Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage

Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage

Background on chemotherapy-induced peripheral neuropathy (CIPN)

Incidence, prevalence, and consequences: Up to 90% of cancer patients experience CIPN at some point during or aer antican‐cer treatment (Seretny et al., 2014). Although CIPN is second to hematologic toxicities in regards to the frequency of incidence, there are currently no approved treatments to prevent or treat CIPN, thus the neurotoxicity can be dose‐limiting for some pa‐tients (Vasko et al., 2016). In addition, CIPN can persist follow‐ing discontinuation of the drug: up to 40% of cancer patients continue to struggle with CIPN fi ve years aer treatment ends (Vasko et al., 2016) — and 10% remain symptomatic aer more than 20 years.us, CIPN directly a ff ects cancer survivorship, quality of life, and may limit future treatment options if cancer recurs (Vasko et al., 2016).

Symptoms and causative agents

CIPN’s diverse toxicities usually manifest as di ff use, bilateral alterations in sensory neuronal function, which can include numbness, paresthesia, allodynia, thermal hyper‐ or hypoal‐gesia, cold intolerance, loss of proprioception, and reduced tendon re fl exes (Vasko et al., 2016).

Many anticancer treatments cause CIPN, particularly:

· Platinum compounds (cisplatin, carboplatin, oxaliplatin)

· Vinca alkaloids (vincristine, vinblastine)

· Taxanes (docetaxel, paclitaxel)

· Epothilones (ixabepilone)

· Immunomodulators (thalidomide, lenalidomide)

· Bortezomib

· Ionizing radiation

Each anticancer agent causes a slightly different comple‐ment of CIPN symptoms (Vasko et al., 2016). For example, platins accumulate in the dorsal root ganglia and reduce neurotransmitter release, causing parasthesias; while taxanes and epothilones disrupt axonal transport, causing sensorim‐otor and autonomic dysfunction, as well as neuropathic pain (Vasko et al., 2016).

Unknown mechanisms of action = lack of e ff ective treatments: Anticancer treatments affect sensory neurons with an increase (burning pain, hypersensitivity to touch) or decrease (numbness, loss of proprioception) in sensory function, and this variability in symptoms of CIPN increases the challenge to identify the mechanisms underlying CIPN.is is compounded by the numerous ways anticancer treat‐ments a ff ect the neurons directly or indirectly. For example, while platinum agents cause DNA damage through DNA cross‐link adducts, some (like cisplatin and oxaliplatin) also produce significant reactive oxygen species (ROS) which creates oxidative DNA damage. Other agents, such as bor‐tezomib are more involved in disruption of microtubular dynamics and axonal transport.is diverse list (Figure 1) would imply that equally diverse anti‐CIPN therapeutics would be needed — in essence, to match the agent with the mechanism of each anticancer treatment (akin to precision medicine principles).

Indeed, a plethora of treatment strategies have already been tried (able 1). Both traditional and alternative/comple‐mentary treatments have been ineffective or inconsistent in suppressing the variety of CIPN symptoms (Pachman et al., 2014). Nevertheless, without de fi nitive therapeutic targets or understanding the mechanism of action, developing preven‐tive or therapeutic agents for CIPN is like operating blindly.

A different approach: DNA damage and repair in CIPN: Although scientists are unsure of how anticancer therapies cause CIPN, the preponderance of sensory problems o ff ers an important clue.e blood‐brain barrier protects the cen‐tral nervous system. In contrast, sensory nerves of the PNS are “exposed.” Their dorsal root ganglia exit the vertebral bodies; from there, individual nerves branch throughout the body, making both vulnerable to damage during cancer treatment (Vasko et al., 2016). Two therapeutic challenges exist regarding CIPN: healing after damage occurs, and neuroprotection before harm can happen.e latter is more desirable — but most likely a much tougher paradigm.

Nonetheless, most existing treatments for CIPN address the problem after the fact. They attempt to alleviate symp‐toms (such as pain) or correct for treatment sequelae (such as nutritional deficiencies). Similarly, modalities (such as physical therapy) compensate for, but do not cure de fi cits in sensory function (Pachman et al., 2014).

Figure 1 Putative sites of sensory neuronal dysfunction following speci fi c anticancer drug treatments, indicated in italics.

Figure 2e role of oxidative DNA damage in altering sensory neuronal function following exposure to anticancer treatments inducing oxidative DNA damage such as cisplatin, oxaliplatin or ionizing radiation.

able 1 Current treatments for chemotherapy-induced peripheral neuropathy (CIPN)

able 1 Current treatments for chemotherapy-induced peripheral neuropathy (CIPN)

Category Examples Antidepressants Tricyclics; duloxetine; venlafaxine Antiepileptics Gabapentin/pregabalin, lamotrigrine Analgesics Lidocaine; ketamine; baclofen; topical capsaicin; topical menthol Opioids Morphine; oxycodoneiophosphatesAmifostine Antioxidants Glutathione; acetyl‐L‐carnitine; alpha‐lipoic acid; vitamin E Minerals Calcium and magnesium Supplements B6 and B12; curcumin; omega‐3 fatty acids; glutamine Psychological Guided imagery; biofeedback; cognitive behavioral therapy; meditation Modalities Physical therapy, occupational therapy, massage therapy, acupuncture, Reiki Devices Neurostimulation (TENS); cold laser therapy; infrared LED therapy

The goal of our laboratory is to provide neuroprotection against the deleterious e ff ects of anticancer treatment, both before it can occur and aer it is observed. Our work strong‐ly supports the idea that any anticancer treatment capable of inducing oxidative stress or DNA damage can harm neurons, thus contributing to neuropathy. Several lines of evidence support this (Vasko et al., 2005; Vasko et al., 2011; Englander, 2013; Hershman et al., 2014; Kelley et al., 2014; Kim et al., 2015):

· DNA damage in sensory neurons following ionizing radia‐tion or chemotherapy correlates with CIPN symptoms.

· BER is the primary means of repairing DNA damage in the nuclei and mitochondria of neurons.

· APE1 is a pivotal enzyme in the BER pathway.

· Reducing APE1 expression increases toxicity to sensory neurons exposed to anticancer therapies — but overexpres‐sion of APE1 prevents the damage.

· APE1 is a multifunctional protein possessing both endonu‐clease and redox capabilities.

· Inhibiting APE1’s redox function partially unfolds the pro‐tein, which alters its ability to activate transcription factors. Disengaging APE1 from its redox activities appears to en‐hance its DNA repair capacity in neurons, but not tumors.

A targeted small‐molecule therapeutic (E3330, now named APX3330) that inhibits redox signaling and enhances DNA repair in sensory neurons, provides neuroprotection in a manner analogous to genetic APE1 overexpression without diminishing the e ff ectiveness of the anticancer treatment.

Thus, we have established a causal relationship between DNA damage and CIPN by modulating the DNA repair capacity of sensory neurons through the BER pathway and have developed a putative therapeutic that could prevent CIPN without compromising anticancer treatments.

Pipeline of molecules: More than a decade of testing APX3330 has con fi rmed its neuroprotective and tumor‐kill‐ing properties, with no evidence of acute drug‐related severe toxicity observedin vivoor in humans when used in a prior series of clinical studies by Eisai for chronic hepatitis C in Japan. APX3330 was recently given a Letter to Proceed from the FDA for Phase 1 clinical trials for safety and MTD deter‐mination (IND125360), which will start in 2017.

Additionally, we are utilizing a SAR (structure‐activity re‐lationship) approach for the development of second‐gener‐ation compounds to target APE1 both for tumor killing and prevention or reversal of CIPN. We have modi fi ed APX3330 and have yielded a number of new compounds that have undergone or will undergo testing on sensory neuronal cultures. One example of a second‐generation compound, APX2009, demonstrated neuroprotective activity against cisplatin and oxaliplatin similar to that of APX3330 — but at lower concentrations (Kelley et al., 2016). APX2009 has also demonstrated e ff ective tumor killing properties and has a fa‐vorable half‐life in human microsomes P450 studies, giving the compound a favorable pharmacokinetic pro fi le suitable for treating patients. Collectively, these data suggest that APX2009 is e ff ective in preventing or reversing platinum‐in‐duced CIPN without a ff ecting the platinum’s anticancer ac‐tivity (Kelley et al., 2016). Further preclinical studies will as‐certain not only APX2009’s relative therapeutic indices, but determination of the other second‐generation compounds anti‐tumor and anti‐CIPN e ff ectiveness.

Conclusions and future directions

Effective prevention and management of CIPN hinges on understanding its pathophysiology. While more than one causal mechanism may be at work (Figure 2), we believe that the induction of oxidative DNA damage in sensory neurons is a major cause of CIPN.is drives our work with BER and APE1 — to fi nd CIPN treatments that do not obstruct thera‐peutic anticancer regimens. Related to this, we are also exam‐ining whether in fl ammation contributes to peripheral sensi‐tization by causing DNA damage which would dovetail with CIPN and mechanism of action. Initial fi ndings in this fi eld by our group has implications linking oxidative DNA damage either from chemotherapeutic agents or in fl ammation and the resulting peripheral neuropathy. Fully elucidating how anti‐cancer drugs damage DNA and how the BER pathway revers‐es this damage can pave the way for identifying therapeutic targets and truly e ff ective treatments for CIPN.

Financial support for this work was provided by the National Cancer Institute [CA122298 (MRK) and the National Institutes of Health, [R21NS091667 (MRK and JCF)]. Additional fi nancial support was provided by, the Earl and Betty Herr Professor in Pediatric Oncology Research, Je ff Gordon Children’s Foundation and the Riley Children’s Foundation (MRK) and IU Simon Cancer Center Neurotoxicity Working Group (MRK and JCF).

Acknowledgments: Many thanks to Lana Christian of Create-Write Inc. for her expert writing and editing assistance.

Mark R. Kelley＊, Jill C. Fehrenbacher

Pediatric Oncology Research; Departments of Biochemistry & Molecular Biology and Pharmacology & Toxicology; HB Wells Center for Pediatric Research; Basic Science Research, Indiana University Simon Cancer Center, Indianapolis, IN, USA (Kelley MR) Department of Pharmacology and Toxicology; Stark Neuroscience Research Institute; Department of Anesthesiology, Indiana University School of Medicine, Indianapolis, IN, USA (Fehrenbacher JC)

＊Correspondence to: Mark R. Kelley, Ph.D., mkelley@iu.edu.

Accepted:2016-12-22

orcid: 0000-0002-9472-1826 (Mark R. Kelley)

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How to cite this article:Kelley MR, Fehrenbacher JC (2017) Challenges and opportunities identifying therapeutic targets for chemotherapy-induced peripheral neuropathy resulting from oxidative DNA damage. Neural Regen Res 12(1):72-74.

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