Disease Team Therapy Planning I
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 specialized cells that are often referred as 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 cancer treatment failure is that CSCs are relatively resistant to current cancer treatments. Although most cancer cells are killed by treatment, resistant CSCs often survive to re-grow additional cancer cells and cause a recurrence of the cancer. As opposed to normal stem cells, CSCs have unique molecules that they present on their cell surface. Recently, we have identified one small molecule that can recognize and bind to one of these unique molecules on CSC. We have also developed a nanotechnology platform to manufacture tiny particles named nanomicelles. 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 to CSCs. Once bound to the CSCs, the nanomicelles will release the drug cargo into the cells causing them to die. In a patient’s body, these drug-loaded nanomicelles will work like “smart bombs” by specifically attacking the cancer cells, which results in lowered toxicity compared to the current therapy. Furthermore, the chemotherapy drug can be released from nanomicelles into 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. We propose to 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 and the 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:
This project will set 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, 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 in 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. Acute leukemia is a major disease 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 side effects of the 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. 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.
EXECUTIVE SUMMARY Project Synopsis The overall goal of this effort is to develop and evaluate a new therapy for treating acute myeloid leukemia (AML), a common and aggressive form of blood cancer. The applicant has developed a technology platform for producing small particles called nanomicelles, which can be imbued with drugs and decorated with biological molecules for delivering targeted doses of chemotherapy to diseased tissues. In this project, nanomicelles will be coated with peptide ligands recognizing a specific molecule on the surface of leukemic stem cells (LSC), the entities responsible for AML initiation and progression. Upon target recognition, the particles will release their payload, thereby enabling a concentrated dose of chemotherapy to be delivered directly to the LSC. In addition, drug released from nanomicelles directly into a patient’s circulation will enable leukemic cells and LSC-derivatives to be targeted throughout the body. Project goals include completion of manufacturing other preclinical activities to enable filing of an investigational new drug (IND) application. In addition, a Phase I clinical trial will be initiated to obtain safety and dosing information. Significance and Impact - The target product profile (TPP) is reasonable and addresses a significant unmet need for less toxic, more effective treatments for AML. However, some reviewers felt that the Phase I trial plan was not described in sufficient detail to determine its potential to inform the TPP. - The clinical impact of this approach may be limited. A number of other liposomal chemotherapies have been developed in industry and have provided only modest improvements in patient outcome. In addition, dose escalation studies suggested that only modest increases could be achieved when administering these drugs. Reviewers were uncertain whether the unique features of the proposed methodology would translate into meaningful advantages. - If successfully developed, this platform could prove broadly useful for delivering other types of cancer drugs to a desired target. - The proposal describes a single candidate and proposes activities that are fully in scope with the RFA. One or more project objectives are very likely to be achieved within the allotted time frame. Project Rationale and Feasibility - The rationale for specifically targeting LSC and leukemic cells to eradicate AML is strong, and the use of the proposed nanomicelle platform represents a clever extension of the applicant’s ongoing research. - Reviewers expressed mixed opinions about the validity of the LSC-targeting ligand. While one reviewer deemed it promising, others were skeptical, asserting that specificity of the target ligand to AML and LSCs is uncertain and no convincing data was provided to support the ligand as a robust target for LSCs in AML. - Much of the preclinical data provided to support this approach were obtained using different drugs and models than the ones to be developed and are therefore of questionable relevance for determining developmental readiness. - Reviewers considered the project plan to be overly aggressive for a four-year time frame. They recommended scaling goals back to IND-enabling preclinical studies and manufacture, as both sets of activities are likely to prove more involved and laborious than anticipated by the applicant. - Reviewers made the following suggestions to strengthen future submissions: Include greater discussion of potential mechanisms of drug resistance in AML with respect to the actual drug to be used; determine the release kinetics of the drug from nanomicelles, particularly for storage sterility and stability of clinical trial material for IND and eventual product; clarify efficacy of the actual product (specific ligand-nanomicelle- drug formulation) to be developed; provide more details on the clinical trial, including whether patients would receive standard of care in addition to the experimental treatment; discuss or consider duration of leukopenia as a potential safety issue. Principal Investigator (PI) and Planning Leader - The PI is a pioneer in combinatorial chemistry and nanotechnology with an extensive track record of publications and patents. He/she is an experienced basic and translational investigator and is well qualified to lead this effort. -The Planning Leader (PL) is scientifically qualified and has experience in conducting clinical trials and submitting INDs. However, he/she has a limited record of project management experience or leading a large group and keeping them on track. A reviewer recommended appointing a qualified industry-experienced project manager to assist the PL.
- This application scored below the initial scientific merit funding line, no programmatic reason to fund the application was proposed, and the GWG voted to place the application in Tier 3, Not Recommended for Funding.