# Translational Studies to facilitate Rational Therapeutic Combinations of Letrozole for the Treatment of Glioblastoma

> **NIH NIH R61** · UNIVERSITY OF CINCINNATI · 2022 · $389,244

## Abstract

The prognosis for patients with glioblastoma (GBM), one of the most lethal brain tumors, remains dismal. Our
recent discoveries provide robust evidence suggesting that letrozole (LTZ), an aromatase inhibitor used in the
treatment of breast cancer, has the potential to be a breakthrough therapeutic for the treatment of GBM. Our
data include: 1) LTZ treatment of patient-derived GBM cells markedly reduced cell viability and spheroid growth;
2) LTZ potentiated the activity of temozolomide (TMZ), the primary agent used in chemotherapy of GBM in TMZ-
resistant cells; 3) Pharmacokinetics/Pharmacodynamics (PK/PD) studies in immunocompetent rats
orthotopically implanted with C6 rat glioma revealed that LTZ readily crosses the blood-brain barrier (BBB),
markedly reduces tumor volume and extends survival (10 vs. > 60 days in control vs. LTZ); and 4)
immunohistochemical analysis of tissues (N > 90 patients) demonstrated that the aromatase expression is
strikingly higher (> 5X) in GBM relative to low-grade gliomas. Moreover, in an ongoing phase 0/1 clinical trial in
which recurrent GBM patients received LTZ (2.5 -12.5 mg, N = 14 subjects) prior to surgical resection, analyses
of the excised tumor revealed that LTZ readily traverses the BBB in humans. RNAseq analysis showed
significant downregulation of oncogenes driving cell proliferation markers and upregulation of tumor suppression
markers (reduced DNA damage repair capacity) in a LTZ dose-dependent manner. Our long-term goal is to
repurpose LTZ as an anti-GBM drug. Given the phenotypic/genotypic complexity of GBM, combination therapy
will be a clinical necessity. To support this goal, our objective here is to conduct comprehensive PK/PD studies
of LTZ and combination agents in patient-derived orthotopic xenograft (PDOX) immunodeficient (athymic nude)
rats. Typically, such studies are performed utilizing athymic/SCID mice. However, the elimination half-life of
LTZ in mice is short (~ 2.5 hours), whereas LTZ PK in rats are closer to that in humans requiring the use of
athymic nude rats. Thus, we propose to conduct a quantitative milestone-based study employing primary and
recurrent patient-derived GBM. We will rigorously test combination agents for LTZ, strongly suggested
collectively by our RNAseq and other data and rationally advance 2-3 combinations for phase II clinical trials.
Specific Aims: 1: Rank-order combination partners for LTZ based on synergistic effects against GBM lines in
vitro 2: Determine in vivo BBB permeability of combination agents ± LTZ. 3: Establish PDOX athymic nude rat
models for in vivo PK/PD studies, 4: Evaluate PK/PD of LTZ ± combination agent employing the PDOX models.
The R61 phase milestones include synergistic inhibition of cell viability (Combination Index, CI< 1) and BBB
permeability (plasma to brain partitioning) (Aims 1 and 2). Concurrently, an athymic nude rat models will be
established/validated in Aim 3. Using these models in the R33 phase (Aim 4), dose-response relatio...

## Key facts

- **NIH application ID:** 10512657
- **Project number:** 1R61NS128232-01
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** PANKAJ B DESAI
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $389,244
- **Award type:** 1
- **Project period:** 2022-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512657

## Citation

> US National Institutes of Health, RePORTER application 10512657, Translational Studies to facilitate Rational Therapeutic Combinations of Letrozole for the Treatment of Glioblastoma (1R61NS128232-01). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10512657. Licensed CC0.

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