Background: Veterans have higher rates of cigarette smoking and obesity, as well as a higher probability of exposure to cancer-causing toxins, which may increase their risks of developing kidney cancer compared to the general population. Kidney cancer is one of the most aggressive and drug-resistant types of cancer. Approximately one-third of kidney cancer patients are diagnosed only after their tumors have already spread, and these patients have a dismal 8% chance of surviving the next five years. In addition to the late diagnosis of kidney cancer, the primary hurdle for patients with kidney cancer is the lack of effective treatments. The vast majority of drugs to treat kidney cancer can be divided into just two groups: those that block blood vessel formation, and those that activate the immune system (immunotherapy). The majority of patients either do not respond to these drugs, or develop resistance, which leaves them with very few other treatment options. Thus, there is a need for a new treatment paradigm, to provide an additional option for patients, and to potentially improve the effectiveness of current drugs.

The clear cell subtype is the most common and aggressive form of kidney cancer. The clear cell appearance is caused by metabolic changes that lead to the accumulation of fatty deposits within tumor cells. This accumulation of fatty deposits makes cells of the clear cell subtype of kidney cancer more sensitive to a type of cell death, termed ferroptosis, than non-cancer cells. Furthermore, cancer cells that are resistant to standard treatments also show increased sensitivity to ferroptosis. We propose that drugs that can induce ferroptosis may be a promising new treatment option for patients with clear cell kidney cancer. We have identified molecules that can induce ferroptosis in mouse models of clear cell kidney cancer, without causing any detectable side effects. In the proposed study, we will work to improve the effectiveness of these ferroptosis-inducing molecules through chemical modifications, and evaluate their potential effectiveness and safety in animal models, with the long-term view to ultimately develop these molecules for the treatment of clear cell kidney cancer in humans.

Areas of Emphasis: Therapeutic Development

Innovative Aspects: While most pharmaceutical companies are working on improving the performance of current treatments with small, incremental benefits, we propose an entirely new way in which to treat clear cell kidney cancer -- through the induction of ferroptosis. This novel strategy is completely different from current treatments and exploits the underlying factors that create the clear cell appearance that is the hallmark of clear cell kidney cancer. Furthermore, we have identified a molecule that can induce ferroptosis in mouse models of clear cell kidney cancer, which will be used as a prototype for further modification and improvements. We believe that this strategy will be of profound benefit to patients by identifying and validating a new treatment paradigm for clear cell kidney cancer.

Applicability of Research: This research will be directly applicable to patients with clear cell kidney cancer. These studies will determine whether ferroptosis induction is both effective and safe for the treatment of clear cell kidney cancer, and if ferroptosis inducers are useful in increasing the effectiveness of current treatments when used in combination. Most notably, this research will provide proof-of-concept data for a first-in-class treatment for clear cell kidney cancer that will provide the basis for additional research investigating ferroptosis induction as a treatment option for kidney cancer, and other cancer types with a clear cell component, including cancers of the cervix, liver, and pancreas.

At the successful conclusion of the KCRP Idea Award, we will have identified a molecule that is suitable for further preclinical development. We estimate an additional 2-3 years will be required to obtain the regulatory approvals necessary for first-in-human trials. Once safety is verified in human Phase 1 trials, Service members, Veterans, and the American public will have access to the new treatment in Phase II/III trials. If approved, our novel ferroptosis inducers will transform the treatment paradigm for kidney cancer by providing a new, effective, and safe treatment option for patients, particularly for the majority of patients who do not respond to current therapies.