Pancreatic cancer remains the most lethal disease with no effective therapeutics. We have recently made conceptual advances in targeting signature genomic deletions, a hallmark of human cancers. We demonstrated earlier that passenger deletions could confer cancer cell specific vulnerabilities, which we termed ?Collateral Lethality?. We deployed this concept in targeting the SMAD4 deletion, which occurs frequently in pancreatic cancer, and have identified malic enzyme (ME) 3 as a target for collateral lethality in SMAD4-deleted pancreatic tumor cells harboring adjacent deletion of malic enzyme 2. We unexpectedly discovered that mitochondrial malic enzymes are required for the uptake of branched chain amino acids (BCAAs) in pancreatic cancer, which has been implicated as a diagnostic plasma marker for early detection of pancreatic cancer. Our overall goals are: to validate ME3 as a therapeutic target for pancreatic cancer in vitro and in PDX models (Aim 1) and in vivo using chimeric PDAC model (Aim 2); and to identify useful therapeutic agents that specifically target ME2 deleted cells (Aim 3). Our goals align well with the NCI directive on ?Scientific Framework for Pancreatic Ductal Adenocarcinoma.?

Public Health Relevance

Pancreatic cancer will soon become the second leading cause of cancer death behind only lung cancer. Using an innovative collateral lethality concept developed in our lab, we have identified novel targets for pancreatic cancer and plan to develop therapeutics against this deadly disease using tools proposed in this grant application.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA225955-03
Application #
9899100
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Forry, Suzanne L
Project Start
2018-04-09
Project End
2023-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Biology
Type
Hospitals
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030