Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients

Mapuskar, Kranti A.; Martinez, G. Vasquez; Pulliam, Casey; Petronek, Michael; Steinbach, Emily J.; Monga, Varun; Furqan, Muhammad; Saunders, Deborah; Pearce, A.; Davidson, S.; Pitre, L.; Fairbanks, R.; Lee, C.M.; Mott, S.L.; Bodeker, Kellie L.; Huang, Cheng-long; Buatti, John M.; Anderson, Carryn M.; Beardsley, Robert A.; Holmlund, Jon; Zepeda‐Orozco, Diana; Spitz, Douglas R.; Allen, B.G.

doi:10.1016/j.redox.2022.102599

Cited by 10 publications

(7 citation statements)

References 41 publications

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“…As future perspectives, recent data have shown that the use of avasopasem manganese, an investigational agent assessed for the control of radiation-induced mucositis in LA-HNSCC patients, is safe and active in protecting from cisplatin-related chronic kidney damage [31]. Although nephroprotective drugs may reduce long-term kidney injury, there is still a strong need to limit the acute one.…”

Section: Discussionmentioning

confidence: 99%

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience

Cavalieri,

Platini,

Barretta

et al. 2023

Oral Oncology

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Section: Discussionmentioning

confidence: 99%

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience

Cavalieri,

Platini,

Barretta

et al. 2023

Oral Oncology

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“…AVA also acts as a potent radiosensitizer in pancreatic, head-and-neck, and non-small cell lung cancers in murine models, and also markedly increases tumor response and survival in pancreatic cancer patients treated with RT [38][39][40]. Additionally, AVA attenuated cisplatin-induced renal injury in head-and-neck cancer patients [41,42].…”

Section: Animals and In Vivo Radiation Treatmentmentioning

confidence: 96%

Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing

Zaher,

Mapuskar,

Petronek

et al. 2024

Antioxidants

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Soft tissue sarcomas (STSs) are mesenchymal malignant lesions that develop in soft tissues. Despite current treatments, including radiation therapy (RT) and surgery, STSs can be associated with poor patient outcomes and metastatic recurrences. Neoadjuvant radiation therapy (nRT), while effective, is often accompanied by severe postoperative wound healing complications due to damage to the surrounding normal tissues. Thus, there is a need to develop therapeutic approaches to reduce nRT toxicities. Avasopasem manganese (AVA) is a selective superoxide dismutase mimetic that protects against IR-induced oral mucositis and lung fibrosis. We tested the efficacy of AVA in enhancing RT in STSs and in promoting wound healing. Using colony formation assays and alkaline comet assays, we report that AVA selectively enhanced the STS (liposarcoma, fibrosarcoma, leiomyosarcoma, and MPNST) cellular response to radiation compared to normal dermal fibroblasts (NDFs). AVA is believed to selectively enhance radiation therapy by targeting differential hydrogen peroxide clearance in tumor cells compared to non-malignant cells. STS cells demonstrated increased catalase protein levels and activity compared to normal fibroblasts. Additionally, NDFs showed significantly higher levels of GPx1 activity compared to STSs. The depletion of glutathione using buthionine sulfoximine (BSO) sensitized the NDF cells to AVA, suggesting that GPx1 may, in part, facilitate the selective toxicity of AVA. Finally, AVA significantly accelerated wound closure in a murine model of wound healing post RT. Our data suggest that AVA may be a promising combination strategy for nRT therapy in STSs.

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“…Several studies have explored the mitochondria as a critical target to improve the outcomes of patients with CKD via preserving the mitochondrial structure and inhibiting mitochondrial oxidative damage, thus preventing CKD progression [ 7 , 78 , 80 , 115 , 116 ]. The use of novel mitochondrially targeted drugs has been partially explored in different injury animal models [ 80 ], including cisplatin [ 116 , 117 , 118 ], unilateral ureteral obstruction (UUO) [ 119 ], ischemia-reperfusion [ 120 ], diabetic nephropathy [ 121 ], sepsis [ 122 ], hypertension-related vascular injury [ 123 ] and before kidney transplantation [ 124 ]. However, compounds that can specifically target the mitochondria, capable of crossing the blood–brain barrier, with a known dose reported to be effective in vivo, are still needed ( Table 1 ).…”

Section: Pathology Of Aki To Ckd Transitionmentioning

confidence: 99%

“…We demonstrated that GC4419 attenuated cisplatin-induced CKD, ameliorating oxidative damage and renal fibrosis one month after injury. More interestingly, retrospective analysis of renal function and biomarkers in a subset of head and neck cancer patients receiving high-dose cisplatin and radiation in a double-blinded, placebo-controlled clinical trial (NCT02508389) demonstrated that a 90 mg AVA treatment prevented a significant reduction in estimated glomerular filtration rate (eGFR) three months as well as six and twelve months after treatment compared to 30 mg AVA and placebo [ 118 ] (NCT03689712) ( Table 1 ). Furthermore, the study also shows that treatment with 90 mg of AVA could potentially contribute to renal repair following cisplatin treatment as seen by an increase in epithelial growth factor (EGF), which is known to aid in renal recovery [ 118 , 155 ], supporting the hypothesis that a selective dismutase mimetic could offer the potential for kidney protection following a high-dose cisplatin treatment.…”

Section: Pathology Of Aki To Ckd Transitionmentioning

confidence: 99%

Mitochondrial Oxidative Metabolism: An Emerging Therapeutic Target to Improve CKD Outcomes

Mapuskar,

Vasquez-Martinez,

Mayoral-Andrade

et al. 2023

Biomedicines

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Chronic kidney disease (CKD) predisposes one toward end-stage renal disease (ESRD) and its associated morbidity and mortality. Significant metabolic perturbations in conjunction with alterations in redox status during CKD may induce increased production of reactive oxygen species (ROS), including superoxide (O2−) and hydrogen peroxide (H2O2). Increased O2− and H2O2 may contribute to the overall progression of renal injury as well as catalyze the onset of comorbidities. In this review, we discuss the role of mitochondrial oxidative metabolism in the pathology of CKD and the recent developments in treating CKD progression specifically targeted to the mitochondria. Recently published results from a Phase 2b clinical trial by our group as well as recently released data from a ROMAN: Phase 3 trial (NCT03689712) suggest avasopasem manganese (AVA) may protect kidneys from cisplatin-induced CKD. Several antioxidants are under investigation to protect normal tissues from cancer-therapy-associated injury. Although many of these antioxidants demonstrate efficacy in pre-clinical models, clinically relevant novel compounds that reduce the severity of AKI and delay the progression to CKD are needed to reduce the burden of kidney disease. In this review, we focus on the various metabolic pathways in the kidney, discuss the role of mitochondrial metabolism in kidney disease, and the general involvement of mitochondrial oxidative metabolism in CKD progression. Furthermore, we present up-to-date literature on utilizing targets of mitochondrial metabolism to delay the pathology of CKD in pre-clinical and clinical models. Finally, we discuss the current clinical trials that target the mitochondria that could potentially be instrumental in advancing the clinical exploration and prevention of CKD.

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Avasopasem manganese (GC4419) protects against cisplatin-induced chronic kidney disease: An exploratory analysis of renal metrics from a randomized phase 2b clinical trial in head and neck cancer patients

Cited by 10 publications

References 41 publications

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience

Pre-treatment risk factors to predict early cisplatin-related nephrotoxicity in locally advanced head and neck cancer patients treated with chemoradiation: A single Institution experience

Superoxide Dismutase Mimetic Avasopasem Manganese Enhances Radiation Therapy Effectiveness in Soft Tissue Sarcomas and Accelerates Wound Healing

Mitochondrial Oxidative Metabolism: An Emerging Therapeutic Target to Improve CKD Outcomes

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