Purinergic Receptor Antagonist Therapeutics in Treating Metastatic Renal Cancer
Abstract
Kidney cancer is the 8th most frequently diagnosed malignancy and it occurs almost twice as often in men than women. It is usually without symptoms in the early stages and is often not diagnosed until it is advanced. The biggest challenge facing renal cancer patients is recurrence and metastasis and a lack of effective therapies for advanced renal cell carcinoma (RCC). Clear cell RCC (ccRCC) is the most common subtype and advanced ccRCC has a poor prognosis, rapidly progressing to distant metastases leading to an extremely poor prognosis. ccRCC is typically non-responsive to traditional chemotherapy drugs and other treatment options are very limited. Treatment for ccRCC includes surgery, radiation therapy, immunotherapy (aldesleukin (Proleukin)), and targeted therapy (sorafenib (Nexavar) and temsirolilmus (Torisel)). Newer generation immunotherapies represent a promising approach for ccRCC patients with the potential for a long duration of response, but many patients are not responsive to these treatments. Additionally, for patients who initially respond, the cancer will often eventually progress on treatment as the tumors develop resistance. Studies by our research team and others show that the naturally occurring adenosine nucleotide has a cancer-promoting effect. This molecule binds to its receptors on the cell surface and increases cancer cell growth and migration. The data from our animal studies and other researchers shows that preventing binding of adenosine to these receptors decreases cancer growth and metastasis. Drugs that can block these receptors represent a new, novel therapy option for cancer treatment. We recently generated a group of molecules that target adenosine receptors and suppress breast cancer bone metastasis as compared to untreated animals. This treatment is highly effective even with less frequent administration. Our pilot study showed that these compounds also inhibit ccRCC cell growth and migration. The major objective of this idea development proposal is to identify a new drug candidate that is specific for this novel drug target for treating ccRCC with high efficacy and low toxicity. A specific Focus Area listed in the FY22 KCRP will be addressed: (1) Develop novel therapeutic strategies for the treatment of kidney cancer, such as novel drug targets, therapeutic modalities and agents, treatment combinations and drug delivery systems. In this study, we propose three specific aims. First, we will identify the lead molecules that reduce ccRCC cell growth, migration, and invasion in cell models via alteration of A2 purinergic pathways. Second, we will evaluate the molecules effectiveness in animal models through the assessment of primary and metastatic ccRCC tumor growth and body immune responses. Third, we will select the compound with the best treatment profile and study its stability within the body and further validate its effectiveness using a mouse model with patient-derived ccRCC cells. These efforts will lead to a finalized drug candidate for the next stage of preclinical study and clinical trials. The outcome from this Department of Defense Kidney Cancer Research Program drug development proposal will generate an entirely new class of therapies that target novel mechanisms with high efficacy and low toxicity. Globally, about 270,000 cases of kidney cancer are diagnosed annually, and 116,000 people die from the disease each year, including active-duty U.S. Service Members, retirees, Veterans, and their Family members. The drug developed in this proposal will offer enormous benefits to these patients with the reduction of kidney cancer-associated symptoms and improvement in survival rate. The estimated time for the proposed project is 3 years. Within the 3 years, we will provide research data on the efficacy of our lead compounds in treating ccRCC growth and metastasis and improving antitumor immunity with various models. Moreover, we will provide important
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310495
Entities
People
- Jean Jiang
Organizations
- United States Army
- University of Texas Health Science Center at San Antonio