# Rational Combination of MAP4K4 Inhibition and Immunotherapy in Pancreatic Cancer

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2021 · —

## Abstract

Summary/Abstract:
Pancreatic Ductal Adenocarcinoma (PDAC) remains remarkably lethal with a 5-year survival rate of less than
9%. Due to its widespread resistance to conventional therapy, PDAC is expected to be the second most common
cause of cancer-related death in the United States by 2030. Oncogenic KRAS mutations are nearly uniform in
PDAC, affecting over 90% of patients. The mutant KRAS is a key driver in the neoplastic phenotype, and leads
to hyper-activation of KRAS, permitting for sustained proliferation, the evasion of apoptosis, as well as facilitating
metastasis and the development of chemo-resistance. In spite of the importance of KRAS in PDAC pathobiology
and extensive research aimed at the discovery of RAS-directed therapeutics, there are no FDA-approved drugs
directed to target RAS; and RAS family proteins are largely considered `un-druggable'. Therefore, there is a need
to identify either alternative- druggable target(s) or better approaches in hopes of improving patient outcomes.
The inflammatory pathway is known to play significant roles in many cancer, including pancreatic cancer.
Number of reports suggest that there is a direct link between inflammation and pancreatic cancer. We identified
MLK3, a novel kinase that is activated by TNFα and plays role in pancreatic cancer pathogenesis. Recently we
identified an MLK3 upstream kinase, MAP4K4, which is also activated by TNFα, suggesting perhaps, TNFα-
MAP4K4-MLK3 axis might play a role in pancreatic cancer, which was corroborated by a recent report indicating
worst outcomes in PDAC patient with high expression of MAP4K4. Considering our observation, we treated
animal model of PDAC with a specific inhibitor of MAP4K4, GNE-495. Interestingly, the GNE-495 was able to
ameliorate PDAC in the pre-clinical animal model, a significant decrease in stroma and increased cell death in
cancerized ductal cells. Since immune cells play vital roles in cancer therapy, we examined peripheral immune
compartment that had no effect of GNE-495. We rationalized to treat animals with 4-1BB agonistic antibody to
activate effector T cells. The combined treatment of GNE-495 along with 4-1BB mab had profound effect on
animal survival and almost stroma/Desmoplasia was absent in tumors. The overall objective of this proposal is
to elucidate the role of MAP4K4 in PDAC and strategize a rational approach to combine MAP4K inhibitor and
immunotherapies to overcome pancreatic cancer. The central objective will be addressed by: (1) defining the
role of MAP4K4 in PDAC, (2) determining the impact of MAP4K4 inhibition in TME, and (3) determining impact
of MAP4K inhibition along with immunotherapy on host immunity.
Upon completion of these three aims, it is our expectation, that first, we will be able to establish the role of
MAP4K4 in PDAC. Second, we would establish clinical significance of targeting MAP4K4, along with
rationalized immunotherapy for an alternative pancreatic cancer treatment strategy.

## Key facts

- **NIH application ID:** 10013728
- **Project number:** 1I01BX004903-01A1
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** AJAY NMN RANA
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2020-10-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013728

## Citation

> US National Institutes of Health, RePORTER application 10013728, Rational Combination of MAP4K4 Inhibition and Immunotherapy in Pancreatic Cancer (1I01BX004903-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10013728. Licensed CC0.

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