Novel targeted Chemotherapeutics for Gliobastoma

This grant application aims to radically transform the therapy of brain tumors by creating new efficacious agent with strong delivery to brainrobust activity against brain tumorsand decreased peripheral dose limiting toxicity in other organsWhile primary brain tumors represent a rare malignancyhigh grade gliomas are aggressive and most patients die of disease progression with a median survival ismonths after diagnosisThe standard of care for newly diagnosed high grade gliomas involves surgical resectionfollowed by fractionated radiation therapyRTand concurrent treatment with temozolomideTMZHoweverof patients are resistant to TMZ and suffer the consequences of chemotherapy without therapeutic benefitThusthere is a pressing need for a novel chemotherapeutic agent that is effective for brain cancersexhibits low systemic toxicityand is effective for TMZ insensitive patientsMost anticancer drugs are ineffective for treating CNS tumorsin large part due to their inability to cross the blood brain barrierBBBAlthough the BBB is frequently impaired in brain tumorsit is still a formidable obstacle for adequate drug deliveryThe large amino acidLATalso known as Tumor AntigenTAis localized in the BBB and allows for the transport of essential amino acids and CNS therapeutics into the brainLATis highly over expressed in almost all gliomasbut displays very low expression level in non proliferative cellsThereforechemotherapeutic agents that can be transported by LATare uniquely suited for crossing the BBB and specifically treating brain tumorsIn Phaseof the SBIR researchwe engineered novel anti cancer compounds that combine the properties of a cytotoxic agent with a proprietary LATrecognition elementWe identified QBSS as our lead candidateQBSS demonstrated robust activity against brain tumors in an intracranial xenograft model of GBM and decreased peripheral dose limiting toxicity in other organsMedian survival of QBSS treated mice was improved compared to vehicleor standard of careSOCtreated animalsThe aims of the proposed Phase II research are geared to determine whether QBSS can achieve investigational new drugINDstatusIn Aimwe will characterize the ADME properties of QBSS and analyze the biodistribution in healthy and intracranial tumor bearing miceIn Aimwe will optimize the dose and dosing regimen for QBSS to develop a safe and effective treatment for GBMIn AimQBSS treatment will be evaluated against the SOC in TMZ resistant and TMZ sensitive animal modelsWe will conduct an exhaustive evaluation of QBSS efficacy in patient derived xenograft models to discover biomarkersand identify patient responder and non responder profilesAimexplores synergistic additive therapeutic effects of combining QBSS with other brain permeable drugs to reduce dose and toxicity and to minimize or delay the induction of drug resistanceSingle and repeat dose Good Laboratory PracticeGLPtoxicokineticTKand toxicity studies will be performed in Aimin support of an IND submission