Researchers at the UNC Lineberger Comprehensive Cancer Center have discovered a hyperactive cell signal that contributes to tumor growth in an aggressive blood cancer. They also developed an experimental therapeutic to block the signal and slow tumor growth. The researchers reported in the journal PNAS they identified a novel therapeutic target for primary effusion lymphoma, a type of non-Hodgkin lymphoma caused by infection with the Kaposi’s sarcoma-associated virus, also known as human herpesvirus-8 (HHV-8). Primary effusion lymphoma is a highly aggressive subtype of non-Hodgkin lymphoma, a type of blood cancer involving abnormally growing white blood cells. Patients with primary effusion lymphoma have a poor prognosis with a median survival time of approximately six months post-diagnosis. Since current treatment options can be ineffective, finding new therapeutic targets is a high priority. UNC Lineberger’s Blossom Damania, PhD, vice Dean for research in the UNC School of Medicine, Distinguished Professor of Microbiology and Immunology, and co-director of the UNC Lineberger Virology and Global Oncology programs, stated: “We found a receptor called Tyro3 that’s highly upregulated and expressed in a subtype of non-Hodgkin lymphoma, called primary effusion lymphoma. We also developed a compound that targeted Tyro3, and we found that it killed primary effusion lymphoma cells and tumors”.
TYRO3 is a member of the TAM (TYRO3, AXL, MERTK) family of transmembrane receptor tyrosine kinases, which share overlapping functions in carcinogenesis and suppression of anti-tumor immunity. TYRO3 was independently cloned by numerous research groups and as a result, has been called by many names, including TYRO3, SKY, RSE, BYK and TIF in humans, Dtk, Rse, Brt, Etk2 and Tyro3 in mice, and REK in chickens. TYRO3 is physiologically expressed in a variety of tissues and is most prominent in the nervous system. In the hematopoietic system, TYRO3 is expressed in dendritic cells, natural killer cells, monocytes and macrophages, platelets and megakaryocytes and osteoclasts. Expression of TYRO3 has been noted in a variety of tumors, including breast cancer, lung cancer, colon cancer, liver cancer, thyroid cancer, melanoma, endometrial cancer, multiple myeloma and several leukemia subtypes. In hematologic malignancies, approximately half of acute myeloid leukemia (AML) patient samples expressed TYRO3. This receptor was also expressed in B and T-cell acute lymphoblastic leukemia (ALL) cell lines and chronic lymphocytic leukemia patient samples. Finally, several studies have implicated roles for TYRO3 in oncogenic phenotypes related to metastasis. Lymphomas, like most types of neoplastic cells, utilize growth factor receptors to enhance their intrinsic oncogenic potential and cell replication.
In their recent study, Damania and her colleagues searched for cell signals called kinases that were hyperactive in primary effusion lymphoma, as well as in other types of non-Hodgkin lymphoma. They collaborated with UNC Lineberger’s Gary Johnson, PhD, Kenan Distinguished Professor in the UNC School of Medicine, to characterize the activity of the kinase signals in the cancer cells. Kinases help to control cell signaling, telling cells to grow and divide. Their studies showed that Tyro3 kinase was uniquely hyperactive in primary effusion lymphoma cells compared with normal cells, and they found it could activate a pathway that promotes the cancer’s survival, the PI3K/PKB signaling cascade. When they treated the cells with a compound they developed, UNC3810A, they saw a dose-dependent activation of cell death and significant suppression of tumor growth. The compound was developed in the lab of Dr. Xiaodong Wang, PhD, research associate professor in the UNC Eshelman School of Pharmacy and Medicinal chemistry director of the UNC Center for Integrative Chemical Biology and Drug Discovery. He said: “UNC3810A was used as an in vivo tool compound to understand the biological roles of Tyro3 in primary effusion lymphoma in this study. The work towards optimizing UNC3810A to preclinical candidate will be continued in my lab”.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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