SBIR-STTR Award

The overall goal of the proposed studies is to establish the feasibility of developing therapies for brain cancers such as glioblastoma multiforme from the schweinfurthin family of antiproliferative agents. These agents are highly toxic to CNS derived tumor cell lines in vitro and more importantly appear to exhibit this activity via a novel cellular target(s). The schweinfurthins also contain chemical functional groups which should facilitate cerebrovascular barrier penetration, a very important aspect of drugs aimed at treating primary brain cancers. Phase One of these studies is comprised of three narrowly focused aims directed at proving the feasibility of finding advancing? a therapeutic lead from this family: These aims include: 1) synthesis of analogs of the schweinfurthins bearing functional groups designed to improve the "drug-like" nature of the compounds; 2) improvement of the published synthesis of the hexahydroxanthene core of the 3-deoxyschweinfurthin motif to allow for more efficient and safe production of larger quantities of material for Phase Two studies; and 3) biological studies aimed at elucidation of the cellular or molecular target of the schweinfurthins. These aims will allow a decision to be made about feasibility of studying these drugs further in pre-clinical animal models as part of Phase Two, and ultimately of bringing drugs based on this unique and potent family of compounds into use against brain cancer

According to the American Cancer Society an estimated 21,810 cases of primary malignant brain tumor will be reported in the US in 2008. The ACS also estimates that 13,070 deaths will occur due to these diseases in this year. This Phase II STTR program advocates the development of drugs for primary CNS cancers from the schweinfurthin family of natural products. The schweinfurthins are a family of natural products isolated by the National Cancer Institute and have a unique pattern of activity against cancer cell lines indicating a potentially untapped and novel mechanism of action. This project will undertake the further development of these agents by carrying out three specific aims: 1) we will synthesize 288 new bis-stilbene analogs of the schweinfurthins aimed at providing more structure function data, improving activity and physical properties for this class of compounds; 2) we will test these compounds as they become available following an assay scheme developed in our Phase I feasibility studies, this will lead to testing of compounds in animal models of glioblastoma; and 3) we will undertake further hypothesis driven explorations of the mechanism of action of the schweinfurthins. The current clinical outcome of patients with glioblastoma and other aggressive CNS cancers makes development of new agents for these indications highly desirable. The three specific aims proposed here are designed to allow us to choose a candidate for IND enabling studies and to further our understanding of the mechanism of action of this novel family of compounds.

Public Health Relevance:
Primary glioma represents a significant challenge to the oncology community. While the incidence of glioma is relatively low at 5-10 per 100,000 individuals, therapeutic interventions for these diseases are of only marginal benefit. According to the American Cancer Society an estimated 21,810 cases of primary malignant brain tumor will be reported in the US in 2008. The ACS also estimates that 13,070 deaths will occur due to these diseases in this year. Research aimed at improving outcomes for this disease is clearly needed to address shortcomings in current therapies.

Thesaurus Terms:
3,4-Dihydro-3-Methyl-4-Oxoimidazo[5,1-D]-1,2,3,5-Tetrazine-8-Carboxamide; 8-Carbamoyl-3-Methylimidazo[5,1-D]-1,2,3,5-Tetrazin-4(3h)-One; Address; Advocate; Alkylating Agents; Alkylators; American Cancer Society; Animal Model; Animal Models And Related Studies; Anti-Cancer Agents; Anti-Tumor Agents; Anti-Tumor Drugs; Antineoplastic Agents; Antineoplastic Drugs; Antineoplastics; Antiproliferative Agents; Antiproliferative Drugs; Assay; Astrocytoma, Grade Iv; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Biological Factors; Brain; Ccop; Cns Neoplasms, Malignant; Cancer Drug; Cancer Radiotherapy; Cancer Cell Line; Cancer Of Brain; Cancer Of The Cns; Cancers; Cell Line; Cell Lines, Strains; Cellline; Central Nervous System Cancer; Cessation Of Life; Chemotherapeutic Agents, Neoplastic Disease; Clinical; Clinical Research; Clinical Study; Clinical Trials, Phase I; Community Clinical Oncology Program; Community Oncology; Data; Death; Debridement; Development; Development Plans; Disease; Disease Outcome; Disorder; Drug Kinetics; Drugs; Early-Stage Clinical Trials; Encephalon; Encephalons; Essex Brand Of Temozolomide; Factor, Biologic; Family; Feasibility Studies; Forecast Of Outcome; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioblastoma; Glioma; Grade Iv Astrocytic Neoplasm; Grade Iv Astrocytic Tumor; Grant; In Vitro; Incidence; Individual; Institution; Iowa; Knowledge; Lead; Libraries; Malignant Neoplasms; Malignant Tumor; Malignant Tumor Of The Brain; Malignant Tumor Of The Cns; Malignant Tumor Of The Central Nervous System; Malignant Neoplasm Of Brain; Malignant Neoplasm Of Central Nervous System; Medication; Molecular Interaction; Nci; Nci Organization; National Cancer Institute; Natural Products; Neoplasms Of Neuroglia; Nervous System, Brain; Neuroglial Neoplasm; Neuroglial Tumor; New Agents; Oncology Programs; Operation; Operative Procedures; Operative Surgical Procedures; Outcome; Patients; Pattern; Pb Element; Pharmaceutic Preparations; Pharmaceutical Preparations; Pharmacokinetics; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Plans, Development; Prognosis; Programs (Pt); Programs [publication Type]; Proteins; Radiation Therapy; Radiotherapeutics; Radiotherapy; Reporting; Research; Research Contracts; Research Resources; Resources; Sttr; Scheme; Schering Brand Of Temozolomide; Schering-Plough Brand Of Temozolomide; Series; Site; Small Business Technology Transfer Research; Solid; Stilbenes; Structure; Surgical; Surgical Interventions; Surgical Procedure; Temodal; Temodar; Terpene Compound; Terpenes; Terpenoids; Testing; Therapeutic; Therapeutic Intervention; Time; Toxicology; Tumor-Specific Treatment Agents; Tumors Of Neuroglia; Universities; Work; Xenograft Model; Analog; Anticancer Agent; Anticancer Drug; Base; Chemotherapy; Cultured Cell Line; Design; Designing; Disease/Disorder; Drug Development; Drug/Agent; Endoplasmic Reticulum Stress; Gene Product; Glioblastoma Multiforme; Heavy Metal Pb; Heavy Metal Lead; Imidazo[5,1-D]-1,2,3,5-Tetrazine-8-Carboxamide, 3, 4-Dihydro-3-Methyl-4-Oxo-; Improved; In Vitro Assay; In Vivo; Intervention Therapy; Irradiation; Malignancy; Methazolastone; Model Organism; Mouse Model; Neoplasm/Cancer; Novel; Outcome Forecast; Phase 1 Study; Phase 1 Trial; Phase I Trial; Physical Property; Programs; Protocol, Phase I; Public Health Relevance; Spongioblastoma Multiforme; Surgery; Temozolomide; Tumor