Defining novel redox stress mechanisms to inhibit kras-driven pancreatic ductal adenocarcinoma

Active Project Grant Awarded Last action

Award ID
F31CA288141
Recipient
Awarding agency
Obligated
$197,600

Award facts

Assistance listing
93.398 Cancer Research Manpower
Completion date 67% complete
Place of performance
Miami, FL 33136, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Pancreatic ductal adenocarcinoma (pdac) is a leading cause of cancer deaths with a 5-year survival rate of 12%. Over 90% of pdac is driven by oncogenic kras, however inhibitors targeting kras have been unsuccessful in the clinic thus far. Targeting oncogenic vulnerabilities is a key alternative approach. Oncogenic RAS-generated reactive oxygen species (ROS) drives tumor progression through hyperactivation of proliferative, anti-apoptotic, and metastatic pathways. However, ROS can also trigger tumor suppressive outcomes through cellular damage. The nucleotide pool-cleansing 8-OXO-dgtpase mutt homolog 1 (MTH1) is a critical redox protective adaptation in RAS-driven tumor cells to overcome tumor-inhibitory ROS mediated consequences. MTH1 has been shown to prevent oncogene-induced oxidative stress and damage, and maintain high kras oncoprotein expression, associated ROS-driven oncogenic signaling, and tumorigenicity in lung cancer. Given the importance of MTH1 in kras oncogenic biology and the fact that over 90% of pdac is driven by oncogenic kras, i propose that MTH1 is similarly important in pdac. In support of this idea, tcga analysis revealed MTH1 expression is significantly higher in tumor tissue compared to normal tissue, and high MTH1 significantly correlates with poor disease-free survival. The RAI lab reported 8-oxodgtpase activity is significantly elevated in patient pdac tumor VS. Normal tissue. Preliminary data show MTH1 loss reduces tumor burden in a subset of PKT cohorts, with lower burden associated with both reduced intratumoral egfr expression and in cytokines associated with an immunosuppressive tumor microenvironment (TME). When MTH1 is depleted via shrna in pdac cell lines, there is a significant decrease in proliferation associated with decreased total egfr. Analysis of human pdac tumor data through timer 2.0 shows intratumoral MTH1 expression significantly correlates with infiltration of myeloid derived suppressor cells (mdscs), suggesting high MTH1 expression supports and/or creates the immunosuppressive TME that make pdac so difficult to treat. Therefor i hypothesize MTH1 is important for pdac tumorigenesis through both tumor cell-intrinsic as well as previously-unappreciated extrinsic mechanisms. To test this hypothesis, i will use our novel PKT mouse models with systemic and pancreas-specific MTH1 loss. Experiments proposed in aim 1 will assess how systemic VS pancreas-specific MTH1 loss affects in vivo kras tumorigenesis; aim 2 will independently ascertain how MTH1 regulates kras- driven transformation and pdac chemoresistance. Upon completion of these studies, we will establish novel mechanisms by which MTH1 regulates tumorigenesis thus filling a GAP in the field regarding the link between MTH1 and kras in pdac. Lastly, these aims have the potential to validate MTH1 as an alternative to targeting oncogenic kras in pdac patients which has been unsuccessful to date.

Transactions

Action Obligated Date
Amendment $50,114
Amendment $49,538
Amendment $48,974
Amendment $48,974
Original award $0

Quick answers

Who received award F31CA288141?

F31CA288141 was awarded to University Of Miami by National Cancer Institute (National Institutes of Health) on January 30, 2025.

How much is award F31CA288141 worth?

$197,600 has been obligated on F31CA288141.

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