Therapeutic Targeting of Cystine Addiction of Renal Cell Carcinoma
Abstract
Background and Objectives/Hypothesis: Most kidney cancers, especially the classical type with the appearance of clear cells, have lost a tumor suppressor gene called VHL. In other words, the loss of the VHL is one of the most important changes in kidney cancers. While it seems obvious that we should target the VHL loss in these kidney cancers, it is often difficult to use drug to correct the loss of a tumor suppressor gene (e.g., VHL). Therefore, no treatment is available to treat VHL loss in kidney cancers. We propose an entirely new method to treat VHL loss based on our finding that VHL-lost kidney tumor cells have an unexpected weakness -- addiction to amino acid cysteine. Just as we require food (sugars or proteins) and oxygen to live, our cells also rely on nutrients from their environment to survive. Compared to normal cells, tumor cells often have increased and different demands for nutrients from the surrounding environment. We have found VHL loss creates an unexpected need of the kidney cancer cells for an outside cysteine or cystine (which is comprised of two cysteine amino acid molecules). While cysteine/cystine is often thought to be nonessential, kidney cancer cells totally rely on them for survival. The removal of cystine rapidly triggers a special kind of cell death program to which kidney cancer cells that have lost VHL are particularly sensitive. The other non-tumor cells with intact VHL are not affected by the cystine removal. Therefore, our hypothesis is that such dramatic differences in cystine requirement indicate that cysteine deprivation treatments may have a wide therapeutic window and few side effects. Importantly, we can use a newly developed enzyme (cyst(e)inase, which removes both cystine and cysteine, that is safe and has very strong anti-tumor effects for many tumors. This enzyme is currently under development by a drug company for clinical trial in the near future. Therefore, if our experiments are successful, our findings can be rapidly translated to clinical trials and may offer a totally new treatment for patients with kidney cancer. Area(s) of Emphasis: Metabolism: How VHL loss leads to cystine addiction of kidney cancer) Targeted Therapies: A new cystine-degrading enzyme expected to be ready for clinical trials in the near future) Immunotherapies: Ferroptosis caused by cystine deprivation is known to help immune systems Innovative Aspects of the Proposed Research Project: The innovative aspect is the unexpected cystine addiction in the VHL-lost kidney cancer cells and their vulnerability to the cystine-deprived cell death by ferroptosis. Therefore, this cystine addiction becomes a weakness that we can take advantage to kill kidney cancers based on changed nutrient need. We have cooperated with a company that is developing cyst(e)inase ready for clinical trials in the near future. Because cells die by ferroptosis known to enhance our immune response, cysteine deprivation may work particularly well with immune therapies, which are becoming the standard treatment for kidney cancer. Therefore, the success of our experiments can be rapidly translated to clinical trials and may offer a totally new treatment. Short-Term Impact: The short-term impact will be the determination of therapeutic potential of cystine deprivation by cyst(e)inase in the mouse models of kidney cancers from human patients. We will also determine whether such treatment can enhance the effects of immunotherapies used for many patients of kidney cancers. In addition, we will test whether VHL or other genes can be used to predict which kidney cancers can be treated by cyst(e)inase. Long-Term Impact: This proposal is based on our very encouraging observations of nutrient addiction of kidney cancers that can be accomplished by a novel enzyme (cyst(e)inase), under clinical development, that effectively starves tumor cells of cysteine required for their survival. We anticipate that
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910842
Entities
People
- Jen-Tsan A Chi
Organizations
- Duke University
- United States Army