Acute myeloid leukemia (AML) is a rare, fast-growing type of cancer, representing 1% of new cancer cases in the United States. People who develop AML have extremely poor outcomes, with relapse occurring in most people and few effective treatment options; therefore, new therapies are urgently needed to prolong survival and offer a better chance of a cure.
AML is a type of blood cancer that develops due to genetic mutations and changes in chromosomes that block the ability of immature immune cells called myeloblasts to fully mature. As a result, the immature cells cannot perform their normal role of fighting infection and disease, leading to symptoms such as fever, weakness and fatigue, loss of weight and appetite, bone pain, easy bruising and bleeding, and frequent infections. People who are living with AML often have different alterations in their genes that pose challenges for treatment and negatively impact outcomes.
Although a rare cancer, AML is the second-most common type of leukemia and causes the highest number of leukemia-associated deaths (Figure 1).
The prognosis for people living with AML is poor. In the United States, only approximately 30% of people with AML will be alive 5 years after diagnosis. The prognosis is even worse for people who redevelop the disease after an initial response or who are non-responsive to initial treatment (known as relapsed or refractory disease, R/R), with only 13% of patients alive at 5 years.
These poor outcomes are partly due to the complex nature of AML development and the numerous differences in the disease among people living with AML. Despite these differences, treatment for AML has generally been the same for the past several decades, and there are very few approved treatment options compared to other tumor types. Physicians recommend specific treatments according to the age of the patient, their health and wellness, and the types of genetic mutations and chromosomal alterations they have. People with AML who are eligible for intensive chemotherapy are initially treated with a strong chemotherapy regimen. The goal of treatment is to kill as many leukemia cells as possible to enable patients to achieve remission and undergo a stem cell transplant, which offers the best chance of a “cure.” Some people with AML may not be able to receive such intensive chemotherapy and may need to be treated with less-intensive options.
Over the past decade, scientists have improved their understanding of the molecular alterations associated with AML development and progression. This has led to several new treatment approaches that target these specific alterations; however, most patients develop drug resistance to these agents, followed by disease recurrence. This suggests that new drug targets and therapies are urgently needed to improve patient outcomes.
Since identifying the protein E-selectin as a key molecule regulating immune cell mobilization, scientists have become aware that E-selectin is also an important regulator of leukemia cell attachment to the endothelium (cells that line blood vessels), cell survival, and resistance to chemotherapy. This suggests that drugs that target E-selectin may be an effective therapeutic approach to fight this disease.
AML cells take advantage of the normal function of E-selectin to alter their surrounding environment and allow their continued growth and survival. The leukemia cells secrete proteins such as TNFα that stimulate the production of E-selectin on endothelial cells. The AML cells are able to bind to E-selectin, which allows them to “hide” in protective niches. This binding to E-selectin activates known pathways of chemoresistance (i.e. NfκB) that promote cancer cell survival. AML cells continue to survive in a dormant state despite treatment with intensive chemotherapy, ultimately resulting in disease resistance. These observations suggest that blocking the interaction between AML cells and E-selectin may inhibit cellular communication signals that promote survival, push the leukemia cells out of hiding, and overcome drug resistance.
To target the protective role of E-selectin, GlycoMimetics, Inc. developed uproleselan, a small molecule that mimics the structure of sialyl Lewisx, a carbohydrate that normally binds to E-selectin. Uproleselan binds to E-selectin, which prevents the normal interaction between E-selectin and sialyl Lewisx and the cellular processes controlled by E-selectin. It is believed that by binding to E-selectin, uproleselan pushes AML cells out of their protective environment, blocks cellular communication signals that promote survival, and sensitizes cancer cells to the toxic effects of chemotherapy. Success of early laboratory studies of uproleselan have led to promising results in an early clinical trial in participants with AML.