Heme-Targeting Agent and Immunotherapy Combinations in Renal Cell Carcinoma
Abstract
The number of patients suffering from kidney cancer is rising around the world. As the most common type of kidney cancer, renal cell carcinoma (RCC) emerges from highly vascularized tumors. In recent years several innovative treatments have emerged for RCC with significant improvements in outcomes. Respectively, the kinase inhibitors everolimus, sunitinib, and cabozantinib revolutionized targeted treatment and achieved significant tumor response in many patients, but ultimately tumor progression was observed. Most recently, immunotherapy with checkpoint inhibitors such as nivolumab and ipilimumab has shown remarkable success in some patients (typically 30%), even for multiply pre-treated tumors. A recent innovation is belzutifan, a HIF-2 antagonist, invented at UT Southwestern, developed by Peloton Pharmaceuticals and acquired by Merck, which just gained FDA approval for RCC and has shown benefits in patients resistant to sunitinib. However, most RCC patients who initially respond to therapy eventually develop resistance allowing tumor progression. Thus, there remains an unmet need to develop new therapies that may be effective in their own right or augment the success of existing treatments. The invasive neovasculature of tumors is immature, lacks pericyte support, and exhibits increased permeability that leads to hypoxia, providing an attractive target for therapy. Our team has recently demonstrated the therapeutic efficacy of a novel heme-targeting agent, cyclopamine tartrate (CycT) in non-small cell lung cancer (NSCLC) cells and mouse tumor models. Specifically, we found that CycT effectively inhibits angiogenesis, normalizes tumor vasculature, and alleviates tumor hypoxia. These findings have established heme targeting by CycT as an effective strategy for suppressing tumors. Our preliminary study indicates that CycT effectively normalized vasculature and inhibited the progression of a patient-derived RCC xenograft model without apparent systemic toxicity. Recognizing the emerging success of immunotherapy, we anticipate that heme-targeting agent-induced vasculature normalization will reprogram the tumor microenvironment (TME) for enhanced immunotherapy response. The overarching goal of the proposed research is to characterize the effects of heme-targeting agent CycT alone or in combination with immunotherapy on tumor growth, metastasis, and microenvironment in RCC RENCA tumors growing in immunocompetent animals. We place considerable emphasis on imaging, which can provide important insights into the time course of drug effect and early indication of efficacy. Multispectral optoacoustic tomography (MSOT) is a newly available method that will directly reveal the extent of vascular normalization. It should provide a prognostic imaging biomarker to evaluate kidney tumor response to CycT and combination therapy. In addition, investigating the mechanism of CycT action in RCC will be essential for understanding its activity at the molecular level and predicting potential off target effects, providing information to circumvent drug resistance, and exploring new targets along the activation pathways.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310220
Entities
People
- Tianyuan Wang
Organizations
- United States Army
- University of Texas Southwestern Medical Center