# Direct Activation of PP2A as a Novel Approach to Group-3 Medulloblastoma Therapy

> **NIH NIH R43** · ATUX ISKAY GROUP LLC · 2022 · $406,500

## Abstract

Project Summary
Medulloblastoma is the most common primary brain tumor in the pediatric population. Once considered a
singular pathology, medulloblastoma is now classified into four molecular subgroups: group 3 tumors account
for approximately 25-30% of medulloblastomas and have the worst prognosis. Despite current multimodal
therapy with surgery, chemotherapy and radiation, infants and children with group 3 tumors have a 5-year
overall survival of 45 and 58%, respectively. Furthermore, children who survive often suffer from long-term
motor, sensory, endocrine, and neuropsychological sequelae. It is undisputable that these children are a
patient population that requires novel therapies, applied alone or in combination with standard approaches, to
effectively treat their disease and provide less toxic therapies with fewer long-term effects. This Phase 1 SBIR
proposal has the objective of demonstrating the feasibility of using novel small molecule activators of the tumor
suppressor PP2A as novel therapeutics for group 3 medulloblastoma. Prototype compounds are known to be
CNS penetrant and have shown efficacy in intracranial animal models of glioblastoma. PP2A activation is a
novel therapeutic strategy in group 3 medulloblastoma and activation of this tumor suppressor restrains
multiple drivers of cancer cell growth and proliferation including pERK, pAKT, MYC and STAT3. Key
milestones are scale-up synthesis of a lead candidate in the prototype tricyclic sulfonamide chemical type with
improved physicochemical properties and bioavailability. The lead compound should have sufficient in vivo
activity in group 3 medulloblastoma models to have reasonable probability, based on allometric scaling to
human, of an efficacious clinical dose with acceptable safety profile. Based on our experience in glioblastoma
and other cancer models we anticipate doses at, or lower than, 10mg/kg, twice daily to be appropriate and
achievable. A second objective is identification of novel, proprietary, back-ups with patent protection
foreseeable. Thus the specific aims for the Phase 1 project are: Aim 1A. Scale-up synthesis of candidate
from tricyclic sulfonamide PP2A activator series for evaluation in group 3 medulloblastoma models. This
candidate will have improved oral bioavailability, metabolic profile, water solubility and in vivo efficacy in
medulloblastoma models versus published prototype. Aim 1B. Synthesis of alternate, back-up compounds
with in vitro profile comparable to prototypes and file patent(s). Aim 2. 2A In vitro and 2B in vivo evaluation of
candidate compounds in human group 3 medulloblastoma patient-derived xenograft models. The objective is
demonstration of activity versus key drivers of medulloblastoma growth and metastasis in group 3 tumor
models. We target in vivo efficacy at <10mg/kg twice daily as a feasible criterion for advancing a candidate in
a Phase 2 SBIR project. New treatment options for group 3 medulloblastoma, and other pediatric cancers, a...

## Key facts

- **NIH application ID:** 10382481
- **Project number:** 1R43CA268329-01
- **Recipient organization:** ATUX ISKAY GROUP LLC
- **Principal Investigator:** Michael Ohlmeyer
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $406,500
- **Award type:** 1
- **Project period:** 2022-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10382481

## Citation

> US National Institutes of Health, RePORTER application 10382481, Direct Activation of PP2A as a Novel Approach to Group-3 Medulloblastoma Therapy (1R43CA268329-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10382481. Licensed CC0.

---

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