The Role of LIN28B-let-7-PBK Axis on the Growth and Metastasis of Group 3 Medulloblastoma

Institution: 

Emory University

Researcher(s): 

Shubin Shahab, MD/PhD

Grant Type: 

Young Investigator Grants

Year Awarded: 

2021

Type of Childhood Cancer: 

Medulloblastoma

Medulloblastoma (MB) is the most common cancerous brain tumor in children and is often fatal. The most aggressive MBs, those designated as Group 3 (G3), often present with metastasis and frequently recur after standard therapy. The pathways that contribute to this aggressive behavior are poorly understood. LIN28B is a protein known to promote the aggressive nature of many cancers. We have recently found that LIN28B levels are high in some G3 MB patients, and that this is associated with worse outcome, suggesting a similar role in this brain tumor. In preliminary experiments, we have found that reducing the levels of LIN28B and PBK, a protein regulated by LIN28B, in G3 MB cells causes them to divide slower; while, increasing the level of LIN28B makes these cells divide faster. LIN28B also regulates the levels of a set of microRNAs that in turn are important regulators of cancer. In this case, we find LIN28B regulating a microRNA let-7 that regulates PBK. In addition LIN28B may also be contributing to the ability of G3 MB cells to metastasize through its effects on PBK and let-7 and other proteins/RNAs. These experiments suggest that LIN28B and proteins/RNAs regulated by it may be involved in the development of G3 MBs, and that targeting these proteins may offer a new approach to treating this disease.

Project Update 2024:

Medulloblastoma, the most common malignant brain tumor in children, was divided about a decade ago into four major molecular subgroups. However, the treatment paradigm has not significantly changed and for the patients with the most aggressive subtype, those classified as Group 3, the survival rates remain less than 60%. There is a need to develop better targeted approaches to treat these patients. We have recently published a paper suggesting the developmental protein LIN28B regulates Group 3 MB growth. Here we explore the LIN28B-let-7-PBK pathway that we believe is playing a major role in G3 MB development. Using RNA sequencing we have now identified the major mechanisms regulated by LIN28B in Group 3 medulloblastoma. We are currently validating some of these mechanisms and investigating ways to exploit these mechanisms to help treat this type of cancer. We have also obtained data showing that a drug targeting this pathway can be combined with an existing drug being used in clinical trials in medulloblastoma to increase their efficacy.