Defining Genetic Vulnerabilities in Pancreatic Neuroendocrine Tumors That Rely on the Alternative Lengthening of Telomeres Pathway
Abstract
Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of endocrine tumors that vary in clinical presentation, natural history, and prognosis, thereby making them a challenging disease to treat. While the majority of cancers maintain telomere lengths by expressing the enzyme telomerase, a subset of cancers maintains telomere lengths via another mechanism, termed Alternative Lengthening of Telomeres (ALT). ALT is cancer-specific and ALT telomeres are defined by dramatic cell-to-cell telomere length heterogeneity, increased chromosomal alterations, and increased replication stress. Our group previously identified a strong correlation between ALT-positive PanNETs and mutations in either ATRX or DAXX. While ALT is present in about 10% of all cancers, the prevalence skyrockets in certain cancer types, including gliomas, sarcomas, and PanNETs. Specifically, for PanNETs, ALT is present in 21%-31% primary tumors and then is greatly enriched in metastatic lesions (71%). PanNETs commonly escape current therapeutic strategies and can have a poor overall survival. Importantly, ALT can be readily detected in tissue samples, and we have previously demonstrated that the presence of ALT is associated with poor outcomes in patients. In summary, ALT (i) is cancer-specific, (ii) can be readily identified in patient samples, (iii) is associated with specific loss-of-function somatic mutations, and (iv) is enriched in aggressive PanNETs. Therefore, we believe ALT is an attractive target in PanNETs that could be exploited for novel therapeutic development to improve the clinical management of patients. We have identified oxidative phosphorylation as the most significantly altered pathway in ALT-positive PanNETs. Oxidative phosphorylation is a metabolic process that takes place in the mitochondria and creates energy for the cell. However, too much oxidative phosphorylation leads to an accumulation of reactive oxygen species within the cell that can cause DNA damage. Damage to telomeric DNA is thought to be a significant factor contributing to activation of the ALT pathway in cancers. Therefore, we hypothesize that increased oxidative stress may not only contribute to the development of ALT, but could be exploited therapeutically in the treatment of ALT-positive PanNETs. Thus, our proposal will directly address two of the fiscal year 2022 Rare Cancers Research Program Focus Areas. Specifically, for PanNETs, we will identify disease-defining molecular pathways, cell context, and microenvironment, as well as identify novel therapeutic strategies. Our overarching hypothesis is that the underlying molecular mechanisms unique to ALT can be exploited by forcing intolerable levels of oxidative stress, thereby allowing therapeutic targeting of a substantial proportion of primary and metastatic PanNETs. Thus, using a combination of human tissue-based and cell line-based approaches, we will: (i) Determine whether oxidative phosphorylation and mitochondrial DNA content are increased in ALT-positive PanNETs, (ii) Validate the presence of mitochondrial dysfunction and oxidative stress in PanNET tissues using a combination of immunohistochemistry and immunoprecipitation, and (iii) Evaluate the mechanistic and therapeutic efficacy of GPX4 inhibition, a peroxidase essential for antioxidant defense, to sensitize ALT-positive PanNETs. In the study proposed here, we will generate the necessary data needed to test this innovative hypothesis in PanNETs, facilitating the identification of new therapeutic leads for the clinical management of patients with ALT-positive PanNETs, which currently lack effective therapies. The data evaluating the response of these cells to intolerable levels of oxidative stress will generate strong support to further test whether inhibition of these pathways is effective as individual, or in combination, treatment modalities in ALT-positive PanNETs. Although clinical trials are underway to test th
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310819
Entities
People
- Christopher M Heaphy
Organizations
- Boston Medical Center
- United States Army