Via Research Recognition Day 2024 VCOM-Carolinas

Biomedical Studies

The Role of Personalized Medicine in Platinum-Based Chemotherapy: Current Knowledge and Future Directions Laura Grace Goldsmith, OMS-III, Steven A. Enkemann, PhD. Edward Via College of Osteopathic Medicine, Spartanburg, South Carolina. Abstract Results

DNA Repair Mechanisms and Resistance • Resistance: associated with the ability of DNA repair mechanisms to recognize and fix platinum-DNA adducts 37,38 • Genetic variations in the repair mechanisms can lead to platinum resistance or increased efficacy of the platinum-cross link induced apoptosis 31,33,36

Transporters • Influx pumps: compounds into the cell à raising the intracellular concentration • Efflux pumps: remove compounds from the cell à lowering the intracellular concentration • Genetic variations in transporters have been found to affect the intracellular concentration of platinum-compounds • Many transporters are involved in the platinum-pathway 7 Metabolism of platinum-chemotherapy • Plasma protein binding affects the amount of drug reaching the cells and the cytotoxic effect; implicated in dosing of the drug • Alter pharmacokinetics by binding the platinum-compound in the blood 11 • Cisplatin & oxaliplatin bind irreversibly to the proteins, carboplatin binds reversibly 12 • Free agents (not bound to plasma proteins) are taken up by the cells to cross-link DNA • Glutathione S-transferases (GST): role in detoxification of platinum agents from cells • GSTP1 polymorphism: varying alleles associated with differences in the onset of peripheral neuropathies when treated with oxaliplatin 14 • rs1695 AG polymorphism : significant increase in onset of peripheral neuropathy, compared to AA 15

Context: Platinum-based chemotherapy has been a mainstay of solid tumor treatment for several decades with the continuing battle of balancing side effect profiles, maintaining cytotoxicity, and preventing pharmacologic resistance. The original compound, cisplatin, has been joined by carboplatin, oxaliplatin, and others in an attempt to improve efficacy and toxicity profiles. The medical field has shifted the battle to the human genome as it investigates how variation in human genes related to the platinum processing pathway could alter the effects of these medications. Methods: Literature searches were conducted to determine the current platinum-based agents utilized in cancer treatment. PubMed and Google Scholar were examined significantly for articles regarding the mechanism of action, side effects, and development of resistance for each agent. Additionally, a search was conducted addressing studies focused on genetic variation and polymorphisms associated with the medication transport and resistance. Results: The metabolism, mechanism of action, and elimination of cisplatin is well understood, but not the other platinum-based chemotherapeutics, such as carboplatin and oxaliplatin. The platinum component of these agents, once inside the cell, is handled by enzymes and transporters that normally regulate copper containing compounds. This ‘platinum-pathway’ contributes to efficacy when in tumor cells, and toxicity, when operating in the ear, kidneys, and elsewhere. A few studies reported variants in expression of CTR1 and OCT2 influx transporters to be associated with ototoxicity, nephrotoxicity, and oxaliplatin-induced peripheral neuropathy, while upregulation of efflux pumps, CTR2 and ATP7A/7B, is associated with decreased cytotoxicity of these agents. A secondary area of interest is the impact DNA repair mechanisms have on altering the cytotoxic effects of platinum. Components of non-homologous end joining, homologous recombination, and nucleotide excision repair contribute to tumor sensitivity or resistance to platinum compounds. Given the complexity of DNA repair mechanisms it is likely that more genes and therefore more human variants will be identified with more research. Conclusion: Genetics play a role in platinum-agent chemotherapy efficacy but further analysis of each compound in conjunction with specific variants of the platinum-pathway and DNA repair pathways is necessary for personalized treatment to be helpful. Nonetheless, a framework for where to look seems to exist and physicians can begin to tailor the treatment of some patients. Platinum-chemotherapy • Alkylating agents – alter helical structure of DNA via cross-links 1-3 • Each compound has similar mechanisms of actions but different leaving groups in the aquation process and different affinities for receptors in the body 4,10 • Constant battle between maintaining tumor cytotoxicity and minimizing adverse reactions • Chemotherapeutic agents lack specificity – lead to adverse effect profiles 5 Introduction

Repair Gene

Study Findings

ERCC1

Upregulation à platinum resistance

ERCC2

Upregulation likely associated with resistance

NER

ERCC5

Upregulation likely associated with resistance

RAD50

Downregulation/deficiency à increased cisplatin toxicity & efficacy

Downregulation/deficiency à decreased recognition of platinum adducts, increased efficacy

BRCA1

BRCA2

Downregulation/deficiency à increase cisplatin efficacy

NHEJ & HR

Table 2. DNA repair proteins associated with treatment success for platinum compounds 31-36 .

Conclusions There are three main areas emerging that influence the likely success of platinum compounds: plasma and cytosolic components influencing the amount of free platinum in the tumor, intratumoral concentration of the compounds affected by transporters, and the DNA repair mechanisms that fix the damage produced by platinum compounds. Further research should be done to investigate what specific genetic polymorphisms lead to the overexpression or under expression of each platinum pathway gene product, along with algorithms that can place a patient into a treat or don’t treat category based on the sensitivity of the tumor or the toxicity profile of the patient. These studies should include cisplatin, carboplatin, and oxaliplatin, given that all three compounds are used world-wide.

Pt cross links guanine bp ao ss eDi tsNi oaAnt No n7 bin b p a d l r H o d o p c d M t l k e u t G i i - c n nD t g s N A tranfascctroiprstion

Aquation P c o po r s l e ma a c t p h c in t o a i uu r o g mn n e d d [activated]

I nshy inbtiht eDs Ni sA Apo c p e to ll s s is of

Active transport pvui ami npfsl ux or Passive diffusion

References

Figure 1. Generalized cytotoxic mechanism of action for platinum-chemotherapy agents 1,7-9 .

We would like to acknowledge the helpful efforts of the Library Staff at the Carolinas Campus who helped in obtaining difficult to find manuscripts. Acknowledgements

Table 1. Approved cancer types targeted with platinum-based chemotherapeutics 1,4-6 .

This work examines the current knowledge regarding platinum-based chemotherapeutics; allowing for better selection of agents based on patient genetic profile, specifically the tumor receptors, mechanisms of resistance, and variations in metabolic pathways.

Figure 2. Cellular transporters with a known role in the intracellular concentration of platinum compounds 7,10,15-30 .

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2024 Research Recognition Day