Early Translational II
$4 965 720
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.
This Development Candidate (DC) Award application proposes to develop a treatment for acute myelocytic leukemia (AML) by targeting leukemic stem cells (LSCs). The incidence of AML in adults is about 13,000 cases annually and roughly 70% of these patients will die of this disease. Clearly current therapies are not very effective. This application is based on the assumption that leukemic stem cells (LSCs) are resistant to the chemotherapeutics commonly used to treat this malignancy and are the cause of disease recurrence. The applicant proposes to improve the effectiveness of treatment by using nanomicelles designed to deliver a high concentration of a standard chemotherapeutic agent specifically and directly to the LSCs. The specific advantage of this technology over conventional chemotherapy is the ability to deliver higher concentrations of drug while minimizing toxicity. Specific targeting to LSCs will be achieved by decorating the nanomicelles with LSC-targeting ligands that bind to receptors expressed on LSCs. The primary objectives of the proposal are to improve the properties of nanomicelles for delivering drugs to LSCs, to establish whether LSC-targeted nanomicelles loaded with a chemotherapy drug indeed target LSCs, and to determine whether the LSC-targeted nanomicelles containing drug have appropriate drug-like properties. The reviewers agreed that the proposal has been logically developed and is based on the principal investigator's extensive experience in nanomicelle delivery systems. If workable, it could have a positive impact on the treatment of patients with AML, especially older patients who have difficulties tolerating systemic chemotherapy. However, evidence that the approach would have such impact was not clearly presented in the proposal; for example, evidence that LSCs are intrinsically resistant to the studied drug or that delivery of higher doses of the anti-cancer agent specifically into LSCs will provide a more efficacious therapy than that currently in use to treat patients. Although the reviewers described the nanomicelle technology as an elegant approach, they had several concerns about the experimental plan that dampened their enthusiasm. For example, reviewers questioned the effectiveness of the readout and commented that determining the effectiveness of the therapeutic candidate on LSCs in primary AML samples will be very difficult because of difficulties in identifying true AML LSCs. Additional concerns centered on the specificity of the targeting ligands. Reviewers commented that the specificity of the 9-mer peptides proposed for targeting is likely to be low, and that some of the targeting ligands are not specific for stem cells, but are also expressed on other cell types. Reviewers appreciated that the nanomicelle-targeting ligand for CCL1 specifically binds to cell lines expressing its cognate receptor, but would have liked to see data showing that the 2 other LSC-binding ligands similarly bind to their cognate receptors. An additional concern is that it is not known whether the receptors for the latter ligands are exclusively or primarily expressed on the surface of LSCs. Reviewers were in agreement that the PI is an expert in combinatorial chemistry and nanotechnology and is highly qualified for the proposed work given past experience with nanomicelle drug delivery systems. The environment is excellent and the collaborators and team are appropriate for the proposed studies, although three people still need to be hired for this project. The budget is focused and appropriate for the research proposed. Overall, enthusiasm for the otherwise elegant nanomicelle technology was dampened because of several weaknesses. These include: (1) difficulties in the assessment of efficacy; (2) concerns about the specificity of targeting; and (3) lack of evidence for the underlying assumption that higher doses of the chemotherapeutic agent will kill LSC.