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Fox Chase Researchers Find New Possible Drug Target Using Pathway Involved in Tumor Development
PHILADELPHIA (June 23, 2022)—Fox Chase Cancer Center researchers have shown in a recent study that taking a new approach to targeting a well-established cancer-promoting pathway may be effective in stopping the progression of certain cancers.
Ras/mitogen-activated protein kinase (MAPK) is a signaling pathway activated in most human cancers. Kinases are proteins that take a phosphate and add it to another molecule in order to change the function of that molecule or prolong its life.
“You can think of a kinase as having two parts. The first part is what it uses to find its prey and the second is how it transfers phosphate to that prey. Most attempts to block the Ras/MAPK cancer-driving pathway have focused on blocking the phosphate transfer process,” said David Wiest, PhD, lead author on the study and co-leader of the Blood Cell Development and Function research program at Fox Chase. Wiest, who is also the Scientific Director of the Research Institute at Fox Chase, conducted the study with other researchers at Fox Chase, Temple University, the Lewis Katz School of Medicine at Temple University, and other research centers.
“The Ras/MAPK cascade enables a cell to sense what is outside and respond to changes like exposure to factors that promote the cell to grow. One component of this pathway is the extracellular signal-regulated kinase, or ERK. Specifically, ERK2 has three important domains. It has an active site that it uses to transfer phosphate and then it has two faces on the left and right side that are used to find two different sets of prey to which phosphate is transferred,” said Wiest.
His lab showed that in normal immune cells, these faces have two separate functions, something which led naturally to their curiosity about the roles of these faces in cancer. They reasoned that if the two faces performed opposing roles in cancer, then blocking the active site would reduce both roles and perhaps be less effective in stopping cancer progression.
They tested this using a model of cancer called polycythemia vera (PV), a rare type of blood cancer in which too many red blood cells are produced. In PV, they determined that the right side domain of ERK2, termed the DBP domain, actually antagonized disease progression, because blocking its function made cancer worse. But the left side domain functioned to promote cancer, since blocking its function using drugs was effective in slowing cancer progression or even killing it.
“So we can think of the D domain that promotes progression as the ‘gas pedal’ and the DBP domain that stops progression as the ‘brake pedal,’” said Wiest.
“This is really the first time someone has used genetic approaches to show the opposing activities of ERK2 in cancer, that one molecule had modular functions that were directed in opposite directions,” he added.
Wiest said he and his colleagues believe that targeting the function of ERK2-D is a better therapeutic strategy than current methods because they have shown in mouse models that targeting this domain effectively reduced disease progression. Their strategy in the future will be to develop potent inhibitors of the D domain in order to direct all of the kinase activity towards its braking activity.
The study, “The ERK2 DBP Domain Opposes Pathogenesis of a JAK2V617F-Driven Myeloproliferative Neoplasm,” was published in the journal Blood.
Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase is also one of just 10 members of the Alliance of Dedicated Cancer Centers. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence five consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.
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