# The role of PI3K in pancreatic cancer genetics and progression

> **NIH VA I01** · NORTHPORT VA MEDICAL CENTER · 2020 · —

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the U.S.A.,
with a five-year survival rate of 4%. It is also a major cause of mortality among the VA patient population.
There is great urgency to identify new therapeutic strategies for PDAC because current treatments have little
impact on patient survival. More than 90% of PDACs have oncogenic mutations in the Kras gene. The
phosphoinositide 3-kinase p110α catalytic subunit (gene name Pik3ca) is a downstream effector of Kras. We
previously reported that pancreas-specific ablation of Pik3ca completely protected mice from oncogenic
KrasG12D-induced tumor formation. The current proposal investigates the role of Pik3ca after pancreatic tumors
have formed. Invasive KrasG12D and Trp53R172H (KPC) cells orthotopically implanted in the pancreas of
immunocompetent mice leads to rapid tumor progression and death of the host animal. However, when Pik3ca
was silenced, implanted KPC tumors completely regressed. Surprisingly, implanted Pik3ca-null KPC tumors
progressed and killed immunodeficient mice, but adoptive transfer of T lymphocytes completely protected the
mice from these tumors. Therefore, we hypothesize that inhibition of Pik3ca in the tumor cells, without
inhibiting PI3K signaling in the immune cells, will allow an immune-mediated regression of pancreatic cancer.
In Aim 1, we will investigate the signaling pathways and genetic profiles of Pik3ca-null versus parental KPC
cells to better understand the immunological changes caused by the knockout tumor cells. We will also
examine the host T-cell response to better understand how pancreatic tumors evade immune surveillance. In
Aim 2, we will assess the therapeutic potential of a strategy that inhibits p110α in pancreatic cancer cells
without inhibiting PI3K signaling in cytotoxic T lymphocytes. Successful completion of this proposal will
produce insights into PI3K-regulated mechanisms that allow PDAC to evade the immune system and progress
to a deadly disease. This understanding may allow future studies to elucidate the most appropriate means of
targeting Pik3ca signaling pathways in PDAC to improve therapy for this deadly cancer.

## Key facts

- **NIH application ID:** 9932277
- **Project number:** 5I01BX004083-03
- **Recipient organization:** NORTHPORT VA MEDICAL CENTER
- **Principal Investigator:** RICHARD Z LIN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932277

## Citation

> US National Institutes of Health, RePORTER application 9932277, The role of PI3K in pancreatic cancer genetics and progression (5I01BX004083-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932277. Licensed CC0.

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