Posted March 3, 2021

Dr. Raul Mostoslavsky, M.D., Ph.D., Massachusetts General Hospital Cancer Center

Pancreatic Ductal Adenocarcinoma (PDAC) is the most common form of pancreatic cancer affecting approximately 90% of patients and is extremely lethal with a 5-year survival rate of 5%-7%.¹ Most PDAC patients have cancerous tissue that is unresectable, locally advanced, or metastatic at the time of diagnosis.² PDAC’s aggressiveness, its ability to hide from the immune system, and general lack of early symptoms make it one of the most difficult and deadly cancers to treat. In addition, conventional treatments such as chemotherapy, surgery, and radiation have not significantly increased survivability.² Investigators in the field must elucidate the molecular mechanisms of PDAC to improve patient outcomes. With a Peer Reviewed Cancer Research Program FY16 Idea Award with Special Focus, Dr. Mostoslavsky investigated several pro-metastatic protein targets and their involvement in PDAC: SIRT6, Lin28b, and a novel glutathione transferase.

The oncofetal protein, Lin28b, is essential for PDAC to metastasize and invade other parts of the body. SIRT6 has several functions such as maintaining glucose homeostasis, the maintenance of genome stability, and suppression of cellular transformation.³ Dr. Mostoslavsky and his team looked at metastatic cell lines from both high and low expression levels of Lin28b and SIRT6 expression in genetically-engineered mouse models. They found that Lin28b expression in SIRT6 knock-out mice was still active independent of SIRT6 expression. They also determined that Lin28b potentially plays a role in metastatic initiation and outgrowth. A mutation in the SIRT6 gene can suppress its activity, causing fetal defects.⁴ It was also discovered that a similar mutation in SIRT6 upregulates tumor growth.³ These discoveries have opened the door for further investigation into the biology of PDAC.

Dr. Mostoslavsky and his team also studied the activity levels of a novel glutathione transferase they discovered in lung metastases as compared to primary lung tumors. Inhibiting expression of this enzyme had no effect on primary tumor growth; however, when shut down in lung metastases, growth was suppressed. The lab team found this same result with genetically-engineered mouse models of high and low SIRT6 expression comparing metastatic PDAC and primary tumors. These results suggest this novel enzyme may have a role in activating non-proliferating cells to become cancerous and metastatic. Dr. Mostoslavsky’s work on this novel target may lead the scientific community to understand more about suppressing further metastasis to vital organs.

The work being done in Dr. Mostoslavsky’s lab could potentially lead to a better understanding of pro-metastatic proteins in PDAC and the team has already begun to garner interest from industry partners looking to contribute to the development of Lin28b inhibitors for the treatment of PDAC. Dr. Mostoslavsky’s findings could lead to the development of new and effective therapeutics to suppress the spread of this lethal disease. With PDAC being one of the deadliest cancers in the US, the need for increased survivability would be a step in the right direction for patients and families.

References:

1. Adamska A, Domenichini A, and Falasca M. 2017. Pancreatic ductal adenocarcinoma: Current and evolving therapies. International Journal of Molecular Sciences 18(7):1338.

2. Sarantis P, Koustas E, and Papadimitropoulou A. 2020. Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy. World Journal of Gastrointestinal Oncology 12(2):173-181.

3. Kugel S, Sebastián C, Fitamant J., et al. 2016. SIRT6 suppresses pancreatic cancer through control of Lin28b. Cell 165(6):1401-1415.

4. Ferrer C, Alders M, and Postma A. 2018. An inactivating mutation in the histone deacetylase SIRT6 causes human perinatal lethality. Genes & Development 32(5‑6):373-388.

Link:

Public and Technical Abstracts:  SIRT6 Suppresses Pancreatic Cancer via the Oncofetal Protein Lin28b

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