ORCID ID
Graduation Date
Spring 5-10-2025
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Programs
Cancer Research
First Advisor
Dr. R. Katherine Hyde
Abstract
Acute leukemias are highly heterogenous blood cancers with current frontline treatment regimens relying on traditional chemotherapeutics such as cytarabine, doxorubicin, and vincristine. These drugs are critically limited by their poor tolerance with significant side effects and inability to cure all patients. Recent efforts have focused on targeting specific mutations with designer small molecule inhibitors, but the inhibitor’s utility is limited to the subset of patients with the mutation and is also unable to cure the disease. A drug that not only has anti-leukemic effects all by itself, but can also modularly target different mutations, could significantly improve outcomes.
The class of polymeric drugs, called PAMDs, could be such therapeutics. PAMDs are polymers synthesized from the CXCR4 inhibitor AMD3100 (Plerixafor) that can form nanoparticles with nucleic acids. Previous work examining one variant, PAMD-Ch17 with cholesterol modifications, in AML showed that the drug can not only deliver siRNAs against key oncogenes to induce leukemia cell death, but can also kill leukemia cells by itself. These results imply that PAMD-Ch17 could be a powerful, modular anti-leukemic agent. Investigating its mechanism of action will be critical to developing this class of drugs for patients.
We therefore further investigated this novel cytotoxicity and found that PAMD-Ch17 is cytotoxic against both myeloid and lymphoblastic acute leukemia cells. Curiously, while it inhibits its target receptor CXCR4, it does not mediate its effects through the receptor. Rather, whole transcriptome sequencing suggested that PAMD-Ch17 mediated its anti-leukemic effects through mitochondrial dysfunction. We subsequently showed that PAMD-Ch17 colocalized to the mitochondria, induced mitochondria superoxide, loss of membrane potential, and mitochondrial dysfunction. We confirmed these findings in mouse primary T-ALL cells and human primary T-ALL cells, and that these effects are significantly less in healthy mouse and human hematopoietic cells. Thus, PAMD-Ch17 may be mediating its selective anti-leukemic effects through a mitochondrial dysfunction mechanism. For the first time, we provide a potential mechanism of action for this drug’s novel anti-leukemic effects and show that these effects are independent of its target receptor, while simultaneously highlighting a metabolic vulnerability in leukemia. Our study not only provides a strong rationale for preclinical studies, but also insight into leukemia metabolism and developing the next generation of polymeric drugs as well.
Recommended Citation
Lam, Calvin, "Elucidating the Mechanism of the Polymeric Drug PAMD-CH17’S Novel Anti-Leukemic Effects" (2025). Theses & Dissertations. 907.
https://digitalcommons.unmc.edu/etd/907
Included in
Biochemistry Commons, Medicinal Chemistry and Pharmaceutics Commons, Molecular Biology Commons
Comments
2025 Copyright, the authors