Posted July 5, 2023

Mei Yee Koh, Ph.D., Kuda Therapeutics, Inc

A 2020 report released by the National Cancer Institute Center for Cancer Research cited clear cell renal cell carcinoma (ccRCC) as the most common type of kidney cancer in adults, accounting for approximately 80% of cases. As most patients do not respond or develop resistance to the current treatments, there is an urgent need for novel therapeutic options. A defining hallmark of ccRCC includes metabolic changes leading to the accumulation of fatty deposits (lipids), causing the “clear cell” appearance. These metabolic changes are driven by molecules called hypoxia-inducible factors (HIFs) and have been observed to promote tumor growth, and to confer susceptibility to a type of cell death called ferroptosis. Ferroptosis occurs due to increased oxidation of lipids caused by the presence of iron, which causes these lipids to change shape and rupture cell membranes, resulting in cell death. ccRCC, with their increased concentration of lipids are highly sensitive to ferroptosis compared to normal tissue. Additionally, although cancer cells frequently develop resistance to programmed cell death (apoptosis), this is typically accompanied by increased susceptibility to ferroptosis, suggesting that the induction of ferroptosis may be a promising strategy to kill cancer cells that are resistant to apoptosis. With a fiscal year 2019 Kidney Cancer Research Program Idea Development Award, Dr. Koh and her team aimed to investigate this novel therapeutic strategy for ccRCC.

Dr. Koh hypothesized that ferroptosis induction may be an effective and selective way to target ccRCC. The research team previously identified novel compounds that blocked the HIFs, which are well validated targets for ccRCC. In investigating the mechanism of action of these HIF inhibitors, the team found that these compounds targeted a novel protein, iron sulfur cluster assembly 2 (ISCA2), whose inhibition both decreased HIF levels, and promoted iron accumulation, which triggered ferroptosis specifically in ccRCC cells. Thus, Dr. Koh and her team serendipitously identified compounds with dual modes of action: first by inhibiting the HIFs that drive tumor progression, and second by inducing cell death through ferroptosis. The mechanism by which ISCA2 inhibition leads to HIF inhibition and ferroptosis was described by Dr. Koh and her team in their 2022 Oncogene publication.

During the period of the KCRP award, structure-activity analysis of the compounds was performed to identify modifications to their chemical structure that could improve their drug-like characteristics including bioavailability, solubility and half-life. These changes would enable the compounds to taken orally and remain stable in the gut and blood circulation to allow them to reach the tumor to mediate their anti-tumor effects. These efforts resulted in the identification of KD061 as the leading candidate. Preliminary experiments demonstrated that oral administration of KD061 resulted in significant almost 70% tumor growth inhibition in a mouse renal cancer model accompanied by significant induction of ferroptosis within mouse tumors. There were no detectable toxicities in the mice at this therapeutic dose supporting KD061 as a safe and effective treatment strategy. Further efforts are underway to further optimize KD061 and evaluate its efficacy in other mouse models of renal cancer.

With these exciting results, Dr. Koh and her research team have created a novel, first-in-class therapeutic that shows promise for future preclinical work and, potentially clinical trials for patients with ccRCC, as well as for those with other tumor types that may be susceptible to ferroptosis. Efforts to bring this molecule closer to patients is already underway - Kuda Therapeutics has recently been awarded at $2M SBIR Phase II award (2R44CA217385-03A1) from the National Cancer Institute to perform the safety and toxicology studies required to bring KD061 to first-in-human trials. If successful, this new therapeutic strategy could transform the treatment paradigm for ccRCC, with the potential to impact patients with other ferroptosis-susceptible tumor types.

Links:
Public and Technical Abstracts: The Investigation of Ferroptosis as a Novel Therapeutic Paradigm for Kidney Cancer

Publications:
Green YS, Ferreira Dos Santos MC, Fuja DG, et al. 2022. ISCA2 inhibition decreases HIF and induces ferroptosis in clear cell renal carcinoma. Oncogene 41(42):4709-4723.

References:
Clear cell renal cell carcinoma. 2020. Center for Cancer Research, National Cancer Institute. https://www.cancer.gov/pediatric-adult-rare-tumor/rare-tumors/rare-kidney-tumors/clear-cell-renal-cell-carcinoma