Targeting nanotherapeutics to eradicate acute leukemia stem cells

Funding Type: 
Early Translational II
Grant Number: 
ICOC Funds Committed: 
Public Abstract: 

Various cells and organs in the human body originate from a small group of cells called stem cells. Recently, it was found that human cancer cells also arise from a group of special stem cells, named cancer stem cells (CSCs). At present, if cancer has spread throughout the body (metastasized), it is rarely curable, and survival rates in these patients are low. One major reason for therapeutic failure is that CSCs are relatively resistant to current cancer treatments. Although most cancer cells are killed by treatment, resistant CSCs will survive to regenerate additional cancer cells and cause a recurrence of the cancer. As opposed to normal stem cells, CSCs have their own unique molecules on their cell surface. Recently, we have identified several small molecules that can recognize and bind to the unique molecules on CSC. We have also developed a nanotechnology platform to manufacture tiny particles named nanomicelles. These nanomicelles have a size of about 1-2/100th of one micron (one millionth of a meter), and can be loaded with chemotherapy drugs that can kill CSCs. In this project, we will coat the drug-loaded nanomicelles with small molecules that specifically bind and kill CSCs. In patient's body, these drug-loaded nanomicelles will work like "smart bombs" in a patient's body. They can identify and bind to CSCs. Therefore, a high concentration of chemotherapy drugs can be delivered to and kill CSCs. Furthermore, chemotherapy drug can be released from nanomicelles to patient's blood and kill cancer cells throughout the body. With these nanomicelles, both cancer cells and cancer stem cells are targeted, and cancer can possibly be eradicated at its very root.

In this project we will focus on one type of cancer called acute myeloid leukemia (AML). It is the most common acute leukemia in adults in the US and a very serious disease. The vast majority of patients with this disease will die either from the disease or from treatment complications. We chose to treat this disease because leukemia cells and leukemia stem cells are located inside the bone marrow or blood vessels that can be easily targeted with our "smart bombs". We will determine the effectiveness and toxicity of the nanomicelles. After we finish all these experiments, we will discuss with the US Food and Drug Administration (FDA) the requirements for manufacturing the "smart bombs" for human use.

Statement of Benefit to California: 

If this project is successful, it will set up an example of targeting cancer through eradicating cancer stem cells, the cells from which other cancer cells originate. Cancer is the second most common cause of death in California. If cancer can be more effectively treated, the life expectancy can be extended and the quality of life for many cancer patients can be improved.

One major aspect of this project is to develop a novel drug delivery system. The drug developed in this project can be used for the treatment of many cancer types. We have shown that chemotherapy drugs delivered in our system are more effective and associated with fewer and milder side effects. Therefore, this project may help improve the treatment outcomes and decrease treatment complications generally associated with cancer therapy.

This project may have huge financial benefits to California. Several investigators of this research team have experience in commercializing their drug discoveries. Several discoveries related to this project have already been filed for patent protection. If this project is successful, some of these patents can be commercialized and bring revenues to California.

The outcome for acute myelocytic leukemia (AML) is poor. Overall, over 70% of patients will die from this disease or treatment-related complications. Patients with AML usually require intense inpatient chemotherapy that is costly. Many patients die from the complications of treatment. This project aims to develop therapeutic agents that specifically target leukemia stem cells and therefore eradicate leukemia at its root. Furthermore, the agents developed in this project may decrease the side effects of treatment and decrease treatment death. If this project is successful, it will decrease the need for stem cell transplantation, another treatment modality that is associated with even higher treatment-related mortality and cost. Furthermore, many patients cannot undergo stem cell transplantation because it is often difficult to find matched donors for stem cells. This is especially true in California because of the genetically diversified population.

If this grant is funded, it will help translate our laboratory research into life-saving clinical applications. There is a huge gap between basic research and clinical applications. This gap is in part traced back to the fact that it is difficult to find researchers who know and can integrate clinical needs with basic research. Many members in this research team have a long track record of bringing bench research into the clinic. If this project is funded, it will not only make this important research possible, but this will also give several of the physician-scientists protected time for translating basic research into clinical applications.