Leukemia Research Highlights

Overall Research Goals

  • Advance novel leukemia therapeutics from the lab to the clinic.
  • Develop precision-medicine treatment platforms for specific leukemia subtypes.
  • Dissect the biology and vulnerabilities of leukemic stem cells to understand and eradicate disease recurrence. 
  • Target the bone marrow  niche to eradicate leukemia and prevent relapse.

Research highlights 

  • Enhanced subtype profiling: While leukemia is typically classified as one of four major groups, it is actually a collection of over a hundred abnormalities that lead to uncontrolled cell growth. Our researchers are actively studying the key biological pathways of these subtypes and whether they have specific genetic or molecular targets to focus therapy on.
  • New therapies for relapsed/refractory disease for patients who have undergone and failed standard treatments. These clinical trials may include novel agents developed at City of Hope, or new combinations or regimens of already-approved therapies that may be more effective. Example 1: The laboratory of Guido Marcucci, M.D., in collaboration with Ya-Huei Kuo, Ph.D., Bin Zhang, M.D., Ph.D., Marcin Kortylewski, Ph.D, and Russell Rockne, Ph.D has demonstrated the biological and preclinical relevance of targeting micro RNA miR-126 in acute myeloid leukemia (AML). They have demonstrated the feasibility of miR-126 knock-down in vivo, utilizing a novel, cutting-edge oligonucleotide (ODN_-based CpG-anti-miRNA-126 (named MiRisten) that disrupts leukemia stem cell self-renewal. MiRisten alters the bone marrow environment to starve leukemia stem cells of the resources they need to grow. Preclinical research shows that miRisten is highly effective against relapsed or treatment-resistant AML This work is published (Zhang et al. Nature Communications, 2021) and is currently supported by an NCI R01CA205247. Marcucci and colleagues are currently investigating pharmacokinetic/ pharmacodynamic modeling to define the optimal dose and schedule of miRisten to be used in vivo in an upcoming clinical trial in AML patients at City of Hope. Example 2: Steven Rosen, M.D. and Vinod Pullarkat, M.D. are testing 8-chloro-adenosine for patients with relapsed/ treatment-resistant AML. This drug is a unique example of emerging therapies that are available exclusively at City of Hope. For the last decade, Dr. Rosen has pioneered the research of 8-chloro-adenosine, guiding this drug from the laboratory to the clinic. Preclinical work has demonstrated that 8-chloro-adenosine, in a number of solid tumors and blood cancers, may prove to be a promising drug with a unique mechanism of action. City of Hope has completed a first-in-human clinical trial of this new therapeutic approach in high­ risk AML. The phase 1 study evaluated the optimal dose of 8-chloro-adenosine as a single agent, and is now being combined with venetoclax in a follow-on phase 1 study in AML patients. 
  • Investigating "leukemia stem cells" that allow the disease to relapse and grow following cancer treatment. By better understanding the biology and weaknesses of these cancer stem cells, scientists and clinicians can develop better treatments that produce lasting cures. Example: The laboratory of Guido Marcucci, M.D., in collaboration with Bin Zhang, M.D., Ph.D, Marcin Kortylewski, Ph.D., Russell Rockne, Ph.D. and Ya-Huei Kuo, Ph.D. has discovered that miR-126 contributes to leukemia stem cell quiescence, self-renewal and resistance to tyrosine kinase inhibitor in BCR-ABL-driven chronic myeloid leukemia (CML) and that bone marrow endothelial cells are a critical supplier of miR-126 to the leukemia stem cells. They have designed an oligonucleotide (ODN)-based CpG-anti-miRNA-126 (named miRisten) which can effectively inhibit miRNA-126 in leukemia stem cells and endothelial cells in CML and AML. Their published studies (Zhang et al, Nature Medicine, 2018 and Zhang et al., Journal of Hematology and Oncology, 2021), supported by an NCI R01CA248475, establish miRisten as a promising therapeutic to target CML and AML leukemia stem cells.
  • Immunotherapies such as bispecific antibodies reprogram the patient’s T cells (a key part of the immune system) to selectively identify and kill cancer cells. These double-sided molecules attach to both T cells and cancer cells, effectively directing the T cells to seek out and destroy the cancer cells, without harming any surrounding healthy cells. To this end, the laboratory of Guido Marcucci, M.D. in collaboration with Bin Zhang, M.D. Ph.D. and John Williams, Ph.D. have created a bispecific antibody called IL1RAP-CD3, which directs the body’s T cells to destroy cancer-producing leukemia stem cells. Preliminary animal testing of this innovative therapy found that it eliminated 100% of leukemia stem cells. Based on this success, Dr. Marcucci and his colleagues are moving towards testing the drug in a first-in-human clinical trial for AML patients at City of Hope. 
  • Mathematical modeling of leukemia evolution to develop personalized numerical models that map the trajectory of a patient’s cancer and pinpoint the most effective treatments for leukemia and other cancers, at just the right moment. In modeling leukemia disease progression in patients over time by drawing data from a patient’s biopsies and scans, these powerful models can help physicians develop the most effective treatment plans for each patient before any therapy is administered, substantially reducing the risk of relapse. Example: Russell Rockne, Ph.D., in collaboration with Guido Marcucci, M.D. and Ya-Huei Kuo, Ph.D., have published their modeling of prediction of AML disease development (Rockne et al., Cancer Research, 2020), supported by an NCI U01CA250046. 
  • Understanding how leukemia cells hijack the translation machinery to allow high expression of short-lived oncoproteins is critical to develop effective therapies to treat this lethal blood disease. Example: The laboratory of Dr. Ling Li, Ph.D, in collaboration Jianjun Chen, Ph.D., Marcin Kortylewski, Ph.D., and Guido Marcucci, M.D. identified a novel regulatory axis in AML in which PRMT9 overexpression induced with eEF1A1 arginine methylation to promote AML cell maintenance. With NCI R01 CA248149 funding, they are evaluating the functions of PRMT9 activity and eEF1A1 arginine methylation in human AML patient specimens and genetic mouse models with a goal of developing novel AML therapies based on PRMT9 inhibition. 
  • Plant based medicine. Dr. Marcucci and his researchers are currently working in collaboration with partners in biopharma, investigating the unique properties of an exotic South American plant that shows truly remarkable cancer-fighting capabilities. The scientists have synthesized this plant into a novel medicine called OST-01. Dr. Marcucci and his team have been testing OST-01 in animals as a treatment for AML and other cancers. OST-01 specifically targets cancer cells and attacks their metabolic and protein-producing machinery, destroying the cancer cells without damaging surrounding healthy tissue. The end result is a marked regression of cancer, with no discernable side effects. In a particularly encouraging follow-up study, Dr. Marcucci found that directly injecting OST-01 into tumor sites led to the rapid shrinking of these cancerous growths. Additional research has shown that OST-01 has the potential to be just as effective against triple negative breast cancer, pancreatic cancer and numerous other cancers as well. Based on the exceptional performance of OST-01, Dr. Marcucci and his colleagues are seeking to advance clinical trials with human patients, to further explore the drug’s cancer-killing abilities and generate powerful new therapies for AML and many other deadly cancers.