Direct activation of PP2A as a novel approach to group-3 medulloblastoma therapy

Ended Project Grant Awarded Last action

Award ID
R43CA268329
Recipient
Awarding agency
Obligated
$813,000

Award facts

Assistance listing
93.395 Cancer Treatment Research
Completion date
Originally
Place of performance
Princeton, NJ, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
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

Transactions

Action Obligated Date
Amendment -$0
Amendment $406,500
Original award $406,500

Quick answers

Who received award R43CA268329?

R43CA268329 was awarded to Atux Iskay Group LLC by National Cancer Institute (National Institutes of Health) on June 1, 2022.

How much is award R43CA268329 worth?

$813,000 has been obligated on R43CA268329.

On GovTribe

See this award's full record

  • Every transaction and subaward
  • The recipient's other awards and teaming partners
  • Similar grant awards
  • Ask GovTribe AI about this award
Try for free Login