H-CARR has three projects:
1.
Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity.
2.
Defining the role of KEAP/NRF2 signaling dysregulation and sensory nerve reprograming during acquisition of cisplatin resistance and metastasis in HNSCC.
3.
Quantification of cisplatin sensitivity and resistance using metabolic imaging and circulating tumor cell (CTC) biomarkers.
The project focuses on understanding how tumor cells in head and neck squamous cell carcinomas (HNSCC) survive platinum-based chemotherapy like cisplatin and develop resistance, leading to treatment failure.
Findings indicate that cisplatin-resistant HNSCC cells reduce energy production from glycolysis and mitochondria, shifting carbon into anabolic pathways. This shift enhances the cells' reductive potential through glucose and glutamine catabolism and increases glutathione peroxidase 2 (GPX2) activity, which is regulated by the KEAP1-NRF2 pathway. Hyperactivation of GPX2 likely suppresses immune responses within the tumor microenvironment by inhibiting NF-κB activation, leading to a tumor environment enriched with immune-suppressive cells and lacking cytotoxic immune cells.
The central hypothesis is that this metabolic adaptation is essential for acquiring cisplatin resistance and contributes to an immunologically silent tumor phenotype, which evades immune surveillance and increases resistance to therapy.
The project aims to:
1.
Identify the key metabolic steps required to create the enhanced reductive state supporting cisplatin resistance in HNSCC.
2.
Determine how glutathione synthesis and utilization are transcriptionally coordinated, particularly through Nrf2, to support this resistance.
3.
Assess how glutathione metabolism affects the development of a suppressive TIME.
(For additional information, please visit NIH RePORTER)
The project focuses on addressing the challenge of cisplatin (CDDP) resistance in head and neck squamous cell carcinomas (HNSCC), including both HPV-positive and negative cases. CDDP is a standard treatment, but many patients develop resistance and distant metastasis after therapy, with no reliable predictors of response. To tackle this problem, multiple CDDP-resistant HNSCC cell line models were developed, originating from diverse genomic backgrounds and TP53 statuses. These models revealed that almost all resistant clones exhibited hyperactivation of the Nrf2 pathway, often due to somatic mutations or reduced RNA expression of KEAP1, the pathway's negative regulator. Nrf2 activation is linked to poor prognosis, immune therapy resistance, metastasis, and chemotherapy resistance, making it a key factor in maintaining acquired resistance.
The project explores the potential of targeting Nrf2 to reverse or prevent resistance, using a novel drug that inhibits glutaminase 1 (GLS) to deplete glutathione pools necessary for Nrf2 activity, effectively reversing CDDP resistance. Additionally, paracrine signaling from reprogrammed sensory neurons in the tumor microenvironment was identified as a contributor to CDDP resistance, with potential pharmacological inhibition offering a strategy to enhance CDDP sensitivity.
Preclinical models suggest that Nrf2 activation not only supports resistance but may also drive more aggressive disease and increased metastasis rates. While Nrf2 hyperactivation is central to acquired CDDP resistance, the project also investigates Nrf2-independent pathways that may contribute to this resistance.
The overarching goal of the project is to define the roles of both Nrf2-dependent and independent pathways in CDDP resistance, understand the mechanistic interactions between resistance, Nrf2 activation, and neuronal reprogramming in the tumor microenvironment, and assess whether targeting metabolism or stabilizing p53 can overcome resistance and tumor progression.
The findings are expected to provide valuable insights that could translate into improved treatments for HNSCC and related cancers of the lung and esophagus, with significant implications for global cancer care.
(For additional information, please visit NIH RePORTER)
Currently, there are no reliable predictors of tumor response or resistance development, making treatment failure often fatal. The project focuses on assessing tumor response using hyperpolarized magnetic resonance imaging (HP-MRI) and detecting biological changes in circulating tumor cells (CTCs) during cisplatin therapy.
Research has shown that CDDP and other genotoxic agents cause measurable changes in tumor cell metabolism, detectable by HP-MRI with [1-13C]-pyruvate and biochemical assays. These changes, linked to shifts in carbon flux from pyruvate to lactate via lactate dehydrogenase (LDH), correlate with the effectiveness of the treatment. The project hypothesizes that metabolic reprogramming driven by Nrf-2 in cisplatin-resistant HNSCC can be detected using HP-MRI and scCTC analysis.
To test this, the project will use preclinical models of HNSCC that are both sensitive and resistant to cisplatin. Glycolytic metabolism changes will be measured at baseline and after cisplatin administration through imaging and biochemical assays. These findings will be validated in vitro and in vivo (Aim 1). Additionally, treatment response in HNSCC patients will be measured relative to changes in tumor metabolism using HP-MRI data collected before and after chemotherapy (Aim 2). Genomic and transcriptomic analysis of CTCs will identify biomarkers associated with cisplatin resistance, providing biological support for the imaging findings.
The project aims to establish HP-MRI as a minimally invasive method to assess tumor resistance to cisplatin and provide real-time feedback to optimize treatment. CTC biomarker analysis will offer critical biological validation. This work has the potential to change clinical decision-making regarding cisplatin use in HNSCC and related cancers, advancing a precision oncology approach and aligning with NIH’s mission to reduce the burden of human illness.
(For additional information, please visit NIH RePORTER)
