# Research Career Scientist Award

> **NIH VA IK6** · JESSE BROWN VA MEDICAL CENTER · 2023 · —

## Abstract

Cancer cells reprogram their metabolism to fuel anabolic processes required for their proliferation and survival.
One way by which cancer cells reprogram metabolism is by hijacking the evolutionarily conserved metabolic
function of the PI3K/Akt/mTORC1 signaling pathway. Another way is by markedly elevating the expression of the
hexokinase isoform, HK2, which catalyzes the first committed step in glucose metabolism. The long-term goal of
this grant application is to overcome challenges in targeting cancer metabolism and Akt for cancer therapy.
Although cancer cells can be selectively detected because of their high glucose metabolism (FDG-PET scan),
exploiting this property for selective targeting is challenging because interference with glucose metabolism could
have adverse consequences. We overcame this roadblock by showing that hexokinase 2, which catalyzes the
first committed step in glycolysis, and is selectively expressed in cancer cells, can be systemically deleted in mice
without any adverse consequences. The proposal is based on findings made in my laboratory at the cellular and
organismal levels, and address the following paradigm shifts: (i) Germ-line deletion of hexokinase 2, which is
markedly elevated in cancer cells, is embryonic lethal. However, we found that its systemic deletion in adult mice
is well tolerated, and therapeutic in several mouse models of cancer. This grant application will specifically
address the role of hexokinase 2 in metastasis. We will investigate the role of hexokinase 2 in EMT and
metastasis through a novel mechanism. (ii) Akt is perhaps the most frequently activated oncoprotein in human
cancer. However, we found that, paradoxically, hepatic deletion of Akt1 and Akt2 in mice induces liver injury,
inflammation, and early onset of hepatocellular carcinoma. We will determine how the HCC cells survive and
proliferate in the absence of Akt. (iii) We found that systemic deletion of Akt1 and Akt2 in adult mice elicits rapid
mortality, and that Akt2 deficiency in mice could be pro-tumorigenic and increased metastasis of chemically-
induced HCC, possibly because of hyperinsulinemia. Therefore, we launched a comprehensive approach in which
Akt1 or Akt2 or both can be conditionally deleted either in a cell autonomous manner or systemically, after tumor
onset, to follow tumor growth and metastasis. Our findings showed marked and unexpected differences between
cell autonomous versus systemic deletions of Akt isoforms with respect to tumor initiation and progression. (iv)
The inhibition of AMPK is considered pro-tumorigenic. Paradoxically, we found that AMPK activation is required
for cell survival during solid tumor formation and possibly metastasis. We will delineate the role of AMPK during
metastasis in human cells and mouse models of breast and prostate cancer. We anticipate that the proposed
studies will uncover new mechanisms of tumorigenesis associated with cancer metabolism, yield strategies that
exploit cancer met...

## Key facts

- **NIH application ID:** 10618282
- **Project number:** 5IK6BX004602-05
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Nissim Hay
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10618282

## Citation

> US National Institutes of Health, RePORTER application 10618282, Research Career Scientist Award (5IK6BX004602-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10618282. Licensed CC0.

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