临床阶段抗癌药物BOLD-100对化疗诱导的周围神经病变具有保护作用

BOLD-100 is a first-in-class, ruthenium-based anticancer agent in Phase 2 clinical development for advanced gastrointestinal (GI) cancers in combination with the chemotherapy regimen FOLFOX (NCT04421820). BOLD-100 plus FOLFOX improves overall survival and progression-free survival in patients with advanced colon (mCRC), gastric (GC), and bile duct cancers (BTC). While FOLFOX is a standard-of-care therapy for GI cancers, its clinical utility is limited by acute and chronic peripheral neuropathies. However, a significantly lower incidence of oxaliplatin-induced peripheral neuropathy (OIPN) was observed in patients treated with BOLD-100 plus FOLFOX, including those who had been treated with FOLFOX in previous lines of therapy. Any-grade neuropathy was reduced compared to benchmark FOLFOX-alone patients; mCRC (14% vs 53%), BTC (36% vs 68%), and GC (19% vs 63%). To assess BOLD-100's neuroprotective effects in vivo , Sprague-Dawley rats received vehicle (10 mL/kg), oxaliplatin (1.5 mg/kg), paclitaxel (1.0 mg/kg), or BOLD-100 (40 mg/kg) alone, plus BOLD-100 in combination with oxaliplatin and paclitaxel. Cold allodynia was measured using the acetone spray test. Rats treated with oxaliplatin alone induced significant cold allodynia by Day 7, while co-treatment with BOLD-100 ameliorated OIPN development. Importantly, BOLD-100 administration starting on day 15 reversed developed OIPN, opening the possibility of BOLD-100 as a treatment option. BOLD-100 also mitigated the development of paclitaxel-induced cold allodynia, highlighting a broader application of BOLD-100. To elucidate the underlying mechanisms, in vitro models using primary dorsal root ganglion (DRG) neurons and differentiated PC12 neuronal cells were used to assess neurite outgrowth. In both models, oxaliplatin treatment reduced average neurite length and number, whereas co-treatment with BOLD-100 protected against oxaliplatin-induced neurotoxicity. Oxaliplatin activates stress pathways leading to neuronal damage, including the unfolded protein response (UPR) - pathways BOLD-100 is known to impact. Oxaliplatin treatment induced upregulation of UPR proteins ATF6 and GRP78, whereas BOLD-100 co-treatment attenuated this upregulation. Furthermore, phosphorylated gammaH2AX, a marker of DNA damage, was markedly elevated following oxaliplatin exposure, while BOLD-100 ameliorated this response. Chemotherapy-induced peripheral neuropathies have limited therapeutic options; these results demonstrate BOLD-100's potential for both neuroprotection and treatment via impacting important stress pathways. Ongoing clinical study BOLD-100-001 is assessing BOLD-100's neuroprotective effects and its ability to enhance patient outcomes and reduce neurotoxicity.