# The role of mTORC2 in reprogramming cancer cell metabolism

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $291,352

## Abstract

The role of mTORC2 in cancer cell metabolism
PROJECT SUMMARY
Metabolic reprogramming is a hallmark of cancer. Mutations in growth factor receptor signaling pathways
promote tumor growth by altering the uptake and utilization of nutrients. De novo synthesis of lipids is a critical
aspect of this process, providing necessary lipids
for membrane biogenesis and signal transduction.
Currently,
there is a major gap in our knowledge about how oncogenic signaling regulates the synthesis of specific
lipids to cause tumor growth, and by what mechanisms.
this RO1 grant (NS 73831), we have demonstrated that
Through studies supported by the first five years of
the mechanistic target of rapamycin (mTORC2), a
critical mediator of growth factor receptor signaling, reprograms tumor cellular metabolism, potently stimulating
the growth of the highly lethal brain cancer glioblastoma (GBM) and causing resistance to almost all current
treatments. Specifically, our preliminary studies indicate that mTORC2 drives nutrient flux into lipogenic
pathways and boosts the synthesis of specific lipids to drive tumor growth by regulating the levels and/or
activities of key rate limiting enzymes. These data reveal a landscape of new, potentially druggable targets.
However, before these mechanisms can be applied to inform the development of new therapies, a number of
urgent questions must be answered. How does mTORC2 regulate GBM nutrient uptake and utilization and
shift it towards the synthesis of specific lipids in cancer? What are the signaling, biochemical and
transcriptional mechanisms and how do they drive tumor growth and drug resistance? Are they druggable?
This proposal is designed to test the hypothesis that mTORC2 promotes GBM growth and drug resistance by
driving lipogenesis and remodeling the composition of specific signaling lipids. Our goal is to understand the
mechanisms most critical for breaking down a major barrier to developing more effective treatments. In aim 1,
we propose a set of experiments that will extend our metabolic analyses into patient-derived GBMs in vivo, to
determine how mTORC2 controls the synthesis of specific phospholipids and sphingolipids to drive GBM
growth and drug resistance, and to identify the signaling, biochemical and transcriptional mechanisms by which
mTORC2 controls the key enzymes that regulate this process. In aim 2, we will determine how mTORC2
controls the uptake and utilization of nutrients towards the synthesis of these specific lipids. In aim 3, we will
identify and develop CNS-penetrant small molecules that target mTORC2-dependent metabolic
reprogramming and evaluate their therapeutic potential. The proposed studies will generate a deeper
understanding of the role of mTORC2 in cancer cell metabolism and will generate a landscape of previously
unappreciated metabolic vulnerabilities that can be targeted by brain penetrant compounds, potentially leading
to better GBM treatments

## Key facts

- **NIH application ID:** 10406763
- **Project number:** 7R01NS073831-13
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** PAUL S MISCHEL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $291,352
- **Award type:** 7
- **Project period:** 2011-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10406763

## Citation

> US National Institutes of Health, RePORTER application 10406763, The role of mTORC2 in reprogramming cancer cell metabolism (7R01NS073831-13). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10406763. Licensed CC0.

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