Cancer Drug Delivery: Pharmacogenetics, Biomarkers, and Targeted Therapies

Cancer Drug Delivery: Pharmacogenetics, Biomarkers, and Targeted Therapies

Jai N. Patel, Jeryl Villadolid
Copyright: © 2017 |Pages: 44
DOI: 10.4018/978-1-5225-0754-3.ch003
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Abstract

Advancements in cancer drug delivery have led to the development of personalized oncology care through molecularly-driven targeted therapies. Understanding molecular and cellular mechanisms which drive tumor progression and resistance is critical in managing new treatment strategies which have shifted from empiric to biomarker-directed therapy selection. Biomarker-directed therapies have improved clinical outcomes in multiple malignancies as monotherapy and in combination with other treatment modalities, however the changing scope of treatment options presents new opportunities and challenges for research. Furthermore, pharmacogenetics may provide a rationale method of personalizing anticancer drug dosing and supportive care management for oncology patients. This chapter reviews biomarker classifications and pharmacogenetics in anticancer therapy and supportive care. Examples of biomarker-directed therapies and clinical assays, in addition to future directions of molecular profiling in oncology therapy management are discussed.
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Introduction

Novel methods of individualizing cancer drug delivery and selection are critical to improve patient outcomes given the large heterogeneity in drug response that exists across the cancer patient population. Until recently, the majority of genomic cancer research has been in discovery and validation; however, as our knowledge of tumor molecular profiling improves, the implementation of genomic cancer medicine in the clinic becomes increasingly tangible, paralleled with the development of dozens of targeted cancer therapies (Tran et al., 2012). Our current understanding of cancer at the molecular level has resulted in a shift from characterizing tumors solely based on their anatomical location and histology to consideration of their molecular profile, opening an array of possibilities for a targeted approach to cancer therapy (Macconaill, Van Hummelen, Meyerson, & Hahn, 2011).

Pharmacogenetic biomarkers found within the tumor and the host offer valuable information for personalizing anticancer drug delivery. As the number of clinical assays available to test for pharmacogenetic biomarkers increases, it is imperative for clinicians to understand the therapeutic implications of mutations occurring within these molecular pathways to aid in drug selection and delivery. This chapter aims to summarize clinically relevant pharmacogenetic biomarkers, which may be used to personalize cancer therapy selection and dosing, in addition to a review of pharmacogenetics in supportive care management related to the treatment of cancer-related symptoms. Tables 1 and 2 summarize clinically relevant somatic and germ-line pharmacogenetic biomarkers and drug targets, and their respective clinical assays available in practice.

Table 1.
Summary of FDA-approved targeted therapies, biomarkers and clinical assay availability.
BiomarkerTherapyFDA-Approved Indication(s)Clinical Assay(s) Available
ALKceritinibNSCLCVysis ALK Break Apart FISH probe kit
crizotinibNSCLC
BCR-ABLbosutinibCMLBCR-ABL Mutation Analysis test
dasatinibALL, CML
imatinibALL, CML, GIST
nilotinibCML
ponatinibALL, CML
BRAFdabrafenibMelanomaCobas 4800 V600E
THxID BRAF test
vemurafenibMelanoma
BTKibrutinibMCL, CLL, WMNo Clinical Assay Available
CDK 4/6palbociclibBreastNo Clinical Assay Available
c-KITimatinibALL, CML, GISTc-KIT pharmDX
regorafenibCRC, GIST
sunitinibRCC, GIST, pNET
CTLA-4ipilimumabMelanomaNo Clinical Assay Available
EGFRafatinibNSCLCEGFR pharmDx
Cobas EGFR Mutation Assay
erlotinibNSCLC
ER/PRanastrazoleBreastER/PR pharmDx
TargetPrint
exemestaneBreast
letrozoleBreast
tamoxifenBreast
HER2ado-trastuzumab emtansineBreastHercepTest1, Pathway
Insite
PathVysion
SPOT-Light
HER2 CISH
lapatinibBreast
pertuzumabBreast
trastuzumabBreast, Gastric
JAKruxolitinibMyelofibrosis, PCVJAK2 V617F Mutation Detection Assay
HTScan JAK2 Kinase Assay Kit
KRAScetuximabCRC, NSCLC, HNCCobas KRAS Mutation Test
Therascreen KRAS RGQ PCR Kit
DxS KRAS Mutation Test Kit, Genzyme’s KRAS Mutation Analysis
panitumumabCRC
MEKtrametinibMelanomaNo Clinical Assay Available
mTOReverolimusBreast, pNET, RCCNo Clinical Assay Available
temsirolimusRCC
PARPolaparibBRCA-mutated ovarianNo Clinical Assay Available
PD-1pembrolizumabMelanomaNo Clinical Assay Available
nivolumabMelanoma, NSCLC
SMOvismodegibBCCNo Clinical Assay Available
VEGFafliberceptCRCNo Clinical Assay Available
axitinibRCC
bevacizumabCervical, CRC, GBM, NSCLC, Ovarian, RCC
cabozantinibMTC
lenvatinibThyroid
pazopanibRCC, STS
ramucirumabGastric
regorafenibCRC, GIST
sorafenibRCC, HCC, DTC
sunitinibRCC, GIST, pNET
vandetanibMTC

BBT: basal cell carcinoma; CLL: chronic lymphocytic leukemia; CML: chronic myeloid leukemia; CRC: colorectal; DTC: differentiated thyroid cancer; GBM: glioblastoma; GIST: gastrointestinal stromal tumor; HCC: hepatocellular carcinoma; HNC: head and neck cancer; MCL: mantle cell lymphoma; MTC: medullary thyroid carcinoma; NSCLC: non-small cell lung cancer; PCV: polycythemia vera; pNET: pancreatic neuroendocrine tumor; RCC: renal cell carcinoma; STS: soft-tissue sarcoma; WM: Waldenstrom’s macroglubulinemia

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