# PI3K/PTEN/Akt signaling and the genesis of cancer

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $467,549

## Abstract

This is the fourth competitive renewal of this grant application that was funded for the past 20
years. Over the years funding through this grant application led to several milestone observations
and new discoveries. In the current grant application, we will follow intriguing observations made
during the last period of funding. Our genetic studies in mice, using systemic deletion of Akt
isoforms after tumor onset, recapitulate some of the adverse effects observed in patients after
treatment with PI3K and Akt inhibitors such as hyperinsulinemia, and hyperglycemia, severe
diarrhea, and liver damage. Our studies in mice could therefore provide mechanistic explanations
for the adverse physiological consequences induced by PI3K and Akt inhibitors. Our results using
mouse models of breast cancer and inducible systemic deletion of Akt isoforms after tumor onset
to emulate drug therapy, suggest the followings: (i) Systemic Akt1 inhibition after tumor onset
reduces metastasis by inhibiting tumor associate and pro-metastatic neutrophils. This is relevant
to human breast cancer as high ratio of neutrophils to lymphocyte (NLR) is associated with worse
overall survival and disease-free survival. (ii) Neutrophils’ specific deletion of Akt1 is sufficient to
inhibit breast cancer metastasis. (iii) Specific Akt1 inhibitors could inhibit tumor progression and
metastasis of Her2 enriched, Luminal B, and triple negative breast cancer. (iv) Systemic Akt1
inhibition prohibits breast cancer metastasis regardless of primary tumor type (Akt1 specific
inhibitors should be developed). (v) Systemic Akt2 inhibition may not be beneficial for breast
cancer therapy because of increased circulating levels of insulin and hyperactivation of the other
Akt isoforms (drugs that inhibit Akt2 might be avoided). (vi) Pan-Akt inhibitors may not be effective
unless they don’t inhibit Akt2 activity to a high extent. In the first part of the current grant
application, we will investigate how tumor associated neutrophils are programmed by the tumors
both transcriptionally and metabolically and how Akt1 deficiency impairs their ability to promote
breast cancer metastasis. In the second part of the grant application will investigate
mechanistically the adverse effects induced by pan-Akt or Akt2 inhibition and how to alleviate
them. The long-term goal of this grant application is to establish the rationale for developing Akt1
specific inhibitors and enable the efficient use of Akt inhibitors for cancer and cancer metastasis
therapy.

## Key facts

- **NIH application ID:** 10587722
- **Project number:** 2R01CA090764-21
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Nissim Hay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $467,549
- **Award type:** 2
- **Project period:** 2001-03-01 → 2028-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10587722

## Citation

> US National Institutes of Health, RePORTER application 10587722, PI3K/PTEN/Akt signaling and the genesis of cancer (2R01CA090764-21). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10587722. Licensed CC0.

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