Despite improvements in clinical care for patients, mortality rates for primary brain cancer remain high. Patients with glioma have a median survival of 1 year with poor responses to current therapies, likely due to the highly angiogenic and invasive nature of these tumors. Therapies effective for a variety of solid tumors are ineffective for gliomas. Thus, there is a critical need for novel therapies targeting these tumors. Heat shock protein 90 (Hsp90) functions to maintain the conformation and activity of many oncoproteins, and has thus become an attractive target for cancer therapy. Inhibitors of Hsp90 have demonstrated inhibition of cancer cell growth in various tumor models and the first inhibitor in clinical development, 17-AAG, is in Phase II/III development for cancer. Indeed, 17-AAG has already shown preclinical efficacy in GL261 cells and GL261 gliomas. Because 17-AAG and most other Hsp90 inhibitors in development cross the blood brain barrier (BBB) poorly, their potential efficacy for treatment of gliomas is limited. NexGenix Pharmaceuticals is currently developing a novel radicicol-based series of Hsp90 inhibitors. These compounds, for which the prototype is NXD30001, inhibit Hsp90 more potently than 17-AAG and have a more favorable pharmacokinetic profile. NXD30001 efficiently depletes Hsp90 client oncoproteins, inhibits tumor cell growth in vitro and in vivo, readily crosses the BBB and accumulates in the brain. Taken together, these characteristics make NXD30001 an attractive therapeutic candidate for gliomas. Objective: The goal of this Phase I SBIR project is to establish proof-of-principle for the development of NXD30001 as a therapeutic for glioma. A successful outcome from this Phase I study will be followed by preclinical development and clinical validation supporting subsequent development and commercialization of NXD30001 for glioma treatment. Specific Aim 1: Anti-tumor effect of NXD30001 on glioma cells in vitro. We hypothesize that NXD30001, given its increased potency relative to 17-AAG, will exhibit greater anti-tumor efficacy in cell based assays with murine (GL261) and human (U87MG, U251MG, LN443, T98G) glioma cells. A dose- and time-dependent effect of NXD30001 treatment on GL261 cell proliferation, cell cycle progression, client protein depletion, cell migration, MMP-2 secretion will be analyzed. In addition, NXD30001 and 17-AAG will be compared in a proliferation assay and Hsp90 client protein depletion assay using a panel of human glioma cell lines. Specific Aim 2: Anti-tumor effect of NXD30001 on GL261 gliomas in vivo. We hypothesize that NXD30001, given its increased BBB penetration relative to 17-AAG, will exhibit greater anti-tumor efficacy in the GL261 in vivo brain tumor model. We will test the efficacy of different doses of NXD30001 on tumor volume, in vivo Hsp90 client protein depletion, histopathology, angiogenesis and invasive potential.
Public Health Relevance: Malignant gliomas are highly aggressive tumors with a high mortality rate that claim up to 10,000 lives each year in the US. Current therapies that are effective for other solid tumors are ineffective in controlling the growth of these inevitably fatal tumors. The proposed research is designed to establish proof-of-principle evidence for the novel heat shock protein 90 (Hsp90) inhibitor, NXD30001, in a glioma model, that will likely support its development as a potential treatment for malignant glioma.
Public Health Relevance Statement: Project Narrative Malignant gliomas are highly aggressive tumors with a high mortality rate that claim up to 10,000 lives each year in the US. Current therapies that are effective for other solid tumors are ineffective in controlling the growth of these inevitably fatal tumors. The proposed research is designed to establish proof-of-principle evidence for the novel heat shock protein 90 (Hsp90) inhibitor, NXD30001, in a glioma model, that will likely support its development as a potential treatment for malignant glioma.
Project Terms: 5-chloro-6-(7,8-epoxy-10-hydroxy-2-oxo-3,5-undecadienyl)-beta-resorcylic acid mu-lactone; 72-kDa Gelatinase; 72-kDa Type IV Collagenase; 72kD type IV Collagenase; ATP phosphohydrolase; ATPase; Adenosine Triphosphatase; Adenosinetriphosphatase; Ansamycin Antibiotics; Ansamycin Antineoplastic Antibiotic; Ansamycins; Assay; Bioassay; Biologic Assays; Biological Assay; Biological Factors; Blood - brain barrier anatomy; Blood-Brain Barrier; Brain; Brain Neoplasia; Brain Neoplasms; Brain Tumors; Cancer Treatment; Cancer of Brain; Cancer of Breast; Cancers; Cell Cycle Progression; Cell Growth in Number; Cell Locomotion; Cell Migration; Cell Movement; Cell Multiplication; Cell Proliferation; Cells; Cellular Expansion; Cellular Growth; Cellular Migration; Cellular Proliferation; Chaperone; Characteristics; Client; Clinical; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Unspecified; Development; Dose; Drug Formulations; Drug Kinetics; EGFR; ERBB Protein; ERBB1; Early-Stage Clinical Trials; Encephalon; Encephalons; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Exhibits; Factor, Biologic; Formulation; Formulations, Drug; Gelatinase A; Gelatinase Neutrophil; Geldanamycin; Geldanamycin Analogue; Generalized Growth; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioma; Goals; Growth; HER1; HSP 90 inhibition; HSP-90; HSP90; HSP90 inhibition; Heat-Shock Proteins 90; Hemato-Encephalic Barrier; Hepatotoxic effect; Hepatotoxicity; Histopathology; Human; Human, General; In Vitro; Inhibition of Cancer Cell Growth; Life; Liver Toxicity; MMP-2; MMP2; Malignant Glial Neoplasm; Malignant Glial Tumor; Malignant Glioma; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Neuroglial Neoplasm; Malignant Neuroglial Tumor; Malignant Tumor; Malignant Tumor of the Brain; Malignant Tumor of the Breast; Malignant neoplasm of brain; Malignant neoplasm of breast; Mammals, Mice; Man (Taxonomy); Man, Modern; Matrix Metalloproteinase-2; Mice; Modeling; Molecular Chaperones; Molecular Configuration; Molecular Conformation; Molecular Stereochemistry; Mortality; Mortality Vital Statistics; Motility; Motility, Cellular; Murine; Mus; Natural Products; Nature; Neoplasms of Neuroglia; Nervous System, Brain; Neuroglial Neoplasm; Neuroglial Tumor; Oncogene Products; Oncogene Proteins; Oncoproteins; Outcome; PEX; Patients; Penetration; Pharmaceutical Agent; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Process; Proteins; Publishing; Radicicol; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Relative; Relative (related person); Reporting; Research; Resistance; SBIR; SBIRS (R43/44); Series; Small Business Innovation Research; Small Business Innovation Research Grant; Solid Neoplasm; Solid Tumor; Stress; Therapeutic; Therapeutic Uses; Time; Tissue Growth; Toxic effect on liver cells; Transforming Growth Factor alpha Receptor; Treatment Efficacy; Tumor Cell; Tumor Volume; Tumors of Neuroglia; Validation; Xenograft Model; angiogenesis; anticancer therapy; base; c-erbB-1; c-erbB-1 Protein; cancer therapy; cell growth; cell motility; clinical care; clinical investigation; commercialization; conformation; conformational state; design; designing; effective therapy; efficacy testing; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; geldanomycin; gene product; glioma cell line; heat shock protein 90 inhibition; hepatoxicity; hsp90 Family; in vivo; inhibitor; inhibitor/antagonist; malignancy; malignant breast neoplasm; meetings; migration; monorden; monordene; neoplasm/cancer; neoplastic cell; novel; ontogeny; phase 1 study; phase 1 trial; phase I trial; pre-clinical; preclinical; preclinical efficacy; preclinical study; proto-oncogene protein c-erbB-1; protocol, phase I; prototype; public health relevance; resistant; response; small molecule; therapeutic efficacy; therapeutic target; therapeutically effective; tumor; tumor growth; tumorigenic; tumors in the brain
