New approach to improve therapeutics for advanced head and neck squamous cell cancer - PROJECT SUMMARY The survival rate for advanced head and neck squamous cell carcinoma (HNSCC) remains lower than 50% due to cancer recurrence, metastasis, and drug resistance. Cisplatin-based chemotherapies have traditionally been the most common treatment option for this disease. Unfortunately, the effectiveness of these therapies is limited to newly diagnosed cases, as patients with recurrent or metastatic HNSCC are either inherently resistant to cisplatin or eventually acquire resistance. Additionally, cisplatin is frequently associated with significant nephrotoxicity, often necessitating dose de-escalations or substitution with less efficacious agents, which presents a major challenge in clinical management. Immunotherapy, such as immune checkpoint blockade (ICB) that blocks PD-1/PD-L1 signaling axis, marked another significant advancement in the treatment of advanced HNSCC, but less than 18% of patients responded to this treatment. Therefore, it is crucial to identify new key regulators that drive resistance and toxicity of the current therapies. Our pilot studies showed that HNSCC cells were very sensitive to polo-like kinase 1 (PLK1) inhibitors, and the addition of PLK1 inhibitors to cisplatin enhanced the anticancer efficacy of cisplatin. Moreover, the inhibition of PLK1 reduced the expression of megalin, a key protein that controls cisplatin accumulation in renal proximal tubular epithelial cells (PTECs), leading to alleviated nephrotoxicity. These findings strongly suggest that the inhibition of PLK1 not only improves treatment outcome of cisplatin but also alleviates cisplatin-induced nephrotoxicity. Interestingly, we found that treatment by either cisplatin or PLK1 inhibitors led to a significant increase in PD-L1 expression in HNSCC cells, raising the possibility of a compromised antitumor immunity from chemotherapy and rationalizing the combining PD-L1/PD-1-based immunotherapy with cisplatin and PLK1 inhibitors for an improvement of treatment outcomes. Based on these novel discoveries, we form the central hypothesis that the combination of cisplatin, PLK1 inhibitors, and anti-PD-1 immunotherapy can be used as an improved therapy to treat advanced HNSCC, even those resistant to cisplatin. To test this hypothesis, we propose three specific aims. In Aim 1, we will determine the role of PLK1 in regulation of cisplatin resistance in HNSCC. In Aim 2, we will investigate whether PLK1 inhibition enhances the efficacy while reducing the nephrotoxicity of cisplatin in animal models. In Aim 3, we will assess the clinical potential of the combination of cisplatin, PLK1 inhibitors, and PD-1-based immunotherapy to treat advanced HNSCC, with a particular focus on cisplatin-resistant HNSCC. The successful completion of this project will establish a novel therapeutic strategy that overcomes cisplatin resistance and nephrotoxicity in advanced HNSCC by integrating targeted and immune-based therapies, addressing a critical unmet clinical need.
