Chemotherapy-induced Peripheral Neuropathy Research Articles

Manganese- and Platinum-Driven Oxidative and Nitrosative Stress in Oxaliplatin-Associated CIPN with Special Reference to Ca4Mn(DPDP)5, MnDPDP and DPDP

Platinum-containing chemotherapeutic drugs are efficacious in many forms of cancer but are dose-restricted by serious side effects, of which peripheral neuropathy induced by oxidative–nitrosative-stress-mediated chain reactions is most disturbing. Recently, hope has been raised regarding the catalytic antioxidants mangafodipir (MnDPDP) and calmangafodipir [Ca4Mn(DPDP)5; PledOx®], which by mimicking mitochondrial manganese superoxide dismutase (MnSOD) may be expected to overcome oxaliplatin-associated chemotherapy-induced peripheral neuropathy (CIPN). Unfortunately, two recent phase III studies (POLAR A and M trials) applying Ca4Mn(DPDP)5 in colorectal cancer (CRC) patients receiving multiple cycles of FOLFOX6 (5-FU + oxaliplatin) failed to demonstrate efficacy. Instead of an anticipated 50% reduction in the incidence of CIPN in patients co-treated with Ca4Mn(DPDP)5, a statistically significant increase of about 50% was seen. The current article deals with confusing differences between early and positive findings with MnDPDP in comparison to the recent findings with Ca4Mn(DPDP)5. The POLAR failure may also reveal important mechanisms behind oxaliplatin-associated CIPN itself. Thus, exacerbated neurotoxicity in patients receiving Ca4Mn(DPDP)5 may be explained by redox interactions between Pt2+ and Mn2+ and subtle oxidative–nitrosative chain reactions. In peripheral sensory nerves, Pt2+ presumably leads to oxidation of the Mn2+ from Ca4Mn(DPDP)5 as well as from Mn2+ in MnSOD and other endogenous sources. Thereafter, Mn3+ may be oxidized by peroxynitrite (ONOO−) into Mn4+, which drives site-specific nitration of tyrosine (Tyr) 34 in the MnSOD enzyme. Conformational changes of MnSOD then lead to the closure of the superoxide (O2•−) access channel. A similar metal-driven nitration of Tyr74 in cytochrome c will cause an irreversible disruption of electron transport. Altogether, these events may uncover important steps in the mechanism behind Pt2+-associated CIPN. There is little doubt that the efficacy of MnDPDP and its therapeutic improved counterpart Ca4Mn(DPDP)5 mainly depends on their MnSOD-mimetic activity when it comes to their potential use as rescue medicines during, e.g., acute myocardial infarction. However, pharmacokinetic considerations suggest that the efficacy of MnDPDP on Pt2+-associated neurotoxicity depends on another action of this drug. Electron paramagnetic resonance (EPR) studies have demonstrated that Pt2+ outcompetes Mn2+ and endogenous Zn2+ in binding to fodipir (DPDP), hence suggesting that the previously reported protective efficacy of MnDPDP against CIPN is a result of chelation and elimination of Pt2+ by DPDP, which in turn suggests that Mn2+ is unnecessary for efficacy when it comes to oxaliplatin-associated CIPN.

Paclitaxel-Associated Mechanical Sensitivity and Neuroinflammation Are Sex-, Time-, and Site-Specific and Prevented through Cannabigerol Administration in C57Bl/6 Mice

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients. One identified mechanism underlying CIPN is neuroinflammation. Most of this research has been conducted in only male or female rodent models, making direct comparisons regarding the role of sex differences in the neuroimmune underpinnings of CIPN limited. Moreover, most measurements have focused on the dorsal root ganglia (DRG) and/or spinal cord, while relatively few studies have been aimed at characterizing neuroinflammation in the brain, for example the periaqueductal grey (PAG). The overall goals of the present study were to determine (1) paclitaxel-associated changes in markers of inflammation in the PAG and DRG in male and female C57Bl6 mice and (2) determine the effect of prophylactic administration of an anti-inflammatory cannabinoid, cannabigerol (CBG). In Experiment 1, male and female mice were treated with paclitaxel (8–32 mg/kg/injection, Days 1, 3, 5, and 7) and mechanical sensitivity was measured using Von Frey filaments on Day 7 (Cohort 1) and Day 14 (Cohort 2). Cohorts were euthanized on Day 8 or 15, respectively, and DRG and PAG were harvested for qPCR analysis of the gene expression of markers of pain and inflammation Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. In Experiment 2, male and female mice were treated with vehicle or 10 mg/kg CBG i.p. 30 min prior to each paclitaxel injection. Mechanical sensitivity was measured on Day 14. Mice were euthanized on Day 15, and PAG were harvested for qPCR analysis of the gene expression of Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. Paclitaxel produced a transient increase in potency to produce mechanical sensitivity in male versus female mice. Regarding neuroinflammation, more gene expression changes were apparent earlier in the DRG and at a later time point in the PAG. Also, more changes were observed in females in the PAG than males. Overall, sex differences were observed for most markers at both time points and regions. Importantly, in both the DRG and PAG, most increases in markers of neuroinflammation and pain occurred at paclitaxel doses higher than those associated with significant changes in the mechanical threshold. Two analytes that demonstrated the most compelling sexual dimorphism and that changed more in males were Cxcl9 and Ccl2, and Tlr4 in females. Lastly, prophylactic administration of CBG protected the male and female mice from increased mechanical sensitivity and female mice from neuroinflammation in the PAG. Future studies are warranted to explore how these sex differences may shed light on the mechanisms of CIPN and how non-psychoactive cannabinoids such as CBG may engage these targets to prevent or attenuate the effects of paclitaxel and other chemotherapeutic agents on the nervous system.

Knockdown siRNA Targeting GPR55 Reveals Significant Differences Between the Anti-inflammatory Actions of KLS-13019 and Cannabidiol.

KLS-13019 was reported previously to reverse paclitaxel-induced mechanical allodynia in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN). Recent studies demonstrated that paclitaxel-induced increases in inflammatory markers (GPR55, NLRP3, and IL-1β) of dorsal root ganglion (DRG) cultures were shown to be reversed by KLS-13019 treatment. The mechanism of action for KLS-13019-mediated reversal of paclitaxel-induced neuroinflammation now has been explored using GPR55 siRNA. Pre-treatment of DRG cultures with GPR55 siRNA produced a 21% decrease of immunoreactive (IR) area for GPR55 in cell bodies and a 59% decrease in neuritic IR area, as determined by high-content imaging. Using a 24-h reversal treatment paradigm, paclitaxel-induced increases in the inflammatory markers were reversed back to control levels after KLS-3019 treatment. Decreases in these inflammatory markers produced by KLS-13019 were significantly attenuated by GPR55 siRNA co-treatment, with mean IR area responses being attenuated by 56% in neurites and 53% in cell bodies. These data indicate that the percentage decreases in siRNA-mediated attenuation of KLS-13019-related efficacy on the inflammatory markers were similar to the percentage knockdown observed for neuritic GPR55 IR area. Similar studies conducted with cannabidiol (CBD), the parent compound of KLS-13019, produced low efficacy (25%) reversal of all inflammatory markers that were poorly attenuated (29%) by GPR55 siRNA. CBD was shown previously to be ineffective in reversing paclitaxel-induced mechanical allodynia. The present studies indicated significant differences between the anti-inflammatory properties of KLS-13019 and CBD which may play a role in their observed differences in the reversibility of mechanical allodynia in a mouse model of CIPN.

Current understanding of the molecular mechanisms of chemotherapy-induced peripheral neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is the most common off-target adverse effects caused by various chemotherapeutic agents, such as cisplatin, oxaliplatin, paclitaxel, vincristine and bortezomib. CIPN is characterized by a substantial loss of primary afferent sensory axonal fibers leading to sensory disturbances in patients. An estimated of 19–85% of patients developed CIPN during the course of chemotherapy. The lack of preventive measures and limited treatment options often require a dose reduction or even early termination of life-saving chemotherapy, impacting treatment efficacy and patient survival. In this Review, we summarized the current understanding on the pathogenesis of CIPN. One prominent change induced by chemotherapeutic agents involves the disruption of neuronal cytoskeletal architecture and axonal transport dynamics largely influenced by the interference of microtubule stability in peripheral neurons. Due to an ineffective blood-nerve barrier in our peripheral nervous system, exposure to some chemotherapeutic agents causes mitochondrial swelling in peripheral nerves, which lead to the opening of mitochondrial permeability transition pore and cytochrome c release resulting in degeneration of primary afferent sensory fibers. The exacerbated nociceptive signaling and pain transmission in CIPN patients is often linked the increased neuronal excitability largely due to the elevated expression of various ion channels in the dorsal root ganglion neurons. Another important contributing factor of CIPN is the neuroinflammation caused by an increased infiltration of immune cells and production of inflammatory cytokines. In the central nervous system, chemotherapeutic agents also induce neuronal hyperexcitability in the spinal dorsal horn and anterior cingulate cortex leading to the development of central sensitization that causes CIPN. Emerging evidence suggests that the change in the composition and diversity of gut microbiota (dysbiosis) could have direct impact on the development and progression of CIPN. Collectively, all these aspects contribute to the pathogenesis of CIPN. Recent advances in RNA-sequencing offer solid platform for in silico drug screening which enable the identification of novel therapeutic agents or repurpose existing drugs to alleviate CIPN, holding immense promises for enhancing the quality of life for cancer patients who undergo chemotherapy and improve their overall treatment outcomes.

Erratum: Shannonhouse et al., "Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca2+ Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy".

Erratum: Shannonhouse et al., "Meclizine and Metabotropic Glutamate Receptor Agonists Attenuate Severe Pain and Ca2+ Activity of Primary Sensory Neurons in Chemotherapy-Induced Peripheral Neuropathy".

The association of chemotherapy-induced peripheral neuropathy with reduced executive function in chemotherapy-treated cancer survivors: A cross-sectional study

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is common and disabling among cancer survivors. Little is known about the association of CIPN with other measures of the nervous system's integrity, such as executive dysfunction. We compared measures of executive function in older chemotherapy-treated cancer survivors with and without CIPN. Materials and MethodsThis cross-sectional study enrolled 50 chemotherapy-treated cancer survivors (65.6 ± 11.5 years, 88% female) post-chemotherapy treatment who were previously referred for outpatient rehabilitation at the request of the cancer survivor or a medical provider. Twenty-two participants (44%) had CIPN defined by patient-reported distal paresthesia or numbness, which began with chemotherapy and continued to the time of cognitive testing. Measures of executive function included Trails-B, Stroop, and rapid reaction accuracy (RRA) and were evaluated between cancer survivors with and without CIPN using t-tests. Multivariable models were then used to determine whether CIPN was an independent determinant of the measures of executive function (Trails-B, Stroop Incongruent, and RRA). Models were adjusted for age, sex, history of anxiety, and benzodiazepine use due to their known associations with CIPN and executive function. ResultsCancer survivors with CIPN (CIPN+) had reduced executive function compared to survivors without CIPN (CIPN-) on Trails-B (CIPN+: 84.9 s ± 44.1 s, CIPN-: 59.1 s ± 22.5 s, p = 0.01), Stroop (CIPN+: 100.6 s ± 38.2 s, CIPN-: 82.1 s ± 17.3 s, p = 0.03), and RRA (CIPN+: 60.3% ± 12.9%, CIPN-: 70.6% ± 15.7%, p = 0.01). There were no differences in cancer stage severity or functional status by patient report or sit-to-stand function. The association between CIPN and reduced executive function was found in multivariable models after adjusting for age, sex, anxiety, and benzodiazepine use for Trails-B (ß:17.9, p = 0.046), Stroop (ß:16.9, p = 0.02), and RRA (ß:-0.072, p = 0.03). DiscussionIn this population, CIPN is associated with reduced executive function in older cancer survivors treated with chemotherapy. Future research is required to further understand this preliminary association, the causality, and the potential risk factors.

NCS-1 protein regulates TRPA1 channel through the PI3K pathway in breast cancer and neuronal cells.

The physical and functional interaction between transient receptor potential channel ankyrin 1 (TRPA1) and neuronal calcium sensor 1 (NCS-1) was assessed. NCS-1 is a calcium (Ca2+) sensor found in many tissues, primarily neurons, and TRPA1 is a Ca2+ channel involved not only in thermal and pain sensation but also in conditions such as cancer and chemotherapy-induced peripheral neuropathy, in which NCS-1 is also a regulatory component.We explored the interactions between these two proteins by employing western blot, qRT-PCR, co-immunoprecipitation, Ca2+ transient monitoring with Fura-2 spectrophotometry, and electrophysiology assays in breast cancer cells (MDA-MB-231) with different levels of NCS-1 expression and neuroblastoma cells (SH-SY5Y).Our findings showed that the expression of TRPA1 was directly correlated with NCS-1 levels at both the protein and mRNA levels. Additionally, we found a physical and functional association between these two proteins. Physically, the NCS-1 and TRPA1 co-immunoprecipitate. Functionally, NCS-1 enhanced TRPA1-dependent Ca2+ influx, current density, open probability, and conductance, where the functional effects depended on PI3K. Conclusion: NCS-1 appears to act not only as a Ca2+ sensor but also modulates TRPA1 protein expression and channel function in a direct fashion through the PI3K pathway. These results contribute to understanding how Ca2+ homeostasis is regulated and provides a mechanism underlying conditions where Ca2+ dynamics are compromised, including breast cancer. With a cellular pathway identified, targeted treatments can be developed for breast cancer and neuropathy, among other related diseases.

Associations between Physical Function and Chemotherapy Induced Peripheral Neuropathy (CIPN) in Patients with Pancreatic Cancer

Associations between Physical Function and Chemotherapy Induced Peripheral Neuropathy (CIPN) in Patients with Pancreatic Cancer

Molecular and Cellular Involvement in CIPN

Many anti-cancer drugs, such as taxanes, platinum compounds, vinca alkaloids, and proteasome inhibitors, can cause chemotherapy-induced peripheral neuropathy (CIPN). CIPN is a frequent and harmful side effect that affects the sensory, motor, and autonomic nerves, leading to pain, numbness, tingling, weakness, and reduced quality of life. The causes of CIPN are not fully known, but they involve direct nerve damage, oxidative stress, inflammation, DNA damage, microtubule dysfunction, and altered ion channel activity. CIPN is also affected by genetic, epigenetic, and environmental factors that modulate the risk and intensity of nerve damage. Currently, there are no effective treatments or prevention methods for CIPN, and symptom management is mostly symptomatic and palliative. Therefore, there is a high demand for better understanding of the cellular and molecular mechanisms involved in CIPN, as well as the development of new biomarkers and therapeutic targets. This review gives an overview of the current knowledge and challenges in the field of CIPN, focusing on the biological and molecular mechanisms underlying this disorder.

Label-Free Visualization and Morphological Profiling of Neuronal Differentiation and Axonal Degeneration through Quantitative Phase Imaging.

Understanding the intricate processes of neuronal growth, degeneration, and neurotoxicity is paramount for unraveling nervous system function and holds significant promise in improving patient outcomes, especially in the context of chemotherapy-induced peripheral neuropathy (CIPN). These processes are influenced by a broad range of entwined events facilitated by chemical, electrical, and mechanical signals. The progress of each process is inherently linked to phenotypic changes in cells. Currently, the primary means of demonstrating morphological changes rely on measurements of neurite outgrowth and axon length. However, conventional techniques for monitoring these processes often require extensive preparation to enable manual or semi-automated measurements. Here, a label-free and non-invasive approach is employed for monitoring neuronal differentiation and degeneration using quantitative phase imaging (QPI). Operating on unlabeled specimens and offering little to no phototoxicity and photobleaching, QPI delivers quantitative maps of optical path length delays that provide an objective measure of cellular morphology and dynamics. This approach enables the visualization and quantification of axon length and other physical properties of dorsal root ganglion (DRG) neuronal cells, allowing greater understanding of neuronal responses to stimuli simulating CIPN conditions. This research paves new avenues for the development of more effective strategies in the clinical management of neurotoxicity.

Transdermal Delivery of Polymeric Nanoparticles Containing Aconite Root for the Treatment of Chemotherapy‐Induced Peripheral Neuropathy

Chemotherapy‐induced peripheral neuropathy (CIPN) poses challenges like pain and numbness, necessitating innovative treatments due to current limitations. Conventional approaches, relying on pain relief medications and dose adjustments, fall short in addressing neurotoxicity, resulting in inadequate pain relief and undesired effects. Aconite root (AR), a medicinal herb withcenturies of use against various diseases, contains a compound named Aconine, which alleviates pain by blocking specific neural channels. However, AR also contains Aconitine, a toxic substance hydrolyzed into nontoxic Aconine through heating. Herein, hyaluronate‐poly(lactic‐co‐glycolic acid) nanoparticles (HA‐PLGA/AR NPs) encapsulating Aconine are fabricated, enabling controlled release, protection, and transdermal delivery, enhancing therapeutic outcomes. High‐performance liquid chromatography identifies optimal Aconine content after 48 h of AR boiling, with minimal neural toxicity confirmed. Characterization via transmission electron microscopy, dynamic light scattering, and in vitro assays demonstrates superior drug release by HA‐PLGA/AR NPs, establishing effective transdermal Aconine delivery. In an in vitro CIPN model with paclitaxel (PTX)‐treated PC12 cells, HA‐PLGA/AR NPs stimulate enhanced neurite growth, validating their localized analgesic impact on CIPN and suggesting potential symptom alleviation. Taken together, HA‐PLGA/AR NPs offer a promising strategy for controlled transdermal Aconine delivery, potentially alleviating CIPN and addressing various neuropathies and diseases.

Abstract 2962: Chemotherapy induced senescence drives peripheral neuropathy

Abstract Chemotherapy is a mainstay of cancer therapy. Unfortunately, while chemotherapy can profoundly impact disease free survival, it is often accompanied with devastating side effects including hair loss, bone loss, cognitive impairment (referred to as "brain fog"), and peripheral neuropathies. While many of these side effects may subside after the completion of chemotherapy, some persist for a lifetime, substantially compromising the quality of life for survivors. Particularly insidious is chemotherapy-induced peripheral neuropathy (CIPN), which can impair a patient's ability to care for themselves. Shockingly, in over 30% of patients, CIPN persists even after the cessation of chemotherapy, subjecting them to a lifetime of numbness and/or pain. Paclitaxel (PTX), a common treatment for breast cancer, induces CIPN in 61-92% of patients depending on the administered dose. Unfortunately, there are currently no preventative or curative measures for CIPN resulting in side effects that persist for months or even years after the cessation of chemotherapy. Considering chemotherapy can trigger cellular senescence, leading to the release of a diverse array of factors collectively known as the senescence-associated secretory phenotype (SASP) that are capable of negatively influencing neighboring cells. To determine if senescence played a role in CIPN we treated with PTX and found that animals displayed reduced axon innervation in the paws and diminished paw withdrawal responses during the von Frey assay, characteristic symptoms of CIPN. To determine if senescent drove PTX-induced CIPN, we utilized the INKATTAC (INK) mouse, a model in which a p16INK4a promoter drives an inducible suicide transgene to eliminate p16+ senescent cells following treatment with AP20187 (AP). Employing the INK mouse, we successfully prevented CIPN by eliminating PTX-induced senescent cells. Furthermore, through bone marrow (BM) transplant studies using BM from INK mice into wildtype recipients, we failed to prevent CIPN. This result establishes that senescent immune cells, do not contribute to CIPN. In an independent approach, we found that senolytic drugs (kill senescent cells), such as dasatinib and quercetin (DQ) or ABT737 (ABT), effectively prevented and reversed CIPN in mice. Additionally, since the p38MAPK pathway has been shown to regulate SASP mRNA stability, we treated with p38 and MK2 inhibitors and found that inhibition prevented CIPN in mice. To address the mechanism behind CIPN we have carried out single cell RNA sequencing (scRNA-seq) to identify the cell population senescing in response to chemotherapy. These analyses will allow us to understand the mechanisms that drive CIPN and may lead to new treatments for patients suffering from CIPN. Citation Format: Taylor Malachowski, Ganesh Kumar Raut, Xianmin Luo, Satarupa Mullick Bagchi, Sheila Stewart. Chemotherapy induced senescence drives peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2962.

Abstract 7451: Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy

Abstract Cisplatin is widely used to treat ovarian malignancies, and over 70% of ovarian cancer patients report experiencing cancer-related cognitive impairment (CRCI) and chemotherapy-induced peripheral neuropathy (CIPN) during and after chemotherapy treatment. Most pre-clinical CRCI/CIPN studies have been conducted on non-tumor bearing rodents. We developed two novel clinically relevant models of CRCI/CIPN: (1) the ID8 syngeneic mouse model in B6(Cg)-Tyrc-2J/J female mice, and (2) the SKOV3.ip1 ovarian cancer xenograft model in female Cr:NIH-RNU rats. We examined cognitive function and serum cytokine levels with respect to cancer progression and/or in response to cisplatin. B6 female mice were injected with 107 ID8 cells or 0.9% saline, i.p. Mice received cisplatin (2.3 mg/kg/day, i.p.) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) for 5d, followed by 5d of rest for two cycles. RNU rats were injected with 107 SKOV3.ip1 cells or 0.9% saline, i.p. Rats received cisplatin (5 mg/kg, i.p) or 0.9% saline (OvT+CIS, OvT+VEH, respectively) every other week for four cycles. OvT+CIS and OvT+VEH mice and rats showed impairments in novel object recognition (NOR), with discrimination ratios ≤0.5. Cisplatin transiently increased hyperalgesia in OvT+CIS mice, which persisted longitudinally in OvT+VEH mice. Serum cytokine levels were elevated in OvT+VEH mice (IL-2, IL-10, INFγ) and OvT+VEH rats (IL-4, IL-10) compared to OvT+CIS (P<0.05). Ovarian cancer may evoke progressive sensory and neurocognitive deficits and increase systemic pro-inflammatory cytokine levels in the absence of chemotherapy. Future studies will address hyperalgesia and cognitive differences between healthy control and ovarian cancer models +/- cisplatin, and biological mechanisms underlying CRCI and CIPN. Citation Format: Naomi Lomeli, Donovan Argueta, Diana C. Pearre, Javier Lepe, Kalpna Gupta, Daniela A. Bota. Translational models of ovarian cancer-associated cognitive impairment and chemotherapy-induced peripheral neuropathy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7451.

Abstract 7181: Low dose interleukin-6 (SON-080) for neuropathies: Toxicology and clinical plans

Abstract Neuropathies are conditions in which peripheral nerves degenerate, resulting in sensory and motor symptoms that can profoundly affect the patients’ quality of life. Chemotherapy-induced peripheral neuropathy (CIPN) is induced by most antineoplastic agents, affecting cancer patients during or following completion of treatment. Neuropathy-specific pain medication is most often inefficient against pain, can cause major side effects that limit their use, do not address non-pain related symptoms, and do not stop CIPN progression. Most evidence suggests that physical exercise is the most efficient approach to reduce neuropathy symptoms and potentially, progression. Other publications have causally linked exercise, through the ability of contracting muscles to release low levels of interleukin-6 into the bloodstream thereby activating several metabolic and physiological pathways that help regenerate muscle and nerve tissue, affect glucose homeostasis, increase lipolysis, improve microvascular blood flow and reduce inflammation. Preclinical disease models of CIPN and diabetic peripheral neuropathy (DPN) have confirmed that IL-6 administered at low doses is capable of stimulating peripheral nerve growth, thereby ameliorating motor and sensory functions and normalizing the associated pain or sensation disturbance of neuropathy. The maximum tolerated (MTD) dose of recombinant human IL-6 (rhIL-6) has been established as a treatment for thrombocytopenia in hundreds of cancer patients using the drug product that was produced in the 1990’s (Process A) dosed intravenously (IV) or subcutaneously (SC). We have developed a cGMP compliant version of rhIL-6 (SON-080) using a state-of-the-art process (Process B) that meets current regulatory guidelines for cell lines and processes. An analytical comparison of SON-080 with Process A rhIL-6 concluded that both drugs are highly comparable for at least 14 different key physicochemical characteristics. Therefore, we expect similar in vivo behavior with Process B material as compared with the Process A molecule. In order to support clinical plans for the safety and toxicity of rhIL-6, a dose range and schedule of administration that matches the current clinical protocol was performed in a cynomolgus monkey primate toxicology model. Under these conditions, SON-080 was found safe and well tolerated with a No Adverse Effect Levels (NOAEL) of 30µg/kg, the highest dose tested. On this basis, a fully controlled Phase 1b/2a clinical study, SB211, is ongoing to evaluate safety, tolerability, and efficacy of subcutaneous SON-080 dosage and administration schedule that targets an exposure mirroring the endogenous release levels elicited by moderate to heavy exercise. Confirmation of safety in the first portion of the trial will pave the way for efficacy evaluation with the objective to provide CIPN patients with a novel, safe, and effective treatment for painful neuropathies. Citation Format: Susan Dexter, Gael Hedou, Richard T. Kenney, Darrel J. Rezac, Pankaj Mohan. Low dose interleukin-6 (SON-080) for neuropathies: Toxicology and clinical plans [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7181.

Asymmetric Carbene‐Alkyne Metathesis‐mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker

Abstract: This study introduces a novel approach for synthesizing Benzoxazine‐Centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene‐alkyne metathesis‐triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis‐mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co‐catalysis, ensuring precise stereo control as validated by X‐ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo‐ and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8g. In vivo studies demonstrate that intrathecal injection of 8g effectively reverses mechanical hyperalgesia associated with chemotherapy‐induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8g as a promising, uniquely acting pain blocker, establishing a C5aR1‐Nav1.7 connection in the context of CIPN.

Asymmetric Carbene-Alkyne Metathesis-mediated Cascade: Synthesis of Benzoxazine Polychiral Polyheterocycles and Discovery of a Novel Pain Blocker.

This study introduces a novel approach for synthesizing Benzoxazine-Centered Polychiral Polyheterocycles (BPCPHCs) via an innovative asymmetric carbene-alkyne metathesis-triggered cascade. Overcoming challenges associated with intricate stereochemistry and multiple chiral centers, the catalytic asymmetric Carbene Alkyne Metathesis-mediated Cascade (CAMC) is employed using dirhodium catalyst/Brønsted acid co-catalysis, ensuring precise stereo control as validated by X-ray crystallography. Systematic substrate scope evaluation establishes exceptional diastereo- and enantioselectivities, creating a unique library of BPCPHCs. Pharmacological exploration identifies twelve BPCPHCs as potent Nav ion channel blockers, notably compound 8g. In vivo studies demonstrate that intrathecal injection of 8g effectively reverses mechanical hyperalgesia associated with chemotherapy-induced peripheral neuropathy (CIPN), suggesting a promising therapeutic avenue. Electrophysiological investigations unveil the inhibitory effects of 8g on Nav1.7 currents. Molecular docking, dynamics simulations and surface plasmon resonance (SPR) assay provide insights into the stable complex formation and favorable binding free energy of 8g with C5aR1. This research represents a significant advancement in asymmetric CAMC for BPCPHCs and unveils BPCPHC 8g as a promising, uniquely acting pain blocker, establishing a C5aR1-Nav1.7 connection in the context of CIPN.

Cytarabine induced peripheral neuropathy in a young patient with acute myeloid leukemia: a case report

Introduction and Importance: Cytarabine, a pyrimidine analog, is commonly used to treat multiple hematological conditions, such as acute leukemias and lymphomas. One of the rare and less reported complications of cytarabine is peripheral neuropathy, in which peripheral nerves are damaged, often causing weakness, numbness, and pain, usually in the hands and feet. Case Presentation: We report the case of a 17-year-old male who developed a gradual onset of weakness and sensory loss in all four limbs during treatment with conventional dose of cytarabine for acute myeloid leukemia. Cytarabine was discontinued after the development of symptoms, and his motor and sensory functions gradually improved over the course of three months. Clinical Discussion: Alongside some well-known side effects of cytarabine including bone marrow suppression, cerebellar syndrome, and cardiotoxicity, peripheral neuropathy is one of the uncommon side effects of cytarabine. Diagnosis includes identifying and grading the severity of chemotherapy-induced peripheral neuropathy (CIPN) through clinical assessment and nerve conduction studies. Management includes withdrawing the chemotherapeutic agent, supportive treatment with drugs such as duloxetine. Recent studies also favor the use of acupuncture and sensorimotor-based exercise intervention for the management of CIPN. Methods: This case report has been prepared in line with the SCARE 2023 Criteria. 15 Conclusion: Although rare, even conventional dosage of cytarabine can cause peripheral neuropathy, and routine neuromuscular examinations can help in the early diagnosis and intervention to limit further progression and reverse the course of the disease.

Pilot Study of the Effectiveness of Repetitive Transcranial Magnetic Stimulation on Pain and Quality of Life in Patients with Chemotherapy-Induced Peripheral Neuropathic Pain

Background. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique that acts on the activity of the cerebral cortex employing electrical currents. Aim. The objective of this project is to evaluate the effectiveness of rTMS on pain and quality of life in patients with chemotherapy-induced peripheral neuropathic pain. Method. Ten patients with chemotherapy-induced peripheral neuropathic pain received 20 sessions of rTMS, consisting of 15 minutes of treatment repeated 5 times per week for four weeks (10 Hz, 20s, 30 trains with 81% intensity). Patients were evaluated using the Brief pain inventory (BPI) and the Functional Assessment of Cancer Therapy and neurotoxicity (FACT-GOG-NTX 13). Results. There were significant differences in BPI mean severity, interference score and FACT-GOG-NTX 13 (p<0,05). Conclusion. The pilot study results suggest that rTMS is potentially beneficial for the treatment of chemotherapy-induced peripheral neuropathy. rTMS over the M1 had an important reduction in pain severity, interference with daily activities, and quality of life scores. However, results should be taken with caution due to the small sample size, absence of a control group and short period of follow-up.

Risk factors of paclitaxel-induced peripheral neuropathy in patients with breast cancer: a prospective cohort study.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and severe adverse reaction in taxane-based chemotherapy. This study aimed to analyze the risk factors of peripheral neuropathy in patients with breast cancer receiving paclitaxel chemotherapy to provide a reference for the early prevention of CIPN. We included 350 patients with breast cancer who received chemotherapy for the first time at the Tangshan People's Hospital between August 2022 and June 2023 and were followed for at least 3 months after the end of chemotherapy. The incidence of CIPN in patients with breast cancer was calculated, and risk factors for CIPN were analyzed using logistic regression analysis. The incidence rate of CIPN was 79.1%. Multifactor logistic regression analysis indicated that age ≥45 years [odds ratio (OR)=5.119, 95% confidence interval (CI)=1.395-18.780] and ≥60 years (OR=9.366, 95% CI=1.228-71.421), history of hypertension (OR=3.475, 95% CI=1.073-11.250), cumulative dose of chemotherapy drugs >900 mg (OR=4.842, 95% CI=1.961-5.946), vitamin D deficiency (OR=6.214, 95% CI=2.308-16.729), abnormal alanine aminotransferase (OR=3.154, 95% CI=1.010-9.844), anemia before chemotherapy (OR=2.770, 95% CI=1.093-7.019), infusion duration of chemotherapy drugs >30min (OR=3.673, 95% CI=1.414-9.539), body mass index ≥24 kg/m2 (OR=8.139, 95% CI=1.157-57.240), mild depression (OR=4.546, 95% CI=1.358-15.223), and major depression (OR=4.455, 95% CI=1.237-16.037) increased the risk of CIPN. Having a regular caregiver (OR=0.223, 95% CI=0.087-0.573), high levels of physical activity (OR=0.071, 95% CI=0.008-0.647), and strong social support (OR=0.048, 95% CI=0.003-0.682) were protective factors against CIPN. Clinical attention should be paid to patients with these risk factors, and active and effective preventive measures should be taken to reduce the occurrence of CIPN and improve the quality of life.

Phytic Acid Maintains Peripheral Neuron Integrity and Enhances Survivability against Platinum-Induced Degeneration via Reducing Reactive Oxygen Species and Enhancing Mitochondrial Membrane Potential.

Phytic acid (PA) has been reported to possess anti-inflammatory and antioxidant properties that are critical for neuroprotection in neuronal disorders. This raises the question of whether PA can effectively protect sensory neurons against chemotherapy-induced peripheral neuropathy (CIPN). Peripheral neuropathy is a dose-limiting side effect of chemotherapy treatment often characterized by severe and abnormal pain in hands and feet resulting from peripheral nerve degeneration. Currently, there are no effective treatments available that can prevent or cure peripheral neuropathies other than symptomatic management. Herein, we aim to demonstrate the neuroprotective effects of PA against the neurodegeneration induced by the chemotherapeutics cisplatin (CDDP) and oxaliplatin. Further aims of this study are to provide the proposed mechanism of PA-mediated neuroprotection. The neuronal protection and survivability against CDDP were characterized by axon length measurements and cell body counting of the dorsal root ganglia (DRG) neurons. A cellular phenotype study was conducted microscopically. Intracellular reactive oxygen species (ROS) was estimated by fluorogenic probe dichlorofluorescein. Likewise, mitochondrial membrane potential (MMP) was assessed by fluorescent MitoTracker Orange CMTMRos. Similarly, the mitochondria-localized superoxide anion radical in response to CDDP with and without PA was evaluated. The culture of primary DRG neurons with CDDP reduced axon length and overall neuronal survival. However, cotreatment with PA demonstrated that axons were completely protected and showed increased stability up to the 45-day test duration, which is comparable to samples treated with PA alone and control. Notably, PA treatment scavenged the mitochondria-specific superoxide radicals and overall intracellular ROS that were largely induced by CDDP and simultaneously restored MMP. These results are credited to the underlying neuroprotection of PA in a platinum-treated condition. The results also exhibited that PA had a synergistic anticancer effect with CDDP in ovarian cancer in vitro models. For the first time, PA's potency against CDDP-induced PN is demonstrated systematically. The overall findings of this study suggest the application of PA in CIPN prevention and therapeutic purposes.