SBIR-STTR Award

Oral mucositis, a severe oral ulceration, is a common toxic effect of radio- or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. About 17.9 million adults have been diagnosed with cancer in the United States, which is ~7.9% of the total population. At least 40%, and up to 70%, of individuals treated with standard chemotherapy regimens or upper-body radiation develop oral mucositis. To date, there is no FDA approved drug to treat oral mucositis in cancer patients. The key challenge for oral mucositis treatment is to repair and protect ulcerated oral mucosa without promoting cancer cell growth. Drs. Wang and Zhang have collaborated with Taiga's scientist Dr. Refaeli to develop a Smad7 fusion protein containing human Smad7 fused to the HIV-1 Tat protein transduction domain (PTD). The Tat-Smad-7 protein can rapidly penetrate cells. Local Tat-Smad7 application to mouse oral mucosa shows prophylactic and therapeutic effects on radiation-induced oral mucositis. Our long-term goal is to develop Tat-Smad7 as a therapeutic biologic to prevent and treat radiation-induced oral mucositis in cancer patients. Aim 1 will optimize the protein production and purification system and establish quantification methods for measuring the efficiency of Tat-Smad7 protein transduction and biochemical activities. These studies will allow us to develop a production platform and standardize biochemical quantification of Tat-Smad7 for Phase II studies and future use in patients. Aim 2 will address one of the most important toxicity issues of treating oral mucositis in cancer patients, i.e., to provide evidence if Tat-Smad7 can be used as a therapeutic biologic to protect normal oral mucosa without compromising radiation-induced killing of cancer cells. We will orthotopically transplant mouse SCC cell lines developed in Dr. Wang's lab into the tongue of syngeneic C57BL/6 mice and expose these tumor-bearing mice to craniofacial radiation to induce oral mucositis. Tat-Smad7 produced in Aim 1 will be applied to the oral cavity so both oral mucositis and cancer cells are transduced by Tat-Smad7. Among the Tat-Smad7 effective dose range, we aim to identify Tat-Smad7 doses that do not protect cancer from radiotherapy. The proposed studies will allow us to meet commercial needs for protein production and provide critical preclinical data on the safety and efficacy of Tat-Smad7 in a therapeutic setting for radiation-induced oral mucositis. We plan to perform these IND-enabling studies via a Phase II application after completing the current application.

Public Health Relevance Statement:


Public Health Relevance:
Narrative Oral mucositis, a painful oral ulceration, is one of the most severe toxicities of cancer therapy. This application produces and tests a novel therapeutic biologic for treating oral mucositis without compromising radiotherapy in cancer patients.

Project Terms:
Acute; Address; Adult; Adverse effects; Affect; Animals; Biochemical; C57BL/6 Mouse; cancer cell; Cancer Cell Growth; Cancer cell line; Cancer Patient; cancer radiation therapy; cancer therapy; Canis familiaris; Cell Line; Cells; chemoradiation; Chemotherapy-Oncologic Procedure; Chimeric Proteins; Chronic; Codon Nucleotides; commercialization; craniofacial; Data; Diagnosis; Dose; Drug Kinetics; Endotoxins; Escherichia coli; Excision; FDA approved; Flow Cytometry; Future; Genetically Engineered Mouse; Goals; Healed; healing; HIV-1; Human; improved; in vivo; Individual; Intensity-Modulated Radiotherapy; Killings; Lesion; malignant mouth neoplasm; Malignant Neoplasms; Measurement; Measures; meetings; Methods; Mus; Neoplasm Metastasis; Normal tissue morphology; novel therapeutics; oncology; Oral; Oral cavity; oral mucositis; Oral mucous membrane structure; Oral Ulcer; Pain; Patients; Peptide Synthesis; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Phase; phase 1 study; phase 2 study; Phosphorylation; Population; Post-Translational Protein Processing; pre-clinical; prevent; Procedures; Process; Production; prophylactic; Proteins; Protocols documentation; public health relevance; Radiation; Radiation therapy; Radio; Recombinant Proteins; Recombinants; repaired; research and development; research study; Safety; Scientist; screening; Smad7 protein; Small Business Innovation Research Grant; System; tat Protein; Testing; Therapeutic; Therapeutic Effect; Tongue; Toxic effect; transduction efficiency; Transplantation; tumor; tumor growth; Ulcer; United States

Oral mucositis, a severe oral ulceration, is a common toxic effect of radio- or chemoradio-therapy and a limiting factor to using the maximum dose of radiation for effective cancer treatment. At least 40%, and up to 70%, of cancer patients treated with standard chemotherapy regimens or upper-body radiation develop oral mucositis. Intensity modulated RT (IMRT) lessens chronic side effects, but not the acute toxicity seen in oral mucosa. The new Stereotactic Body RT (SBRT) that directs RT to the tumor mass should reduce oral mucositis, but this will not apply to patients who need chemotherapies, targeted therapies, or conventional RT. The immunotherapy is gaining momentum for cancer therapy, but oral mucositis appears to occur more often with immunotherapy. To date, Palifermin, a protein derived from keratinocyte growth factor, is the only targeted therapy approved by the Food and Drug Administration (FDA) for preventing oral mucositis in patients with hematopoietic malignancy followed by bone marrow transplant (4% of the at-risk population), but it has no effect on existing mucositis. Allander Biotechnologies has developed a proprietary biologic that shows prophylactic and therapeutic effects on radiation-induced oral mucositis in mice upon topical application to oral mucosa. Our biologic possesses multiple functions needed for oral mucositis healing. In the Phase I funding period of this grant, we have developed the biologic production system and demonstrated that treating mice with this biologic alleviated radiotherapy-induced oral mucositis but did not compromise its killing of adjacent oral cancer. In this Phase II application, we will establish the scale-up process and quality controls for manufacturing our biologic. We will generate efficacy data to optimize pharmacodynamics (PD) biomarkers. We will generate preliminary toxicity data to design pharmacokinetics (PK) and toxicology studies required for filing an Investigational New Drug (IND) application. By the end of Phase II funding, we will have established manufacturing procedures for our biologic and protocols (analytical, bioassay, PK and toxicology) ready for generating additional IND data under Good Laboratory Practice (GLP) conditions.

Public Health Relevance Statement:
Narrative Oral mucositis, a painful oral ulceration, is one of the most severe toxicities of cancer therapy. This application will generate resources, robust quality control tools, drug efficacy biomarkers and preliminary safety data. These data will help us design FDA required studies to apply for an IND application that will move our biologic into future clinical trials to treat oral mucositis.

Project Terms:
acute toxicity; Adverse effects; Affect; Animal Hospitals; Animals; Antigen-Antibody Complex; Autopsy; Biological; Biological Assay; Biological Markers; Biopsy; Biotechnology; Blood Circulation; Blood specimen; Bone Marrow Transplantation; Cancer Patient; cancer therapy; Canis familiaris; chemoradiation; chemotherapy; Chemotherapy-Oncologic Procedure; Chronic; Clinical Trials; Colorado; Cyclic GMP; Data; design; Dose; drug efficacy; Drug Kinetics; efficacy study; Endotoxins; Engineering; Escherichia coli; experimental study; Feces; flasks; Funding; Future; Gastrointestinal tract structure; Glomerulonephritis; good laboratory practice; Grant; Gray unit of radiation dose; Guidelines; healing; Hematopoietic Neoplasms; HIV-1; Human; immunogenicity; Immunotherapy; Intensity-Modulated Radiotherapy; Investigational Drugs; Investigational New Drug Application; keratinocyte growth factor; Killings; malignant mouth neoplasm; Maximum Tolerated Dose; Measurement; Modeling; Mucositis; Mus; Neoplasm Metastasis; novel; oral mucositis; Oral mucous membrane structure; Oral Ulcer; Pain; Pathogenesis; Pathway interactions; Patients; Peptides; pharmacodynamic biomarker; Phase; phase 2 study; Phase I Clinical Trials; Population; Populations at Risk; prevent; Procedures; Process; Process Measure; Production; prophylactic; Proteins; Protocols documentation; Quality Control; Radiation; Radiation therapy; Radio; Reference Standards; Reporting; Research Contracts; Residual state; Resources; Rodent; Safety; safety and feasibility; safety study; Sampling; scale up; Serologic tests; Serum; Surrogate Markers; System; targeted treatment; Testing; Therapeutic Effect; tool; Topical application; Toxic effect; Toxicology; Transforming Growth Factor beta; tumor; United States Food and Drug Administration; Universities; Urine; Veterinary Medicine