SBIR-STTR Award

Tumors survive cancer therapy in part by blocking the entrance and permeation of drugs into the cancer. We have developed a conjugatable therapeutic, “JOC-x”, that selectively opens up tumor tight junctions, which dramatically enhances penetration. This results in markedly increased concentrations of cancer drugs in the tumor. JOC-x may allow doctors to treat patients with cancer drugs at increased doses, which directly correlates with enhanced therapeutic effects. At the same time, it could reduce or eliminate the side effects of cancer therapy and address one of the major needs of the current state-of-the-art: Developing therapies that are both more effective and less toxic. Importantly, JOC-x can be used to improve clinical outcomes with cancer drugs that are already on the market as well as the next generation of cancer drugs. The goal of this proposal is to develop and test a JOC-x conjugate formed by linking the tumor- targeting tight junction opener with a chemotherapeutic agent through a polymeric backbone. The targeting and enhancing construct (1) Will be targeted to tumors (2) Will open the tumor microenvironment (3) Will therefore allow for dramatic levels of drug accumulation (4) Will result in increased killing of tumor cells and improved clinical efficacy We will do this research in two straightforward steps: we will first produce and characterize JOC-x conjugates and then we will test the conjugates for enhanced therapeutic efficacy in animal models of ovarian cancer. If we are successful, we will further move this new type of therapy towards clinical testing in humans.

Public Health Relevance Statement:
Project Narrative Improving cancer therapy is a major need in global health. By opening up tumor tight junctions with a targeted chemotherapy conjugate we will allow safer and more effective cancer therapies.

Project Terms:
Address; Adenoviruses; Adverse effects; Animal Model; Antineoplastic Agents; antitumor effect; Back; base; Binding; Biochemical; Bone Marrow; Cancer Survivor; cancer therapy; Cell Line; chemotherapeutic agent; chemotherapy; Clinical; clinical application; clinical efficacy; Cysteine; Cytotoxic agent; Data; desmoglein 2; Dose; Doxorubicin; Drug Delivery Systems; Drug Targeting; Enhancers; Epithelial; Escherichia coli; Formulation; global health; Goals; Growth; Helianthus species; Human; Immunocompetent; Improve Access; improved; Intercellular Junctions; interest; intestinal epithelium; Killings; Lead; Link; Lipids; Malignant neoplasm of ovary; Malignant Neoplasms; Marketing; Methodology; Modeling; Monitor; mouse model; nanoparticle; neoplastic cell; next generation; nonhuman primate; Normal tissue morphology; oncology; Outcome; Ovarian; Patients; Penetration; Pharmaceutical Preparations; Phase; Polymers; pre-clinical; preclinical efficacy; preclinical study; Property; Proteins; Recombinant Proteins; Recombinants; Research; research clinical testing; response; Safety; Serine; Serotyping; Site; technology development; Testing; Therapeutic; Therapeutic Effect; Therapeutic Monoclonal Antibodies; therapy development; Tight Junctions; Time; Toxic effect; Transgenic Mice; Treatment Efficacy; tumor; tumor microenvironment; Vertebral column; Xenograft procedure

A central mechanism of tumor drug resistance is the maintenance of tight junctions between malignant cells preventing penetration of molecules into the tumor microenvironment. We have generated junction openers (“JO”) that are small proteins that bind to desmoglein 2 (DSG2), a junction protein that is overexpressed in many cancers. Intravenous injection of JO increases tumor penetration and efficacy of many types of cancer therapy. Our studies have shown that the effective doses of chemotherapy can be reduced when the drugs are combined with JO. JO accumulates in tumor tissue as much as 100-fold above normal tissues making it a targeting mechanism to tumors. We have also published that application of JO has not been associated with toxicities in hDSG2 transgenic mice and that the co-administration of JO and chemotherapy was well tolerated in non-human primates. In phase 1 we were able to show that: (1) we can make JOC-x conjugates for a number of cancer treatment and imaging applications; and (2) that the JOC-x constructs retain their activity in tumor models. We now are motivated to build on the promising data generated in phase 1 and move these conjugates towards clinical testing by: (1) Preparing JOC-x for cGMP compliant production by process development, scaling, and writing manufacturing batch records; (2) Producing JOC-x conjugates with distinct functionalities to demonstrate utility and flexibility of the platform; and (3) Testing these JOC-x conjugates in animal models At the conclusion of the research proposed here we will have produced a conjugatable tumor tight junction opening candidate that can be used in a number of embodiments. Each of the products could become stand-alone therapeutics and be developed towards clinical testing.

Public Health Relevance Statement:
PROJECT NARRATIVE Although progress has been made with cancer treatment there are still significant barriers to successful cures. By developing a tumor specific tight junction opener for cancer therapy we intend to make an impact on global health.

Project Terms:
Agonist; Animal Model; Back; Binding; Binding Proteins; Biological; cancer cell; cancer imaging; Cancer Model; cancer therapy; cancer type; Carcinoma; chemotherapy; Chromatography; Clinical; Coupled; Cyclic GMP; Cysteine; Data; desmoglein 2; Development; Dose; Doxorubicin Hydrochloride Liposome; Drug resistance; Ensure; Epithelial; epithelial to mesenchymal transition; Epithelium; Fermentation; flexibility; global health; Human; Image; Immune; Immune Targeting; Immunotherapy; in vivo; in vivo evaluation; Intravenous; intravenous injection; lipid nanoparticle; Maintenance; Malignant neoplasm of ovary; Malignant Neoplasms; Methodology; Modeling; Monoclonal Antibodies; Mus; nonhuman primate; Normal tissue morphology; Oncolytic viruses; overexpression; Particle Size; Patients; Penetration; Pharmaceutical Preparations; Phase; phase 1 study; Poly I-C; Polymers; prevent; Process; Production; Proteins; Publishing; Recombinant Proteins; Records; Reproducibility; Research; research clinical testing; scale up; Seeds; Serine; Signal Pathway; Site; Sterically Stabilized Liposome; T cell therapy; Testing; Therapeutic; Therapeutic Effect; Tight Junctions; TLR3 gene; Toxic effect; Transgenic Mice; Treatment Efficacy; tumor; tumor microenvironment; Tumor Tissue; Work; Writing; Xenograft Model; Xenograft procedure