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Harnessing Metabolic Dependencies in Pancreatic Cancer.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	Harnessing Metabolic Dependencies in Pancreatic Cancer./
Author:	Encarnacion Rosado, Joel.
Description:	1 online resource (166 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-09, Section: B.
Contained By:	Dissertations Abstracts International85-09B.
Subject:	Biology. -
Online resource:	click for full text (PQDT)
ISBN:	9798381730784

Harnessing Metabolic Dependencies in Pancreatic Cancer.
Encarnacion Rosado, Joel.

Harnessing Metabolic Dependencies in Pancreatic Cancer. - 1 online resource (166 pages)

Source: Dissertations Abstracts International, Volume: 85-09, Section: B.

Thesis (Ph.D.)--New York University, 2024.

Includes bibliographical references

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a 5-year survival rate of 11%. The tumor microenvironment (TME) of PDAC is characterized by excessive fibrosis and deposition of extracellular matrix, termed desmoplasia. This unique TME leads to high interstitial pressure, vascular collapse, and low nutrient and oxygen diffusion. Together, these factors contribute to the unique biology and therapeutic resistance of this deadly tumor. To thrive in this hostile environment, PDAC cells adapt using non-canonical metabolic pathways and rely on metabolic scavenging pathways such as autophagy and macropinocytosis. In this regard, we had two major goals in this work: (Aim 1) dissect the role of autophagy in pancreatic cancer metabolism and (Aim 2) target glutamine metabolism.In aim 1, we demonstrated that autophagy inhibition in PDAC alters mitochondrial function by losing succinate dehydrogenase complex iron sulfur subunit B (SDHB) expression by limiting the availability of the labile iron pool. PDAC uses autophagy to maintain iron homeostasis. This work highlights a critical link between autophagy, iron metabolism, and mitochondrial function that may have implications for PDAC progression. In aim 2, we demonstrated that treating PDAC cells with a Gln antagonist, 6-Diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in various in vivo models using DRP-104 (sirpiglenastat), a novel prodrug version of DON that was designed to circumvent DON associated toxicity. We found that ERK signaling is increased as a compensatory mechanism. Combinatorial treatment of DRP-104 and Trametinib led to a significant increase in survival in a syngeneic model PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a new therapeutic avenue for PDAC.In summary, our work demonstrated that targeting the metabolism of PDAC, either at the autophagy-lysosome level or broadly inhibiting metabolism through glutamine antagonism, mitigates the growth of PDAC tumors. Although encouraging, none of these approaches led to a tumor regression rather than a cytostatic response. We anticipate that understanding the interactions of PDAC tumors with the TME will provide new insights resulting in durable therapeutic responses.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381730784Subjects--Topical Terms:

599573
Biology.
Subjects--Index Terms:

AutophagyIndex Terms--Genre/Form:

554714
Electronic books.

Harnessing Metabolic Dependencies in Pancreatic Cancer.
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