Early Translational IV
$5 110 388
Acute myeloid leukemia (AML) is the most common acute leukemia in adults with less than 30% of patients cured with current treatment. In most cases, AML cells arise from a group of specialized cells, named leukemia stem cells (LSC). LSC often survive conventional chemotherapy currently used in clinic, regenerate leukemia cells and cause a recurrence of the disease. We recently developed a small molecule that can recognize and bind to AML LSC. We also developed 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 LSC. In this project, we will covalently decorate the drug-loaded nanomicelle surface with the LSC-specific small molecules, enabling delivery of the drug specifically to LSC. In the patient’s body, these drug-loaded nanomicelles will work like “smart bombs”, and deliver a high concentration of chemotherapy drugs to LSC and kill these cells. Furthermore, the chemotherapy drug can be released from nanomicelles to patient’s blood and kill leukemia cells throughout the body. With these nanomicelles, both leukemia cells and LSC are killed, and leukemia can possibly be eradicated at its very root. In addition, formulation of chemotherapeutic drug into nanomicelles could significantly decrease the toxicity. This is clinically significant as 10-15% patients die from the toxicity of the chemotherapy they currently receive.
Statement of Benefit to California:
Leukemia is the 7th most common cause of cancer death in California. Acute myeloid leukemia (AML) is the most common cause of leukemia death. Over 70% of AML patients will die from this disease or treatment-related complications. These patients usually require costly and highly toxic chemotherapy at the inpatient setting. 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 can decrease treatment-related toxicity and 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. This project may have huge financial benefits to California. Several investigators of this research team have experience in commercializing their discoveries. Three patent applications related to this proposed therapeutics have already been filed. If this project is successful, we will consult the US Food and Drug Administration to bring this drug into clinical applications, and license the patents for commercial development.
The goal of this Development Candidate (DC) proposal is to optimize and characterize a nanomicelle designed to deliver a high concentration of a conventional chemotherapy drug, daunorubicin (DNR) to acute myeloid leukemia (AML) stem cells. AML is the most common acute leukemia in adults and has a high mortality rate with fewer than thirty percent of patients cured by current treatments. Ten to fifteen percent of patients die from the toxicity of standard chemotherapy. It is hypothesized that using a targeted delivery method will enable a higher dose of DNR to be delivered specifically to AML stem cells, with lower toxicity to the patient. In milestones 1-2, the applicant will optimize the molecular structure of the delivery nanomicelle to maximize stability in the circulation and rapid drug release inside targeted cells while minimizing the amount of targeting molecule needed on the nanomicelle surface. In milestones 3-4, the specificity of delivery by the targeted nanomicelle will be assessed using cell lines expressing the target and patient blood samples. Milestone 5 will focus on pharmacokinetic and toxicity studies, and milestone 6 will test efficacy using patient AML samples in a mouse model. Objective and Milestones - The objective and milestones are reasonable but lack success criteria and Go/No-go decision points. - The Target Product Profile is straightforward, but the rationale for how nanomicelles could target AML stem cells outside of the blood circulation was not compelling, nor was the rationale for delivery, dose and regimen. Rationale and Significance - There are currently other drugs in Phase 1 and Phase 2 that are using liposomal delivery of DNR and other chemotherapeutics for AML, so this is not a unique approach. - The pharmacokinetic advantages claimed for the nanomicelles are based on measurements of total drug, not drug available to cells. Similar liposomal formulations of DNR have not demonstrated major advantages in AML treatment. - There is no evidence that this approach would have a transformative effect on leukemia therapy. Feasibility and Design - The preliminary data show only incremental (~20%) improvement in AML stem cell killing in vitro with the targeted nanomicelles compared to the untargeted nanomicelles. - The assumption is that increased local concentration of DNR will increase effectiveness of killing AML stem cells, but there is no evidence of that presented. - The proposed delivery route of the therapeutic is intravenous, and it is not clear whether the drug-bearing nanomicelle would be able to exit the vasculature to get to the bone marrow where the AML stem cells presumably reside. - It is not clear whether the human targeted nanomicelle will cross-react with the mouse target, affecting the ability to do meaningful toxicity studies in mice. - The targeted protein is also expressed on normal dendritic cell subsets, thus there could be toxicity from this therapeutic due to killing of dendritic cells. - The possibility that AML stem cells express drug efflux pumps that cause them to be resistant to DNR was not addressed. - It was recommended that an in vivo assessment of DNR concentration in AML stem cells after administration of the targeted nanomicelles be done early to test the hypothesis that a high concentration can be achieved. Qualification of the PI (Co-PI, Partner PI, if applicable) and Research Team - The team is strong. The PI and co-PI are experts in micelle development and have multidisciplinary teams with expertise in all functional areas. - Both the PI and co-PI have strong track records of taking projects to IND development based on their own preclinical research. Collaborations, Assets, Resources and Environment - Adequate resources are available at the institution, and the institution expresses strong support for this project. Responsiveness to the RFA - There is no evidence presented that the proposed therapeutic is targeting cancer stem cells. Ideally, this would be done by demonstrating that treatment can cure already established disease and prevent transfer of the disease to a secondary recipient.