# Fate and efficacy of targeted therapies for metastatic tumors

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2020 · $387,917

## Abstract

ABSTRACT
Patients with advanced breast cancer have a high propensity to metastasize to the brain with human epidermal
growth factor receptor (EGFR) positive and triple-negative breast cancer (TNBC; estrogen receptor, progesterone
receptor and Her2 negative) subtypes showing the highest incidence of brain metastases. Most patients have
multiple metastatic lesions at the time of diagnosis making surgery an inadequate therapeutic option on its own.
Furthermore, impaired cognitive decline induced by whole-brain radiation therapy (WBRT) and the tight blood brain
barrier (BBB) preventing the brain permeability of systemic therapies in the brain pose challenges for the success of
existing therapies and result in failure to improve overall patient survival. To effectively treat multiple highly
aggressive breast metastatic foci in the brain, there is an urgent need to develop tumor specific multi-targeting
agents that simultaneously target multiple aberrant signaling pathways in TNBC and utilize delivery vehicles which
specifically seek metastatic foci in the brain. In our previously published and preliminary studies, we have 1)
extensively demonstrated that engineered human and mouse neural stem cells (NSC) and mesenchymal stem cells
(MSC) home extensively to primary and metastatic tumors in the brain and provide on-site means to deliver novel
tumor specific agents; and 2) engineered EGFR-specific nanobodies (ENb) and their pro-apoptotic variant, bi-
functional ENb-TRAIL and shown its potential to target both cell proliferation and death pathways in a mechanism
based manner in broad spectrum of tumor cells. The long term goal of this proposal is to test the mechanism based
therapeutic efficacy of systemically delivered NSC-ENb-TRAIL in TNBC derived mouse models of breast to brain
metastasis that mimic the clinical scenario of breast metastatic tumor growth and progression. We will initially
screen established and patient derived TNBC lines for their response to EGFR and DR4/5 targeted therapies and
assess their propensity to metastasize to brain. The mechanism based response of TNBC to NSC-ENb-TRAIL and
the fate and therapeutic efficacy of NSC-ENb-TRAIL in brain metastasis mouse models generated from brain
seeking patient derived TNBC lines will be assessed. We hypothesize that simultaneous targeting of EGFR and
DR4/5 will significantly influence epithelial-mesenchymal transition (EMT) and tumor growth and progression. Based
on our exciting preliminary data on the combined use BBB permeable histone deacetylase inhibitor (HDACi), CN147
and ENb-TRAIL and the previous findings that concomitant use of HDACi with DR4/5 agonists and EGFR inhibitors,
the combined therapeutic efficacy of NSC-ENb-TRAIL and CN147 will be assessed. We hypothesize that ENb-
TRAIL and HDACi will have therapeutic efficacy in metastatic TNBC with a broader range of genetic backgrounds
and with varying sensitivity to ENb-TRAIL in vivo. The proposed studies in this application are likely...

## Key facts

- **NIH application ID:** 9987539
- **Project number:** 5R01CA201148-06
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Khalid A Shah
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $387,917
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987539

## Citation

> US National Institutes of Health, RePORTER application 9987539, Fate and efficacy of targeted therapies for metastatic tumors (5R01CA201148-06). Retrieved via AI Analytics 2026-07-25 from https://api.ai-analytics.org/grant/nih/9987539. Licensed CC0.

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