Chemotherapy-induced peripheral neuropathy is a major clinical problem, and better therapies are needed for both its treatment and prevention. According to Charles Loprinzi, MD, a medical oncologist at the Mayo Clinic in Rochester, Minnesota, to devise better preventive and treatment approaches, the mechanisms of chemotherapy-induced peripheral neuropathy must be better understood.
At the 2019 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) Annual Meeting in San Francisco, Dr. Loprinzi discussed a number of novel, mechanism-based approaches currently being evaluated in prospective clinical trials.1
Targeting Neuronal Uptake Transporters
“To understand chemotherapy-induced peripheral neuropathy, we need to understand what goes on in the lab,” said Dr. Loprinzi.
To begin, facilitated transport mechanisms help chemotherapeutic drugs to cross cell membranes and move into cells. Organic anion transporting polypeptides (OATPs) are more commonly utilized by taxanes, whereas organic cation transporters (OCTs) are used more often by platinum drugs to cross the cell membrane.
Preclinical studies have shown that transporter-mediated uptake of chemotherapy into the dorsal root ganglion triggers sensory neuron damage. In mice, genetic or pharmacologic knockout of transporters localized to the dorsal root ganglion protects against chemotherapy-induced peripheral neuropathy from paclitaxel, vincristine, and oxaliplatin.
To understand chemotherapy-induced peripheral neuropathy, we need to understand what goes on in the lab.— Charles Loprinzi, MD
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“Given this information, it is reasonable to ask whether this might work in humans, Dr. Loprinzi noted. “To address this, first, a small-molecule library screen was conducted to see what available drugs might block these transporters.” This small-molecule library screen identified that tyrosine kinase inhibitors that are already approved by the U.S. Food and Drug Administration for human use do just that. Proof-of-principle animal studies, with nilotinib (an OATP1B2 inhibitor) and dasatinib (an OCT2 inhibitor), support that these two drugs inhibit chemotherapy-induced peripheral neuropathy, without affecting chemotherapy drug clearance; additionally, there is no apparent negative effect on antitumor efficacy.
Two trials are currently in development: one is evaluating nilotinib in patients with breast cancer who are initiating treatment with paclitaxel, and another is looking at dasatinib in patients with stage IV colorectal who are initiating oxaliplatin-based therapy.
Mitochondrial Enzyme and Oxidative Stress
Calmangafodipir reduces reactive oxygen species and subsequent nerve injury. In a placebo-controlled, double-blind, randomized phase II trial, the drug reduced cold allodynia and other sensory symptoms; it did not appear to prevent antitumor activity, based on the fact that progression-free survival and overall survival were similar in the placebo and active-agent arms.
Two trials, both in the relatively early stages of accrual, are being conducted to evaluate the effects of calmangafodipir in patients with stage IV colorectal cancer who are 1) initiating oxaliplatin-based therapy (ClinicalTrials.gov identifier NCT02054741) and 2) starting adjuvant oxaliplatin-based therapy.
Targeting APE1 Function
Drug-induced DNA damage in sensory neurons causes chemotherapy-induced peripheral neuropathy, particularly from cisplatin and oxaliplatin (as opposed to taxanes). This process produces significant reactive oxygen species and oxidative DNA damage. The base excision repair pathway is the primary means for repairing oxidative DNA damage, and an enzyme called APE1 (apyrimidinic endonuclease/redox effector factor) is important for the removal of damaged DNA bases and in blocking inflammation-inducing transcription factors.
Decreased expression of the APE1 repair enzyme in sensory neurons increases neurotoxicity, but a first-in-class small molecule APE1 modifier, APX3330, is neuroprotective and also appears to have some antitumor activity. According to Dr. Loprinzi, a trial evaluating APX3330 in patients receiving adjuvant oxaliplatin-based therapy has been designed and is awaiting final funding.
Inhibition of Neuro-inflammatory Processes in the Spinal Cord
Certain neuropathic chemotherapy drugs drive the development of chemotherapy-induced peripheral neuropathy by dysregulating sphingolipid metabolism. This leads to increased formation of S1P, which binds and activates S1PR1 (sphingosine-1-phosphate receptor 1). The downstream effect of S1PR1 blockade is the inhibition of neuro-inflammatory processes in the spinal cord, which leads to decreased nuclear factor kappa B and P38 kinase, decreased glial cell activation, as well as decreased inflammatory cytokines. “These effects appear to help to prevent neuropathy,” said Dr. Loprinzi.
Mechanisms Under Study in Chemotherapy-Induced Peripheral Neuropathy
- To target neuronal uptake transporters
- To reduce reactive oxygen species
- To target APE1 function
- To inhibit neuro-inflammatory processes in the spinal cord
- To target the GM1 pathway
- To inhibit serotonin–norepinephrine reuptake and nociceptor sodium channels
Fingolimod, an approved and commercially available drug used in preventing multiple sclerosis–associated neuropathy, is a functional S1PR1 antagonist. According to Dr. Loprinzi, this drug is relatively well tolerated but expensive. (He noted that progress is being made toward the release of a generic version of the drug.)
In animal models, oral fingolimod has shown efficacy in both preventing and treating neuropathic pain from a variety of chemotherapeutic agents, without interfering with the antitumor efficacy of chemotherapy. Data have even supported its potentially synergistic antitumor properties.
Two currently open clinical trials—one, in patients with breast cancer who are initiating adjuvant paclitaxel and the other, in patients with established, long-standing chemotherapy-induced peripheral neuropathy—will evaluate the efficacy of fingolimod for preventing neuropathy and/or treating established neuropathy.
Targeting the GM1 Pathway
Ganglioside-monosialic acid (GM1) is a type of glycosphingolipid, located in the outer layer of the plasma membrane. It is critical for nerve development, differentiation, and repair after injury, and some data support that it decreases neuro-inflammatory responses.
In preclinical studies, GM1 has been effective in the prevention of chemotherapy-induced peripheral neuropathy. Additionally,a retrospective study supported that GM1 was associated with less oxaliplatin-associated acute and chronic neurotoxicity.2
“We don’t know exactly how GM1 works, but this retrospective study supported that it was helpful in patients with cancer,” said Dr. Loprinzi. “This was not a randomized trial, but it provided a hint that this drug might be useful.”
In an initial published randomized clinical trial, 120 patients with gastrointestinal cancers received oxaliplatin with GM1 or the standard of care. GM1 was associated with a modest benefit in preventing high-grade neuropathy.3
In a more recent randomized trial from China, treatment with GM1 resulted in a significant reduction in the severity and incidence of chemotherapy-induced peripheral neuropathy after four cycles of taxane-containing chemotherapy in patients with breast cancer.4
“In this trial, a dramatic benefit was reported; people who received GM1 did not experience much neuropathy,” noted Dr. Loprinzi. “However, the peculiar thing was that 3 months after stopping the drug, the neuropathy was totally resolved in the placebo group. This phenomenon has not been reported in published studies in the United States; in this setting, taxane-induced neuropathy does improve by 3 months after the chemotherapy has been stopped, but it does not totally resolve.”
According to Dr. Loprinzi, strides are being made toward repeating this study in a non-Chinese population.
SNRIs and Nociceptor Sodium Channel Inhibition
In a randomized phase III intervention study of duloxetine, a serotonin–norepinephrine reuptake inhibitor (SNRI), in established chemotherapy-induced peripheral neuropathy, this drug was associated with a significant reduction in established neuropathy-related pain symptoms.5
“Duloxetine is the only drug to be firmly approved in the ASCO Guidelines; it has been established that it helps to decrease chemotherapy-induced peripheral neuropathy, to a moderate degree,” noted Dr. Loprinzi. “This is not a drug that works well in all patients.”
Patients who enrolled on this study rated their neuropathic pain at 6 out of 10, prior to starting the drug. Patients in the placebo arm improved to 5 out of 10, whereas patients in the duloxetine arm ranked their pain at a 4 out of 10 after study completion. “So, it helps some patients,” stated Dr. Loprinzi. “This was not dramatic, but it was statistically significant.”
Emerging preclinical data do support that duloxetine may prove to be effective for the prevention of chemotherapy-induced peripheral neuropathy. According to Dr. Loprinzi, a National Cancer Institute–funded clinical trial, currently in the advanced stages of development, will evaluate the efficacy of duloxetine in the prevention of oxaliplatin-associated neuropathy. Accrual should begin in early 2020. ■
DISCLOSURE: Dr. Loprinzi has served as a consultant for Asahi Kasei, Disarm Pharmaceuticals, Metys Pharmaceuticals, and PledPharma.
REFERENCES
1. Loprinzi C: Novel therapeutics for chemotherapy-induced neuropathy. 2019 MASCC/ISOO International Symposium on Supportive Care in Cancer. Abstract eP720. Presented June 21, 2019.
2. Chen XF, et al: Biomed Pharmacother 66:279-284, 2012.
3. Zhu Y, et al: World J Surg Oncol 11:19, 2013.
4. Su Y, et al: J Natl Cancer Inst. May 15, 2019 (early release online).
