Acute myeloid leukemia (AML) is a particularly aggressive disease that develops when cells in the bone marrow turn into cancerous blood cells. Even when chemotherapy or other treatments kill leukemic cells circulating in the blood, the cancerous stem cells can linger in the bone marrow, enabling the disease to re-emerge.
With support of internal seed funding, an interdisciplinary team of chemists, biomedical engineers, and basic scientists at the University of Rochester report progress in targeting and destroying these leukemic stem cells with a modified form of micheliolide, a natural product found in plants of the magnolia family.
Targeting cancer stem cells with micheliolide analogs:
1) Various cancer fighting drugs (analogs) are made from a parent drug, micheliolide.
2) These drugs (analogs) are individually placed into nanoparticles (blue objects).
3) Drug-loaded nanoparticles go through various screening steps to select a lead drug that will perform best against this particular cancer. Those not chosen are removed.
4) A bone targeting ligand is added to the nanoparticle loaded with the lead drug to aid in direct targeting of the bone marrow.
5) The drug-loaded bone-targeting nanoparticles are then introduced to the cancer model or patient.
6) The targeting ligand attaches the drug-loaded nanoparticle directly to proteins on the surface of bone and delivers the drug to the bone marrow.
Image credit: University of Rochester illustration / Michael Osadciw
This compound, part of the chemical arsenals that plants use to keep predators from chewing on their leaves, possesses cytotoxic activity against AML cells and leukemia stem cells. This activity was improved via modifications of the molecule by the Rochester team. These improved semisynthetic micheliolide “analogs” were then packaged in polymeric nanoparticles designed to deliver the toxic chemical specifically to the bone marrow, without causing dangerous side effects to other organs.
“The overall goal is to be able to selectively target and kill cancer stem cells in the bone marrow. In combination with chemotherapy, this system could provide a means to kill both the mature cancer cells in the blood and the cancer stem cells in the marrow,” says Rudi Fasan, the Andrew S. Kende Professor of Chemistry and a co-corresponding author of a paper in Advanced Therapeutics describing the research.
Along with Fasan, Danielle Benoit, professor of biomedical engineering and director of the University’s Materials Science Program, and Benjamin Frisch, assistant professor of pathology and laboratory medicine and a Wilmot Cancer Institute investigator, are the key partners in this collaborative project launched with support of a University Research Award. The collaboration reflects the enhanced opportunities for research resulting from the close proximity of the University’s Medical Center and its science and engineering facilities at the River Campus.
Three labs, three synergistic roles
Fasan’s lab, which specializes in developing novel ways to synthesize and discover new biologically active compounds, has been investigating a class of plant-derived natural products called sesquiterpene lactones, which display a broad range of biological activities including anti-inflammatory, anticancer, and antimalarial activity. These studies led him and his students, including coauthor and former PhD student Hanan Alwaseem, now a scientist at Rockefeller University, to the identification of micheliolide as a promising starting point for the development of antileukemic agents.
To boost micheliolide’s modest anticancer potency, the lab employed a novel approach it has developed over the past years, using engineered cytochrome P450 enzymes, to selectively oxidize key positions on the molecule’s structure. This strategy created “handles” useful to further modify the molecule with traditional chemical means enabling the creation of new and improved analogs of the natural product.
The Benoit Lab, which develops therapeutic biomaterials for tissue regeneration and targeted drug delivery, created the nanoparticle delivery system. Lead author Marian Ackun-Farmmer ’20 (PhD), a former graduate student in Benoit’s lab and now a postdoc at the University of Maryland, says the delivery system combines polymer strands that include both hydrophobic (water repellent) and hydrophilic (water attracting) components.
The micheliolide analogs attach to the hydrophobic components, which load inside the nanoparticle, while the hydrophilic components on the outer surface help maintain nanoparticles within the blood stream to carry drugs to their target. The Benoit lab also added a peptide that targets the nanoparticle specifically to bone marrow. The nanoparticles—less than 100 nanometers in size—show a “robust” ratio of drug load to nanoparticle volume of 20 percent.
The Frisch Lab focuses on models of leukemia, and how leukemic cells affect the bone marrow in which they reside. “My lab is interested in how these leukemic cells and stem cells interact with the bone marrow environment, in ways that support the leukemia, but also in ways that are a detriment to normal blood cell production,” Frisch says.
A mouse model from the lab enabled the researchers to test the potency of the micheliolide analogs and the ability of the nanoparticle drug delivery system to navigate the microenvironment of the bone marrow.
Progress, but more to be done before clinical trials
There is still a lot of work to be done before the system can be tested in clinical trials, say the researchers. Though the system has shown promising capacity to kill leukemic stem cells, treating AML requires an approach that combines killing the leukemic stem cells with restoring the bone marrow microenvironment, which is disrupted by the presence of cancerous cells, Ackun-Farmmer says.
Moreover, the mouse model used so far replicates a very aggressive form of leukemia.
The researchers plan to use other mouse models from the Frisch lab that will enable longer periods of observation, which in turn will help them better understand how to increase the potency of the micheliolide analogs and hone the accuracy of the nanoparticle delivery system as it navigates the microenvironment within the bone marrow.
“Down the line we also plan to test this system with what are called patient-derived xenografts,” Frisch says. “Using a primary sample from AML patients grown in immune compromised mice allows you test the efficacy of your therapy on human tissue” before involving humans in clinical trials.
Nonetheless, the progress achieved so far demonstrates the value of the initial internal seed funding that made the project possible, the researchers say.
“The beauty of this project, and the purpose of the University Research Award mechanism, is that it enabled a very synergistic combination of the expertise from our three groups,” Fasan says.
“If the Medical Center wasn’t so close to the River Campus and the Departments of Chemistry and Biomedical Engineering, I wouldn’t be able to go to them for the tools that really drive my research forward, and vice versa,” Frisch adds. “It’s a mutually beneficial situation.”
Source: University of Rochester