# Engineering knotted peptide therapeutics for pediatric brain tumor patients

> **NIH NIH R01** · FRED HUTCHINSON CANCER RESEARCH CENTER · 2020 · $793,459

## Abstract

Brain tumors cause more deaths in children than any other form of cancer. Most pediatric brain tumor patients
receive surgery and radiation as key elements of treatment. To help surgeons maximally and safely remove
brain tumors, we previously discovered and developed Tumor Paint, which delivers fluorescent signal to brain
tumor cells in pediatric clinical trials. Chlorotoxin (CTX), the scorpion-derived tumor targeting peptide, crosses
the blood brain barrier (BBB) and specifically binds to cancer cells. Because chlorotoxin can deliver fluorescent
molecules to the cytoplasm of brain tumor cells, we hypothesized that it could carry therapeutic molecules as
well. As we focus on developing therapeutic candidates that use CTX or CTX pharmacophores, it becomes
essential to understand the mechanism of BBB penetration.
In addition to work on CTX-based brain tumor therapies (e.g., delivery of chemotherapy or immunotherapy to
brain tumors), we have made significant progress on a candidate drug that could potentially help every child
who undergoes radiation therapy for brain tumors. Because brain irradiation causes severe and irreversible
neurocognitive damage in children, we aspire to engineer a therapeutic agent that blocks the toxic respiratory
burst of microglia in normal brain following radiation. Blockade of the Kv1.3 potassium ion channel on microglia
has been shown to block radiation damage to normal brain in mice. We have engineered an optide (optimized
peptide) that specifically blocks Kv1.3 but unfortunately does not, in its current form, cross the BBB.
The gap in knowledge that we intend to address is that the mechanism by which CTX and some other optides
penetrate the BBB is unknown. Because the Lys27 face of CTX is sterically hindered by a fluorophore in the
Tumor Paint clinical candidate that crosses the BBB in children, we hypothesize that the pharmacophore
responsible for BBB penetration lies on a different face than the face that contains Lys27.
The key hurdle that prevents clinical development of an optide that blocks Kv1.3 to alleviate radiation-induced
brain damage is that it does not cross the BBB and therefore fails to reach its target. We hypothesize that we
can engineer the candidate Kv1.3 blocker in a manner that fosters BBB penetration.
Our Specific Aims are:
Aim 1: To identify the pharmacophore of chlorotoxin responsible for BBB penetration
Aim 2: To identify the transporter responsible for optide penetration of the BBB
Aim 3: To create an optide that has a therapeutic pharmacophore and a BBB-penetrating pharmacophore
The significance of this work is that we will produce a clinical development candidate that could alleviate
severe brain damage caused by irradiation in children. The foundational knowledge could be applied to a new
generation of drugs for many brain disorders.

## Key facts

- **NIH application ID:** 9838735
- **Project number:** 5R01CA223674-03
- **Recipient organization:** FRED HUTCHINSON CANCER RESEARCH CENTER
- **Principal Investigator:** JAMES M OLSON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $793,459
- **Award type:** 5
- **Project period:** 2018-01-12 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9838735

## Citation

> US National Institutes of Health, RePORTER application 9838735, Engineering knotted peptide therapeutics for pediatric brain tumor patients (5R01CA223674-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9838735. Licensed CC0.

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