some cases, however, this process can have the opposite effect, leading to sensitization, e.g., for vinca alkaloids in cases where taxanes are not or no longer effective. The link between resistance due to efflux pumps and the pharmacokinetics and metabolism of the drugs is also covered. Other types of resistance that are addressed include detoxification of drugs within the cancer cell and blockade of apoptosis, post-translational modifications of microtubules and other protein pathways, micro-RNAs, induction of oncogenes, and cancer stem cells, which, taken together, offer particularly multifold possibilities for preventing drug activity. The use of biomarkers for the prediction of clinical outcome and for the direction of future therapy is also addressed.
Gastrointestinal stromal tumors (GISTs) are rare entities, which, however, represent the most common mesenchymal tumor of the gastrointestinal tract. The discovery of gain of function mutations on KIT and PDGFRA receptor genes led to a deep revolution in the knowledge of this tumor. This paved the way to the introduction of imatinib and other tyrosine-kinase inhibitors (TKIs), which terrifically revolutionized the prognosis of GIST patients. Currently, it is well established that tumor mutational status is the main player in clinical outcome; however, with the research advances, it has been slowly understood that GIST landscape is more complex than expected and the TKIs available are not effective for all the GIST subtypes. For this reason, in the era of tailored/personalized medicine, each GIST patient should be considered individually and genetic consult should be the first step to take in consideration in the therapeutic decision making process.
Fluoropyrimidines (FP) are given in the combination treatment of the advanced disease or as monotherapy in the neo-adjuvant and adjuvant treatment of colorectal cancerand other solid tumors including breast, head and neck and gastric cancer. FP present a narrow therapeutic index with 10 to 26% of patients experiencing acute severe or life-threatening toxicity. With the high number of patients receiving FP-based therapies, and the significant effects of toxicities on their quality of life, the prevention of FP-related adverse events is of major clinical interest. Host genetic variants in the rate limiting enzyme dihydropyrimidine dehydrogenase (DPYD) gene are related to the occurrence of extremely severe, early onset toxicity in FP treated patients. The pre-treatment diagnostic test of 4 DPYD genetic polymorphisms is suggested by the currently available pharmacogenetic guidelines. Several prospective implementation projects are ongoing to support the introduction of up-front genotyping of the patients in clinical practice. Multiple pharmacogenetic studies tried to assess the predictive role of other polymorphisms in genes involved in the FP pharmacokinetics/pharmacodynamic pathways, TYMS and MTHFR, but no additional clinically validated genetic markers of toxicity are available to date. The development of next-generation sequencing platforms opens new possibilities to highlight previously unreported genetic markers. Moreover, the investigation of the genetic variation in the patients immunological system, a pivotal target in cancer treatment, could bring notable advances in the field. This review will describe the most recent literature on the use of pharmacogenetics to increase the safety of a treatment based on FP administration in colorectal cancer patients.
Aim: The purpose of this study was to locate the levels of hypoxia in glioblastoma PET images measured with 18F-fluoromisonidazole in human subjects. It is recognized that tumors with hypoxia are resistant to treatment by radiotherapy and chemotherapy.
Methods: The images were acquired in dynamic mode for 15 min or 30 min and in static mode for two single scans at 2 h and 3 h to allow the accumulation of the radiotracer in the tumor. The images were analyzed at the voxel basis with compartmental analysis (CA) and with the usual tumor-to-blood uptake ratio (TBR). Kmeans algorithm was applied to cluster the levels of hypoxia in the images.
Results: TBR at a threshold of 1.2 at imaging times of 15 min, 2 h and 3 h produced images with different clusters. Also, the comparison of TBR with the distribution volume obtained with CA had a similarity index of 0.61 ± 0.05.
Conclusion: We found some differences in defining the hypoxic volume within a tumor using TBR. The compartmental analysis allowed discrimination of the tumor hypoxic sub-volumes which can be useful for a better treatment with radiotherapy.