City of Hope scientists have identified and developed two potent small molecules that appear to suppress tumor growth in multiple cancers even when other treatments cease to work, possibly due to the development of drug resistance. Called bisantrene and brequinar, these cancer inhibitor compounds target a protein known as “fat mass and obesity-associated protein.” Nicknamed FTO, the protein plays a critical role in cancer development and progression, primarily because it regulates cancer stem cells and immune evasion. In other words, FTO promotes the growth, self-renewal, metastasis and immune escape of cancer cells. THis because FTO is an enzyme regulating methylation events. Generally methylation is associated with DNA and proteins; FTO, instead promote leukemogenesis by regulating methylation of the other nucleic acid or RNA. Examples of FTO-high cancers include acute myeloid leukemia (AML), an aggressive brain cancer called glioblastoma, pancreatic cancer and breast cancer.
The study, published in the journal Cancer Cell on June 11, provides new insight into how cancer stem cells replenish and visibility into how cancer evades our immune system. It highlights the possibility that targeting FTO with potent inhibitors could eventually become a treatment for certain cancers. In the study, City of Hope scientists demonstrated that the two new FTO inhibitor compounds they created had potent anti-tumor effects and substantially improved overall survival in mice with AML or a solid tumor such as breast cancer. Jianjun Chen, PhD, the Simms/Mann Family Foundation Chair in Systems Biology at City of Hope, and corresponding author of the new study, stated: “The cancer inhibitors we developed are at least 10 times more effective in killing acute myeloid leukemia cells than several previously reported FTO inhibitors. In the near future, we should use these two compounds alone or in combination with other therapeutic agents such as targeted therapy, standard chemotherapy, immunotherapy or radiotherapy to treat patients with FTO-high cancers”.
An estimated 11,200 people are expected to die due to AML in 2020. The five-year survival rate is 29%, according to National Institutes of Health SEER data. Breast cancer is the second most common cancer among american women. Therefore, there is priority to find more selective therapies for these conditions. Chen and his colleagues saw the need to address these big problems; they have been conducting research on RNA modification in cancer for eight years and is a pioneer in this field — developing personalized treatments that will enable the practice of precision medicine. The lab team began working on bisanthrene and brequinar three years ago and they noted that many cancer patients either do not respond to treatments that are currently available such as chemotherapy, targeted therapy or immunotherapy, or that they responded to the therapeutics in the beginning but relapse later due to cancer-regenerating stem cells and the escape of cancer cells from our immune surveillance.
It turns out that modifying FTO or using small molecules to inhibit FTO interrupts the supply chain that enables cancer to develop and progress. Studies showed that treatment with a relatively low dose of bisantherne or brequinar (5 mg/kg/day 10 times every other day) could, at the very least, double the median survival in mouse models with AML. Bisantherne became more potent after researchers modified it letting it bypass certain barriers that do not like water-based molecules. Both drugs prevent FTO from connecting with target messenger RNAs, including cancer-causing genes c-Myc and C-EBPa, as well as immune checkpoint gene LILRB4. Because bisantrene and brequinar have been tested in multiple clinical trials under the guises of other objectives, Chen and his colleagues believe this basic research has access to a freeway entrance that will fast track it into clinical trials.
There are already molecules known to inhibit FTO: among these rhein, a natural compound from rhubarb; entacapone, an old antidepressant; and meclofenamic acid, one of the first NSAIDs that is not used much with this purpose. However, they do not show exclusive specificity for FTO. The National Institutes of Health (NIH) has already funded the next step: the Chen lab is working to further optimize the drugs to develop improved FTO inhibitor compounds that are more efficacious with minimal side effects for humans.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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