Kidney Cancer
In 2020, there were more than 600,000 people living with kidney cancer in the United States. The majority of kidney cancers consist of the clear cell renal cell carcinoma (ccRCC) subtype – the most common and aggressive sub-type of kidney cancer. Unfortunately, approximately 30% of ccRCC patients are diagnosed with metastatic disease, which has a 5 year survival rate of just 15%. New treatment options are urgently needed to address this deadly disease.
Kidney cancer cells are uniquely sensitive to ferroptotic cell death
A defining hallmark of ccRCC is increased lipid (fat) accumulation within tumor cells, which gives rise to the ‘clear cell’ appearance. The increased lipid content within these tumor cells also increase their sensitivity to ferroptosis, a type of cell death associated with excessive iron accumulation. Increased iron levels oxidizes the lipids within cancer cells, causing the cells to rupture and die.
The HIFs drive kidney cancer progression
Close to 90% of patients with ccRCC lose the functionality of the von-Hippel Lindau (VHL) tumor suppressor protein, leading to the accumulation of hypoxia-inducible factor (HIF) proteins within tumor cells. This process activates the formation of blood vessels, driving tumor growth.
HIF-2α has been recognized as a central driver of ccRCC progression, and the inhibition of HIF-2α has been shown to block tumor growth.
Dual Targeting of Ferroptosis-HIF
Our compounds promote iron accumulation, which results in cell death via ferroptosis. It also blocks the production of HIF-2α, which reduces blood vessel formation, blocking tumor growth. Thus, our novel therapeutic strategy both triggers tumor cell death and inhibits tumor growth. By targeting two unique vulnerabilities of ccRCC cells, this paradigm-shifting treatment strategy shows promise in effectively and selectively causing the destruction of tumor cells.
Our studies show that our lead compound shows profound anti-tumor efficacy in animal models of kidney cancer with no detectable toxicities at the therapeutic dose.
Ongoing Efforts
We are currently optimizing our lead molecule for pre-clinical IND enabling studies. Beyond ccRCC, this first-in-class therapeutic strategy will have widespread application in a variety of tumor types associated with HIF-2α activation or lipid accumulation including ovarian and brain cancers.