Targeting Unusual Nutrient Acquisition Routes of Nutrient-Deprived Cancers
Abstract
Nutrients - carbohydrates, proteins, and fats - are the currency of cellular growth. This is particularly true for cancer cells, which do what they can to acquire as much of these nutrients as possible to sustain their uncontrolled growth. The opposite of growth is tumor shrinkage and eventual death of cancer cells, which is precisely what chemotherapy and radiation treatments aim to achieve. Yet, somehow, there are cancer cells that survive these harsh conditions and eventually begin growing again once the treatments are discontinued. What is so special about these remaining cancer cells that allows them to survive malnutrition and a barrage of toxins? It appears that many of these cancer cells have a mutation in the infamous gene called RAS, which rewires the way these cancers acquire nutrients. Trapped inside tumor cores or other malnutritioned tissues following chemotherapy, these cancer cells no longer wait for blood vessels to deliver nutrients. Instead, they start scavenging food from their surroundings, and they also cannibalize dead cells. Every cell needs to digest this scavenged food inside cellular stomachs called lysosomes before it can be recycled back to the cell. These recycled nutrients are then converted into energy, and used as building blocks for the growth of the cell. To fight those cancers, many researchers are currently trying to find ways to stop cancer cells from scavenging food, by either blocking the scavenging directly or by attacking mutant RAS. However, what if, instead of preventing cancer cells from eating, we simply trapped all the food inside the cellular stomach? Most recently, a number of molecular machines, called nutrient transporters, were found to act as gates for releasing digested nutrients from the cellular stomach, and our plan is to immobilize that gate with drugs. Imagine a situation where the cancer cell consumes all of the food that it can scavenge, but after digestion, the food becomes trapped inside of its stomach compartment. The release no longer works because of the drug that blocked the food gate. After having their main food supply cut off, cancer cells that are addicted to scavenging will stop growing. At the same time, normal cells would ultimately not care, because their food and energy does not come from scavenging. This Career Development Award from the U.S. Department of Defense will allow Dr. Kacper Rogala to build an entire therapeutic program in his laboratory at Stanford University by focusing on drugging survivor cancer cells that scavenge food from their surroundings. Dr. Rogala wants to specifically focus this project on two fiscal year 2022 ( FY22) Peer Reviewed Cancer Research Program Topic Areas: Bladder Cancer and Colorectal Cancer. Approximately half of these cancers carry mutations in RAS and a few other genes that transform them into food scavengers. This project will develop new prototype anti-cancer therapeutics addressing one of the FY22 PRCRP Overarching Challenges: Therapeutics - Transform cancer treatment through the identification of new targets, especially for advanced disease and metastasis. Importantly, this Award will also allow Dr. Rogala to grow as a cancer researcher by learning new research skills and expertise. And most importantly, because Dr. Rogala was trained as a laboratory scientist, with limited experience working with oncologists or patients, this proposal will fill that gap. Through participation in the Virtual Cancer Center program, and interactions with the medical staff and patients at the Stanford Cancer Institute, Dr. Rogala will learn about the most pressing therapeutic needs and how his laboratory discoveries can be translated to the clinic for the benefit of patients. Military personnel are at an elevated risk of developing bladder and colorectal cancers, mainly due to repeated exposure to toxic substances in the field and in military bases. This project will specifical
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310723
Entities
People
- Kacper B Rogala
Organizations
- Stanford University
- United States Army