# Mechanisms of melanoma brain metastasis by CTCs isolated from patients' blood and CSF

> **NIH NIH R01** · UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR · 2021 · $174,462

## Abstract

Melanoma Brain Metastasis (MBM) carries a dismal prognosis with a median overall survival of only 4-6 months.
If patients develop leptomeningeal disease, the overall survival is even lower. The incidence of MBM has been
reported to be up to 43% in clinical settings and up to 75% in the autopsy series. Although notions that Circulating
Tumor Cells (CTCs) act as “seeds” of intractable metastasis are established, there is no knowledge characterizing
MBM-colonizing CTCs. Single-cell CTC transcriptional profiling has also demonstrated that CTCs isolated from
patients are very distinct from cell lines that are widely used for drug discovery. This is even more compelling
considering that significant discrepancies of biomarkers among CTCs and corresponding primary and metastatic
tumors have been observed. Moreover, while the presence of CTCs in the cerebrospinal fluid (CSF) remains the
gold standard, the sensitivity of cytology is only 50-56% at time of the first CSF analysis. Therefore, the
development of effective therapy approaches - CTC-based tests - could have a tremendous clinical impact to treat
MBM. We hypothesize that the neurotrophin receptor p75NTR and Heparanase (HPSE), two markers implicated
in MBM models, are novel CTC biomarkers to predict clinical MBM and potential therapeutic targets to prevent
MBM. The objective of this application is to demonstrate that the p75NTR/HPSE axis is diagnostic in clinical
MBM; and that p75NTR and HPSE are novel therapeutic CTC targets to combat MBM. In aim 1, we will: a) isolate
and characterize p75NTR/HPSE CTC subsets from blood and CSF (multiparametric flow cytometry and
DEPArrayTM technologies among others), and compare the expression of p75NTR/HPSE combinations in CTCs
of melanoma patients diagnosed either with or without MBM; b) directly link patient-isolated CTC subsets,
possessing p75NTR/HPSE expression and combinations, to clinical MBM. In aim 2, we will assess effects of
regulating functions of p75NTR/HPSE CTC subsets on MBM development by using small-molecule p75NTR and
new HPSE inhibitors along with CTC xenografts; and complement these effects with regulatory p75NTR/HPSE
gene expression (pINDUCER lentiviral toolkit). In aim 3, we will: a) determine roles of CTC-expressed Merlin as
an important integrator of p75NTR/HPSE pathways altering CTC proliferation vs. growth arrest; b) delineate
HPSE-induced, syndecan-mediated modulation of Merlin/Hippo signaling to affect CTC properties driving MBM.
Uncovering MBM CTC phenotypes offers the opportunity to modify treatment by extending studies directly to
human melanoma. This project lead by an inter-disciplinary and well-integrated team will study and validate new
and specific CTC biomarkers responsible for CTC-induced MBM. It has high therapeutic impact and is paradigm-
shifting. We are uniquely positioned to perform this study not only for having access to an extensive cohort of
blood/CSF samples from melanoma patients but also for the extensive expertise...

## Key facts

- **NIH application ID:** 9828544
- **Project number:** 5R01CA216991-04
- **Recipient organization:** UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
- **Principal Investigator:** Dario Marchetti
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $174,462
- **Award type:** 5
- **Project period:** 2017-12-15 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828544

## Citation

> US National Institutes of Health, RePORTER application 9828544, Mechanisms of melanoma brain metastasis by CTCs isolated from patients' blood and CSF (5R01CA216991-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828544. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*