Disease Team Research I
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.
The goal of the research described by this proposal is to develop a novel drug delivery system to treat acute myeloid leukemia (AML). The proposed approach involves the generation of nanomicelles loaded with an established chemotherapeutic agent and targeted to leukemia stem cells (LSCs). Specific small molecules bound to the nanomicelle surface will mediate targeting to LSCs. This approach should allow the direct delivery of high concentrations of anti-neoplastic agents, thereby facilitating efficient eradication of cancer cells. Development plans include evaluation of various LCS-targeting molecules, pharmacology and toxicology studies in rodents and large animals, scale-up production under GMP conditions, and filing of an IND during the fourth year of the project. The majority of AML patients die of the disease or from treatment complications, so the development of more effective therapies would address an unmet medical need. Tumor regrowth and clinical relapse appear to be due to LSCs that are relatively resistant to cytotoxic chemotherapeutic agents. Reviewers agreed that the development of novel approaches for targeted killing of LSCs, as well as more effective approaches to eradicate bulk cancer cells, could contribute to more effective leukemia treatments. However, reviewers were not enthusiastic about the proposed approach and felt that it was not supported by adequate scientific rationale. In particular, compelling evidence is lacking to support the view that better delivery of chemotherapeutic drugs will improve treatment of AML. Additionally, the applicant has not adequately considered the potential impact of inherent drug resistance mechanisms and inhibition of apoptotic pathways that could defeat the proposed therapeutic strategy. Reviewers had significant concerns about the feasibility and maturity of the proposed project. Although the preliminary data demonstrated development and drug loading of nanomicelles and the identification of potential ligands for LSC targeting, key studies supporting feasibility are incomplete or absent. For example, stability studies of nanomicelles loaded with the proposed therapeutic drug have not been done, and no data were presented using nanomicelles coated with LSC-specific ligands in either in vitro or in vivo models of AML. Reviewers also noted that in the absence of data demonstrating specific targeting of nanomicelles to LSCs, the project’s focus on stem cells (and hence, its responsiveness to the current RFA) is questionable. Additionally, the lack of adequate experimental detail in preliminary data elevated reviewer concern about the project’s feasibility. The research plan was considered to follow a logical progression of activities toward the project goals. However, reviewer enthusiasm was lessened by some concerns about the ability of the research team to achieve these objectives. For example, concerns were raised about whether adequate numbers of AML patient samples would be available for testing and whether appropriate and productive interactions among the investigators have already been established. Moreover, it was unclear that the research team had adequate experience and expertise to carry out some technically challenging aspects of the study such as the engraftment and recovery of human leukemias in the immunodeficient mouse model. Reviewers considered the project milestones to be appropriate but expressed concern that they were vague and lacking adequate detail. The relationship of milestone outcome to Go/No-Go decisions was obscure. Additionally, reviewers felt that the applicant had not adequately addressed alternative strategies should pitfalls be encountered. Some reviewers considered the timeline to be feasible, but others suggested that the preclinical AML model studies would likely require additional time and that discussions with the FDA should occur earlier in the timeline. Reviewers had serious concerns about the applicant’s experience and ability to lead and manage the project. The PI is a junior investigator with few publications in the area of the proposal and no apparent track record in leading multi-collaborator studies. Although the Co-PI is an expert in combinatorial chemistry in drug design, evidence of an established and significant collaboration with the PI is lacking. Reviewers were further concerned that no leadership plan was supplied and that the proposed interactions between investigators were poorly defined. The proposal involves an impressive assemblage of researchers, but reviewers were unclear on the level of commitment of many of the collaborators to the project. Additionally, there were concerns that trainees who lack appropriate experience will perform a significant amount of the work. Reviewers acknowledged the availability of an excellent facility for GMP manufacturing of the nanomicelles. The proposed project is focused on the development of a novel therapy for AML. A strength of the proposal is its focus on a significant medical need. Key weaknesses include the absence of evidence demonstrating that better drug delivery will improve treatment against AML, serious concerns about feasibility and maturity of the project, and the limited experience of the applicant to lead a project of this scope.
- Andrew Balber