Leveraging SCARB1 Overexpression for the Treatment of ccRCC with Low-Density Lipoprotein Nanocarriers
Abstract
Despite current advances in new molecular and immunotherapy, the 5-year survival rate for advanced kidney cancer remains around 12%. This finding clearly highlights an urgent need for novel treatments. The most common form of kidney cancer exhibits a unique metabolic derangement encompassing an addiction to cholesterol where copious amounts of this lipid is needed for the cancer cell s survival. To date this is an understudied area in kidney cancer biology. N o other research teams have tried to leverage this deviant metabolic activity for therapeutic purposes against kidney cancer. The focus of the current Kidney Cancer Research Program Idea Development Award is to exploit the overactive cholesterol uptake pathway in kidney cancer cells using an engineered cholesterol carrier (low-density lipoprotein (LDL)) that is reformulated with the natural omega-3 fatty acid called docosahexaenoic acid (DHA). The LDL-DHA formulation has previously been shown to kill tumors cells without injury to normal cells. For the current grant application we anticipate the LDL-DHA formulation will be cytotoxic to kidney tumors, while being non-injurious to the normal kidneys. As such, this grant proposal directly addresses the FY22 KCRP Focus Areas to 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. The proposed grant will explore the following specific aims: First we will investigate the binding, uptake, and cytotoxicity of the LDL- DHA formulation against a panel of normal and malignant kidney cells. Secondly, we will develop a rat model of kidney cancer to assess LDL-DHA drug delivery kinetics, safety and short term anticancer effects. Lastly, we will compare effectiveness of LDL-DHA vs current front-line treatment, sunitinib, to provide sustained long term antitumor control in the rat model of kidney cancer. This work is highly innovative in that the LDL-DHA treatment consists of completely natural components at are well tolerated by the body, thus minimizing the likelihood for adverse effects. At the completion of these studies we will have demonstrated that targeting the abnormal cholesterol uptake pathway in kidney tumors is a viable strategy for treating this cancer; LDL-DHA is an effective new treatment against kidney cancer that is safe and actually provides health benefits to the normal kidneys. Novel therapies like LDL-DHA that demonstrate selective tumor toxicity and kidney protective properties are critical for the management of high-risk kidney cancer patients who have underlying conditions like kidney disease. LDL-DHA can be a viable treatment option for difficult to treat patients who have few therapeutic options. Ultimately, it is our goal to bring this technology to the kidney cancer patients where it is anticipated to provide a safe and efficacious approach to managing this aggressive cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310866
Entities
People
- Ian Corbin
Organizations
- United States Army
- University of Texas Southwestern Medical Center