# NextGen RNAi Delivery to Breast Tumors for Selective mTORC2 Blockade

> **NIH NIH R01** · VANDERBILT UNIVERSITY · 2020 · $450,319

## Abstract

Project Summary– Patients who receive the unfortunate diagnosis of triple negative breast cancer (TNBC)
have very poor therapeutic options and suffer from a high rate of post-surgery recurrence, metastasis, and
mortality due to this devastating disease. Recurrence occurs due chemotherapy-resistant cell survival after
drug treatment and surgery. Recurrent TNBCs are lethal, and no molecularly targeted therapies are approved
for these patients. Up to 40% of TNBC specimens collected from residual disease after chemotherapy have
genomic alterations that cause activation of the phosphatidyl inositol-3 kinase (PI3K) / mechanistic target of
rapamycin (mTOR) signaling axis, suggesting the crucial role of this pathway in TNBC chemotherapy
resistance and recurrence. Based on published data and our own preliminary data, we are especially
interested in therapeutic targeting of the mTOR kinase-containing complex mTORC2, which we believe is a
key node in this pathway that drives cell survival and drug resistance in TNBCs. However, there are no existing
drugs that selectively inhibit mTORC2, motivating the current proposal which his focused on development of
the first highly selective and potent nanomedicine inhibitor of mTORC2 for treating patients with TNBC. Our
central biological hypothesis (supported by our rigorous preliminary studies) is that selective mTORC2
inhibition, achieved in a way that spares mTORC1 signaling, will produce superior therapeutic response in
TNBCs relative to existing drugs that can inhibit mTORC1 but not mTORC2 or that nonspecifically block both
mTORC1 and mTORC2. The overall goal of this collaborative, multi-PI project is to optimize pharmacokinetics
of nanoparticle technology for effective delivery of mTORC2-targeting RNAi to TNBC tumors. We specifically
propose to test apply next generation nanocarrier surface chemistry and dual carrier/cargo hydrophobization
principles to yield an optimized, enabling technology for development of a previously inaccessible mTORC2-
selective therapeutic. The proposed project is uniquely accessible through the expertise of the multi-PI
interdisciplinary team with bioengineering expertise in polymeric nanotechnologies for intracellular biologic
drug delivery (Duvall), BC PI3K/mTOR signaling pathway therapeutics (Cook), and cutting edge preclinical
models of BC, including highly clinically-relevant patient derived xenograft (PDX) models (Brantley-Seiders).
The group’s interdisciplinary skillset will enable previously-inaccessible mTORC2 investigations and lead to
more effective therapies for TNBC patients. This advance will foster unprecedented studies of mTORC2 while
providing a novel strategy to treat PI3K/mTOR-driven TNBCs.

## Key facts

- **NIH application ID:** 9968175
- **Project number:** 5R01CA224241-03
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** DANA M BRANTLEY-SIEDERS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,319
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9968175

## Citation

> US National Institutes of Health, RePORTER application 9968175, NextGen RNAi Delivery to Breast Tumors for Selective mTORC2 Blockade (5R01CA224241-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9968175. Licensed CC0.

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