Targeting P2X7 Receptor in Renal Cell Carcinoma
Abstract
Renal cell carcinoma (RCC) is a lethal disease whose incidence is on the rise. Clear cell RCC (ccRCC) is the most frequent (75%to 80%) subtype of RCC. Traditional chemo- and radiation therapies are largely ineffective in the treatment of all RCC subtypes. The development of multi-targeted tyrosine kinase inhibitors (TKIs) and immunotherapeutic agents notably changed the treatment paradigm of advanced kidney cancer. However, despite the therapeutic progress, complete and durable responses have been noted in only a few cases. Thus, ccRCC continues to be a treatment-resistant malignancy. Adenosine 5 -triphosphate (ATP) is the principal molecule for storing and transferring energy in cells. In the process of tumorigenesis, a large amount of intracellular ATP is released into the tumor microenvironment (TME). Extracellular ATP levels are more than 1,000-fold higher in the TME than in normal tissues and can reach high micromolar concentrations. Besides energy transduction, ATP plays a critical role in extracellular signaling activating ATP-gated purinergic receptors. Among all ATP-gated receptors, P2X7 receptor (P2X7R) has unique characteristics including a very high activation threshold. Therefore, P2X7R function is expected to be highly relevant for TME with extremely high abundance of extracellular ATP. Indeed, P2X7R contributes to tumor progression and therapeutic resistance in various cancer types. Importantly, the expression of P2X7R is increased in ccRCC at both mRNA and protein levels. Our preliminary studies demonstrate that stimulation of P2X7R results in the activation of pro-tumorigenic signaling and the augmented expression of several key immunosuppressive and pro-angiogenic factors in ccRCC cells. P2X7R has two active isoforms, full-length P2X7A and truncated P2X7B, that impart different functional properties. P2X7B might be of special relevance in cancer as P2X7B retains P2X7A growth-promoting activity while it lacks P2X7A-associated cytotoxicity. Therefore, P2X7A may act as a tumor suppressor, whereas P2X7B may function as a tumor promoter. Given that high extracellular ATP levels in solid tumors are capable of inducing P2X7A-mediated pore formation and thereby promote cell death, it is unlikely that cells expressing P2X7A could survive in the TME. Therefore, it is anticipated that malignant cells express P2X7R predominantly in a form where pore activity is attenuated, such as P2X7B isoform. Thus, tumor cells can gain a selective advantage by silencing the negative (death-inducing) response linked to P2X7A activation and keeping only the positive (pro-tumorigenic) P2X7B-associated properties. Based on our preliminary findings and published data, we hypothesize that high levels of extracellular ATP activate pro-survival and pro-tumorigenic signaling in ccRCC by stimulating P2X7B. Therefore, antagonism of P2X7B could have significant negative effect on survival and tumorigenic potential of ccRCC cells. To test our hypotheses and to elucidate the role of P2X7R as a potential prognostic biomarker and a novel therapeutic target in ccRCC, we propose the following Specific Aims: (1) Evaluate P2X7R as a potential therapeutic target in ccRCC. First, we will examine the role of P2X7R in supporting pro-tumorigenic properties of ccRCC cells. Next, we will delineate the role of P2X7A and P2X7B isoforms in regulating ccRCC tumorigenesis in vivo. In addition, we will examine the therapeutic potential of P2X7R inhibition in cell and animal models of human ccRCC. (2) Establish the association of P2X7R with ccRCC clinical outcomes. Response to TKIs remains unpredictable in individual ccRCC patients. There are currently no validated markers to allow selection of patients destined to gain maximal clinical benefits. The studies proposed in this aim will address this unmet medical need by establishing the relationship between the expression levels of P2X7R isoforms and clinical outcomes providing prognost
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310833
Entities
People
- Vladimir Kolenko
Organizations
- United States Army