Targeting nanotherapeutics against acute leukemia stem cells

Funding Type: 
Disease Team Research I
Grant Number: 
DR1-01461
ICOC Funds Committed: 
$0
Disease Focus: 
Heart Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
Public Abstract: 
Various cells and organs in the human body originate from a small group of primitive 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. In the project’s last year (about 4 years from now), we expect to manufacture sufficient amount of nanomicelles that will meet the quality requirements for clinical trials in human patients with acute myeloid leukemia. We will also write a clinical trial protocol to seek FDA approval for clinical trials in human.
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 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 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. Acute leukemia is the sixth most common cause of cancer death in males and females in California. The outcome for acute leukemia is poor. Overall, over 70% of patients will die from this disease or treatment-related complications. Patients with acute leukemia 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.
Progress Report: 
  • Disease Team Award DR1-01461, Autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the first year of CIRM support, we have developed and validated a development candidate, cardiospheres, which are three-dimensional (3D) functional microtissues engineered in culture and suitable for implantation in the hearts of patients via minimally-invasive catheter-based methods. Cardiospheres, derived from heart biopsies using methods developed by the Principal Investigator, have now been successfuly delivered via magnetically-navigated injection catheters into healthy heart tissue surrounding zones of myocardial damage in preclinical models. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. We have also developed standard operating procedures for cardiosphere manufacturing, and are in the process of developing release criteria for the 3D microtissue development candidate. Next steps include efficacy studies, with a view to an approved IND by mid-2012.
  • Disease Team Award DR1-01461, autologous cardiac-derived cells for advanced ischemic cardiomyopathy, is targeted at developing novel therapies for the treatment of heart failure, a condition which afflicts 7 million Americans. Heart failure, when symptomatic, has a mortality exceeding that of many malignant tumors; new therapies are desperately needed. In the second year of CIRM support, pivotal pre-clinical studies have been completed. We have found that dose-optimized injection of CSps preserves systolic function, attenuates remodeling, decreases scar size and increases viable myocardium in a porcine model of ischemic cardiomyopathy. The 3D microtissues engraft efficiently in preclinical models of heart failure, as expected from prior work indicating their complex multi-layer nature combining cardiac progenitors, supporting cells and derivatives into the cardiomyocyte and endothelial lineages. Analysis of the MRI data continues. We have developed standard operating procedures for cardiosphere manufacturing and release criteria, product and freezing/thawing stability testing have been completed for the 3D microtissue development candidate. We have identified two candidate potency assays for future development. The disease team will evaluate the results of the safety study (immunology, histology, and markers of ischemic injury) and complete the pivotal pig study in Q1 2012. With data in hand, full efforts will be placed on preparation of the IND for Q2 2012 submission.

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