Recent developments of novel pharmacologic therapeutics for prevention of chemotherapy-induced peripheral neuropathy

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and dose limiting toxicity, negatively impacting both quality of life and disease outcomes. To date, there is no proven preventative strategy for CIPN. Although multiple randomized trials have evaluated a variety of pharmacologic interventions for the treatment of CIPN, only duloxetine has shown clear efficacy in a phase III study. The National Cancer Institute’s Symptom Management and Health Related Quality of Life Steering Committee has identified CIPN as a priority for translational research in cancer care. Promising advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to transform the care of patients with this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets that are currently being evaluated in CIPN.

Introduction

Many chemotherapeutic agents, including tubulin poisons and platinum-based agents can induce acute and/or chronic, dose-dependent sensory peripheral neuropathy that is characterized by paresthesia, allodynia and ataxia. The incidence of chemotherapy-induced peripheral neuropathy (CIPN) is particularly high with agents such as paclitaxel and oxaliplatin, occurring in up to 80% of patients receiving such agents (1). With continued dosing, these symptoms increase in severity and can persist for years (2), causing long-term functional impairment that impacts quality of life (3). The mechanistic basis of this side effect is not entirely clear (4). Prior studies have demonstrated that these agents induce morphological and biochemical alterations in dorsal root ganglion (DRG) satellite glial cells, which can lead to hyperplasia and hypertrophy of macrophages in the peripheral nervous system, and also increase microglial and astrocyte activation within the spinal cord (5). In addition, these agents also inflict direct damage to Schwann cells (6) and neurons (7).

Efforts over the last 30 years have yielded a multitude of methods to predict, prevent, or manage CIPN (8). There are two overarching approaches in CIPN management: to target the underlying pathological mechanism responsible for CIPN or to address the CIPN symptoms themselves. Many strategies to combat CIPN originate from other patient populations who experience neuropathy, such as those with diabetes. In fact, it is important to control comorbid conditions which could contribute to peripheral neuropathy, including diabetes, inflammatory conditions, and nutritional disorders (9,10). The predictive approaches have primarily concentrated on discovering hereditary biomarkers which could recognize patients at an increased risk for CIPN using candidate gene (11-14) or genome-wide association studies (15,16).To date, however, these studies have found non-overlapping single or pathway biomarker associations that prevent prompt clinical application(5,15,17,18). Furthermore, the shortage in available alternative therapies that could supplant standard of care treatments and possibly the need for patient-mediated chemotherapy treatment dose reduction may deter patients from taking action when a toxicity biomarker is detected. Because of the current state of the field and the presumed negative ramifications of treatment dose reduction on disease management, the development of preventative techniques, to efficaciously impart neuroprotection during chemotherapy treatment, is imperative.

Although many prophylactic interventions have been proposed, many of these have not been evaluated in animal models or humans. While more than, 40 randomized controlled clinical trials of preventative or therapeutic agents for CIPN have been investigated none of these trials have provided conclusive evidence for a clinically beneficial agent (19), with the exception of the serotonin and norepinephrine reuptake inhibitor, duloxetine, in a phase III study (20). The magnitude of benefit from this agent is small. Furthermore, the translational exploration of many of the proposed intervention strategies has been hampered by the recognition that (i) most drugs causing CIPN have multiple intracellular targets and, hence, blocking a single injurious event may only have partial protective effects; (ii) the protective approach may diminish the antitumor properties of drugs given the potential overlap in cell death signaling pathways between normal cells and tumor cells; and (iii) heavy reliance on patient reported outcomes as study endpoints introduces variability and measurement noise. In total, a desirable approach is to simultaneously protect the peripheral nerves against drugs without antagonizing the therapeutic effects in tumors.

The National Cancer Institute’s Symptom Management and Health Related Quality of Life Steering Committee has identified CIPN as a priority are for translational research in cancer care (21) and recent advances in preclinical research have identified several novel preventative and therapeutic targets, which have the potential to be translated into clinic for improved management of this debilitating neurotoxicity. Here, we provide an overarching view of emerging strategies and therapeutic targets (Fig.1) that are currently being evaluated for CIPN.

Figure 1.

Schematic depicting mechanisms of CIPN in neuronal cells. Purple/orange demonstrate proteins/enzymes/receptors involved in CIPN. Green indicates targetable preventative/treatment strategies while blue indicates interconnected mechanisms of CIPN. Abbreviations: Tyrosine phosphorylation (Tyr-p), proto-oncogene tyrosine-protein kinase (YES1), Lck/Yes novel tyrosine kinase (LYN), manganese superoxide dismutase (MnSOD), reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψm), sterile alpha and TIR motif-containing protein (SARM1), nicotinamide adenine dinucleotide (NAD), heat shock protein 90 (HSP), B-cell lymphoma 2 (BCL2), inositol 1,4,5-triphosphate receptor (IP3R), apyrimidinic endonuclease/redox effector factor (APE1), sphingosine-1-phosphate (S1P), sphingosine-1-phosphate receptor 1 (S1PR1), nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB), nicotinic acetylcholine receptor (nAChR), ganglioside-monosialic acid (GM1), serotonin transporter (SERT or 5-HTT), norepinephrine transporter (NET), sodium channel subtype (Na(v)1.7).

Targeting neuronal uptake transporters

CIPN commonly originates from substantial accumulation of chemotherapeutic drugs into DRGs as evidenced by the observed levels of these agents in the sciatic nerve and spinal cord; the centrifugal and centripetal branches of the neural axons in DRGs appear to be the location of this transport. Preceding investigations have found that facilitated transport mechanisms are responsible for the cellular uptake of platinum drugs associated with CIPN (22). Conversely, the typical dissemination patterns and pathological transformations that occur after administering these platinum agents are confined only to cells in tissues able to deliver paclitaxel from blood to these cells. Indeed, transmembrane transport of taxanes and platinum-based chemotherapeutics is now hypothesized to be mediated by specific organic anion transporting polypeptides (OATPs) and organic cation transporters (OCTs), respectively. Preclinical studies have demonstrated that transporter-mediated uptake of these agents into DRGs is an initiating event to trigger the pathophysiological changes to sensory neurons (5,23,24). In particular, recent studies have demonstrated that genetic or pharmacological knockout of transporters localized to the DRG in mice, such as OATP1B2 (OATP1B1 in humans), organic cation transporter novel type (OCTN2) and OCT2, protects against CIPN associated with paclitaxel (25), vincristine (26), and oxaliplatin (23,27). Small-molecule library screens have identified the class of FDA-approved tyrosine kinase inhibitors (TKIs) as being exquisitely sensitive blockers of these uptake transporters, in vitro and in vivo, through a mechanism involving the inhibition of regulatory kinases that activate transporters by tyrosine phosphorylation (27). Subsequent proof-of-principle studies with nilotinib (an OATP1B2 inhibitor) and dasatinib (an OCT2 inhibitor) have demonstrated that targeting of specific transporters could be an effective neuro-protective strategy for regimens involving paclitaxel and oxaliplatin, without affecting systemic drug clearance or negatively influencing antitumor efficacy. The hypothesis that TKIs, such as nilotinib and dasatinib, can be repurposed as pharmacological inhibitors of transporters that are essential to the uptake of chemotherapy drugs into peripheral neurons to ameliorate CIPN is currently being tested in ongoing phase 1b trial and double-blinded, placebo-controlled, randomized phase 2 studies (Table 1). Risk and benefit analysis must be performed on a patient-specific basis to determine the appropriateness of TKIs in the prevention of CIPN because of adverse effects which include QTC prolongation and cytopenias (28). The findings obtained from these studies will provide future directions on the potential of inhibition of uptake transporters as a prevention strategy to reduce the onset, incidence, and severity of various forms of CIPN.

Table 1:

List of emerging clinical trials for the prevention and treatment of CIPN

Intervention	Target/Pathway	N	Patient Population (NCT # if available)	References
Nilotinib	OATP1B1-3 uptake transporter inhibitor	95	Breast cancer patients initiating paclitaxel	(25,71)
Dasatinib	OCT2 uptake transporter inhibitor	20	Stage 4 colorectal patients initiating oxaliplatin-based therapy	(22,72)
Calmangafodipir	Reduction of ROS	1) 420 2) 280	1) Stage 4 colorectal patients initiating oxaliplatin-based therapy (POLAR M ) 2) Adjuvant oxaliplatin based therapy (POLAR A)	(31,73)
APX3330	Enhance APE1 expression	30	Adjuvant oxaliplatin-based therapy	(39,40)
Fingolimod	S1PR1 antagonism	1)10-20 2)10-20	1)breast cancer patients initiating adjuvant paclitaxel 2) patients with established long-standing CIPN	(43,44)
Duloxetine	Serotonin-norepinephrine reuptake inhibitor	248	Patients initiating oxaliplatin-based adjuvant therapy	(20,74)
GM-1	Lipid peroxidation inhibition	188	Patients initiating oxaliplatin-based adjuvant therapy ()	(53,75)

Mitochondrial enzyme and oxidative stress

One of the proposed mechanisms of CIPN is neuronal mitochondrial injury, which can promote the degeneration of somatosensory neurons (29). Oxidative stress from chemotherapy is the primary inducer of mitochondrial damage and neutralization of reactive oxygen species is a potential preventative strategy for CIPN. Calmangafodipir, derived from mangafodipir, a magnetic resonance imaging contrast agent, mimics the mitochondrial enzyme manganese superoxide dismutase and reduces reactive oxygen species and subsequent nerve injury (30). Preclinical data, regarding this agent, are strongest with platinum agents; however, neuroprotection from calmangafodipir may also be possible with other chemotherapeutic classes as well. In a placebo-controlled, double-blinded randomized phase 2 study in patients with metastatic colorectal cancer, calmangafodipir reduced cold allodynia and other sensory symptoms during and after treatment (31). Progression-free and overall survival outcomes were not adversely impacted in this study. Two international trials, POLAR A and POLAR M, are currently evaluating the efficacy of calmangafodipir for the prevention of oxaliplatin-induced neuropathy in colorectal cancer patients (Polar M: ). These phase III, multicenter, placebo-controlled trials are evaluating stage II and III patients in POLAR A using a randomized 1:1 ratio of 5 µmol/kg calmangafodipir (n=140) or placebo (n=140), while POLAR M is evaluating metastatic patients using a 1:1:1 ratio of 5 µmol/kg calmangafodipir, 2 µmol/kg calmangafodipir, or placebo (each arm, n=140). Results are expected by the end of 2020.

Preclinical data also suggest promising activity associated with a commonly used anti-hypertensive and cardio-protectant drug, carvedilol. In rodent models, administration of carvedilol reduced levels of nitrotyrosine and subsequently increased expression of mitochondrial superoxide dismutase in both sciatic nerves and DRG tissues (32). Based on this mechanism of action, the drug has the potential for preventing an alteration in mitochondrial membrane potential in sciatic nerves and the loss of intra epidermal nerve fiber density in the foot pads (32). Although there are a number of ongoing studies evaluating carvedilol for a variety of clinical conditions, there is currently no clinical study for the prevention of CIPN. Since there are ongoing cancer trials evaluating the cardio-protective properties of carvedilol, prevention of CIPN might be considered as an exploratory endpoint.

Prevention of axonal degeneration

Acute axonal degeneration is another principal pathway implicated in CIPN from a variety of chemotherapeutic agents. Axonal degeneration is dependent on several pathways. The sterile alpha and TIR motif-containing protein (SARM1), expressed primarily in the nervous system, and its downstream cascade are key instigators of acute chemotherapy-induced axonal destruction (33). Activated SARM1 induces the rapid destruction of the essential metabolic co-factor nicotinamide adenine dinucleotide lead to axonal degeneration (34). The exact location of SARM-1 is under investigation, with some evidence suggesting that it may be localized to neuronal mitochondria and may associate with other mitochondrial proteins to induce apoptosis (35). Hence, targeting of SARM-1 is an emerging strategy for the prevention of CIPN with targeted drugs currently being in development.

In addition to the SARM-1 pathway, there are other targetable molecules that may protect axonal health. In preclinical DRG cell lines and rodent models, ethoxyguin prevents paclitaxel-and cisplatin-induced distal axonal degeneration via HSP 90 modulation, without compromising antitumor efficacy (36). Clinical trial testing of this agent is currently under consideration. Additionally, the Bcl2 family of proteins, including Bclw, may play a role in axonal degeneration caused by paclitaxel. The addition of the peptide Bclw prevented chemotherapy-induced nerve degeneration by interaction with IP3 receptor activity on neurons. Thus, modulation of Bclw levels might represent another novel therapeutic strategy for prevention of CIPN (37).

Targeting apurinic/apyrimidinic endonuclease function

Another mechanism of nerve injury from chemotherapy, particularly cisplatin and oxaliplatin, is secondary to drug-induced DNA damage in sensory neurons (38). The base excision repair pathway is the primary means for repairing oxidative DNA damage; within this pathway, the enzyme apyrimidinic endonuclease/redox effector factor (APE1) is important for the removal of the damaged bases. Reduction of APE1 expression in sensory neurons increases neurotoxicity (39), and the targeting of APE1 by small molecule APX3330 is protective against CIPN while also having de novo anti-tumor efficacy (40). APX3330 is entering human clinical trials as an antineoplastic agent as well for prevention of CIPN.

Targeting inhibition of neuronal apoptosis and astrocyte activation

Fingolimod is commercially available as a marketed drug for multiple sclerosis. Preclinical models have suggested that this agent may also be a promising agent to prevent CIPN. In animal models, oral administration of fingolimod can both prevent and treat neuropathic pain from a variety of chemotherapeutic agents, without the development of tolerance to an analgesic effect. Importantly, fingolimod does not interfere with antitumor efficacy of chemotherapy (41,42) and may have synergistic antitumor properties, making it an attractive agent for CIPN prevention studies during chemotherapy. The protective mechanism of action for fingolimod is based on the direct disruption on the sphingosine-1-phosphate (S1P) activation pathway, leading to an analgesic effect that is independent of the opiate pathway. Certain chemotherapy classes including taxanes (paclitaxel)(41), platinum based agents (oxaliplatin)(41), and proteasome inhibitors (bortezomib) (42) drive the development of CIPN by dysregulating sphingolipid metabolism, leading to increased formation of S1P, which binds and activates sphingosine-1-phosphate receptor 1 (S1PR1). Fingolimod may also promote peripheral nerve regeneration by S1P signaling (43,44). The downstream effect of S1PR1 blockade is the inhibition of the NF-kB pathway. Fingolimod’s associated adverse effects which include bradycardia, atrioventricular conduction block, and hypotension must be considered when utilizing this drug for CIPN prevention and treatment (45).

Through a different mechanism, but with the ultimate downstream effect on NF-kB pathway, nicotine is under investigation as another potential therapeutic strategy for both prevention and treatment of paclitaxel-induced CIPN (46). Associated data suggest that targeting the nicotinic acetylcholine receptor-mediated pathways may be promising for the prevention and treatment of CIPN induced by paclitaxel or oxaliplatin (47). A primary concern is that nicotine may also stimulate tumor growth, although the evidence for tumor proliferation has been inconsistent in preclinical models (47). Interestingly, smoking history has been classified as a risk factor for CIPN, however, this finding has limitations due to its determination from a secondary analysis whose primary endpoint was not related to this topic (48). Regardless, preclinical mechanistic data support further investigation through clinical trials utilizing commercially-available nicotine replacement have been proposed. Other strategies include nicotinic acetylcholine agonists (49) or nicotinic receptor antagonists (50), as novel strategies for the prevention and treatment of CIPN.

Targeting the gangliosinide-monosialic acid pathway

Ganglioside-monosialic acid (GM1) is a type of glycosphingolipid, located in the outer layer of the plasma membrane, which is critical for nerve development, differentiation and repair after injury (51). The proposed mechanisms of neuroprotection involve nerve regeneration, removal of oxygen free radicals, and inhibition of lipid peroxidation. In preclinical studies, GM1 has been effective for the prevention of CIPN (52). In the first published randomized clinical trial, 120 patients with gastrointestinal tumors received either oxaliplatin standard of care or with GM1 combination therapy (53). GM1 was associated with a reduced severity of oxaliplatin-induced neurotoxicity in this preliminary study, rendering clinically and statistically significant results and meeting the primary endpoint. The control group endured grades 2 and 3 neurotoxicity at a greater probability than the GM1 group (logistic ordinal regression), while the GM1 group experienced grades 0 or 1 neurotoxicity at a greater probability (logistic ordinal regression). A retrospective study was also performed to assess the efficacy of monosialotetrahexosylganglioside (GM1) for preventing oxaliplatin induced neurotoxicity: from a total of 278 cases, 114 in GM1 group and 164 in control group, incidence of grade 1–3 and grade 3 acute and chronic neurotoxicity were lower in GM1 group (54). Additional placebo-controlled studies are needed, to better assess the utility of this agent and a clinical trial study is currently ongoing, .

Serotonin-norepinephrine reuptake and nociceptor sodium channel inhibition

Serotonin and norepinephrine dual reuptake inhibitors, such as duloxetine and venflaxine, are effective antidepressants with evidence of efficacy for improving neuropathic pain (55). To date, duloxetine, a serotonin-norepinephrine reuptake inhibitor has been the only randomized phase III intervention study in CIPN associated with a significant reduction in neuropathic pain symptoms (20). Other studies with duloxetine have similarly supported the efficacy of this drug for reducing neuropathy symptoms following chemotherapy treatment (56,57). The mechanism of duloxetine-induced analgesia is thought to be related to the blocking of serotonin and norepinephrine transporters, as well as blocking of sodium channel currents and affecting the descending inhibitory pain neural networks (58-60). As a consequence, spontaneous nerve impulses from peripheral nerves are not transmitted to the central nervous system, diminishing pain symptoms. While the published data on the analgesic effects of duloxetine is on treatment of neuropathic pain, emerging preclinical data suggest that duloxetine may also be effective for prevention of CIPN. A new NCI funded clinical trial is currently undergoing protocol development to evaluate the efficacy of duloxetine for prevention of oxaliplatin neuropathy.

The GABA-analogue and the voltage-gated Ca⁺² channel antagonist, pregabalin, is also frequently recommended for pain associated with CIPN, because of its efficacy in managing diabetic neuropathic pain (61), neuropathic cancer pain (62), and rat CIPN models (63). However, a pilot trial did not suggest that pregabalin could prevent CIPN (64). This suggests that CIPN is a distinct condition independent from other peripheral neuropathies, such as those associated with diabetes, fibromyalgia, and neuropathic cancer pain in which pregabalin is effective (65). Gabapentin is another drug frequently recommended for CIPN management and shares the same mechanism of action as pregabalin. Similarly, trials do not demonstrate gabapentin’s efficacy in treating established CIPN, best illustrated in a phase III trial (66).

The voltage-gated sodium channel 1.7 (Nav1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes. In preclinical models, utilization of peripheral sodium channel blockers targeting Na(v)1.7 was able to reverse hyperalgesia and allodynia without damaging motor function (67). In humans, SCN9A gene mutations that cause Na(v)1.7 deficiency lead to an inability to sense pain, or congenital indifference to pain (CIP), whereas gain-of-function missense mutations lead to spontaneous pain characterized by inherited erythromelalgia (IEM) (68). Recent work demonstrates that the expression and function of the Na(v)1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), more interestingly, it also shows that Nav1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms (69). Data from a randomized, double-blind placebo-controlled crossover pilot study investigating the Na(v)1.7 antagonist, XEN402, indicates that patients with IEM experience 42% less pain from Na(v)1.7 blocking than placebo (P=0.014) (70). Further study is warranted to investigate the utility of Na(v)1.7 blocking agents such as XEN402 in patients experiencing neuropathic pain, including chemotherapy-induced neuropathic pain.

Conclusions

There are many novel promising targets that look promising for the prevention of CIPN and/or treatment of established CIPN. Several of these are currently entering clinical trials. If multiple agents are successful in clinical investigation, future studies will need to investigate the right target for individualized patients given at the right dose. Genomic and clinical predictors of response will hopefully be developed and validated as the potential for multiple promising agents may become a reality. The identified preclinical targets of CIPN discussed in this overview may be helpful as biomarkers of CIPN toxicity and treatment efficacy.