Targeted toxins (e.g., immunotoxins) are therapeutics that have at least two important components: (1) a toxin domain that is capable of killing cells and (2) a targeting domain that is capable of selectively localizing the toxic domain to only those cells which should be killed. By selecting a targeting domain that binds only to certain diseased cells (e.g., a cell which only expresses a cell surface receptor when in a diseased state), targeted toxins can kill the diseased cells while allowing healthy, essential cells to survive.

Topoisomerase 1 (TOP1) is an essential enzyme that plays a critical role in DNA transcription and replication. TOP1 inhibitors are a known class of anti-cancer agents that work to interrupt DNA replication in cancer cells, causing cell death. Since the discovery of the TOP1 inhibitor camptothecin (CPT) from plant extracts more than 60 years ago, two CPT analogs (irinotecan and topotecan) were approved by the FDA for cancer treatment. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is an enzyme involved in DNA repair created when TOP1 is inhibited.

The National Cancer Institute seeks parties interested in collaborative research to further co-develop monoclonal antibodies for the treatment of mesothelin-expressing cancers. The antibody was able to inhibit tumor growth in mouse xenograft models, and corresponding immunotoxins were able to inhibit tumor cell growth in vitro

The occurrence of thyroid cancer has been increasing in the United States. For some patients, with particularly advanced and metastatic cancer, current treatments such as thyroidectomy and adjuvant radioactive iodine therapy can lead to poor outcomes. Hence, there is a need for new thyroid cancer treatments.

BRAF is an oncogene that encodinges a serine-threonine kinase (B-Raf kinase) important in regulating cell growth and differentiation. Spontaneous mutations in the BRAF gene allow cells to continuously divide, leading to the development of cancer. A substitution of glutamic acid for valine at amino acid number 600 (designated V600E) accounts for 90% of BRAF mutations and is a driver of many cancers. The V600E mutation is present in ~3% of all cancer cases, representing a patient population of 540,000 patients per year.

Polo-like kinase 1 (Plk1) is a critical protein involved in regulation of mitosis, and aberrant expression of this kinase is found in various cancer types.  Inhibition of Plk1 is currently being pursued in pre-clinical drug development for novel anti-cancer therapeutics.  Plk1 contains an allosteric domain, known as the polo-box domain (PBD), that is responsible for localizing the kinase domain to mitotic structures through protein-protein interactions.  

Englerin A, a natural product, has shown growth-inhibiting activity against renal cancer cell lines. The compound is an agonist of protein kinase C (PCK) theta, which results in cell cytotoxicity, insulin inhibition, and selective activation of viral replication in T cells.  Englerin A derivatives are promising treatment strategies for any diseases associated with PKC theta and/or ion channel proteins.

Tumor necrosis factor receptor type 2 (TNFR2)-expressing regulatory T cells (Tregs), present in the tumor microenvironment, play an important role in tumor immune evasion. TNFR2 plays a crucial role in stimulating the activation and proliferation of Tregs, a major checkpoint of antitumor immune responses. In addition to its expression on Tregs, TNFR2 is also known to be overexpressed on some types of tumors and the survival and growth of these tumor cells is promoted by ligands of TNFR2.

Glaucoma is one of the world’s leading causes of irreversible blindness. There is no cure and vision lost from glaucoma cannot be restored. Glaucoma is associated with fluid build-up in the eye resulting in an increased intraocular pressure (IOP). The pressure may cause damage to the optic nerve and lead to progressive degeneration of retinal ganglion cells (RGC) and vision loss. Currently, available treatments for glaucoma delay progression by reducing IOP, but no therapies exist to directly protect RGC from degradation and loss. 

Current treatments for cancer and viral infection are limited remedies that often suppress cell or viral replication rather than eliminate diseased cells entirely from the body. A further limitation is that these therapies often compromise healthy cells as well, leaving problems of recurrence and side effects.

Researchers at developed a novel therapeutic nanoparticle (NP) system harboring therapeutic small siRNA that can significantly enhance effectiveness and specificity of treatments by killing diseased cells.