This grant application aims to radically transform the therapy of brain tumors by creating new efficacious agent with strong delivery to brain, robust activity against brain tumors, and decreased peripheral dose-limiting toxicity in other organs. While primary brain tumors represent a rare malignancy, high-grade gliomas are aggressive and most patients die of disease progression with a median survival is 9-15 months after diagnosis. The standard of care for newly diagnosed high-grade gliomas involves surgical resection, followed by fractionated radiation therapy (RT) and concurrent treatment with temozolomide (TMZ). However, 60% of patients are resistant to TMZ and suffer the consequences of chemotherapy without therapeutic benefit. Thus, there is a pressing need for a novel chemotherapeutic agent that is effective for brain cancers, exhibits low systemic toxicity, and is effective for TMZ-insensitive patients. Most anticancer drugs are ineffective for treating CNS tumors, in large part due to their inability to cross the blood?brain barrier (BBB). Although the BBB is frequently impaired in brain tumors, it is still a formidable obstacle for adequate drug delivery. The large amino acid 1 (LAT1), also known as Tumor Antigen 1 (TA1), is localized in the BBB and allows for the transport of essential amino acids and CNS therapeutics into the brain. LAT1 is highly over-expressed in almost all gliomas, but displays very low expression level in non-proliferative cells. Therefore, chemotherapeutic agents that can be transported by LAT1 are uniquely suited for crossing the BBB and specifically treating brain tumors. In Phase 1 of the SBIR research, we engineered novel anti-cancer compounds that combine the properties of a cytotoxic agent with a proprietary LAT1 recognition element. We identified QBS10072S as our lead candidate. QBS10072S demonstrated robust activity against brain tumors in an intracranial xenograft model of GBM and decreased peripheral dose-limiting toxicity in other organs. Median survival of QBS10072S treated mice was improved compared to vehicle- or standard of care (SOC)-treated animals.
The aims of the proposed Phase II research are geared to determine whether QBS10072S can achieve investigational new drug (IND) status.
In Aim 1, we will characterize the ADME properties of QBS10072S and analyze the biodistribution in healthy and intracranial tumor-bearing mice.
In Aim 2, we will optimize the dose and dosing regimen for QBS10072S to develop a safe and effective treatment for GBM.
In Aim 3, QBS10072S treatment will be evaluated against the SOC in TMZ-resistant and TMZ-sensitive animal models. We will conduct an exhaustive evaluation of QBS10072S efficacy in patient derived xenograft models to discover biomarkers, and identify patient responder and non-responder profiles. [Aim 4 explores synergistic/additive therapeutic effects of combining QBS10072S with other brain permeable drugs to reduce dose and toxicity and to minimize or delay the induction of drug resistance.] Single and repeat dose Good Laboratory Practice (GLP) toxicokinetic (TK) and toxicity studies will be performed in Aim 5 in support of an IND submission.
This SBIR Phase 2 grant application is relevant to the mission of the National Institute of Health. The main objective is to develop novel anti-cancer agents for patients with brain tumors. Most chemotherapeutics are unsuccessful against brain tumors since they are unable to cross the blood brain barrier (BBB) effectively. Small polar nutrients can cross the BBB and reach brain cancer cells through specific influx transporters with expression at both the BBB and the tumor. We have engineered a novel chemotherapeutic agent that mimics endogenous nutrients, crosses the BBB, and enters tumors and suppresses tumor growth in animal models. Key to our targeted approach is high efficacy against brain tumors and low systemic toxicity. Transporter- targeted chemotherapy provides a novel effective armamentarium against brain tumors with potential utility for treatment of other cancers.
