Simultaneous Ligand-Directed Cytotoxic Toxin and Endosome Disruptor Delivery to Ablate Prostate Cancer
Abstract
Prostate cancer is the second most common cancer, representing 10.7% of all new cancer cases within the U.S. This year 26,120 men in the U.S. will die from prostate cancer, the second leading cause of cancer death amongst men. A safe and effective chemotherapeutic option would relieve the burden of this disease on our healthcare system. The most common treatments, surgical prostatectomy or radiation therapy, are only viable for early-stage prostate cancers. Chemotherapeutics are preferred for metastatic cancers. Metastatic prostate cancer is a very deadly disease with a 5-year survival rate of only 28%. Prostate cancers that have metastasized are most commonly treated with androgen depletion therapy, which is only transiently effective. Thus, the need for an effective treatment to combat metastatic prostate cancer remains. The specificity of chemotherapies for cancer cells is established by either targeting a common cancer-inducing mutation or by inhibiting mitotic division. Preventing mitosis limits cancer progression but does not effectively eliminate the cancer. Alternatively, specificity toward cancer can be encouraged by directing chemotherapies to a cancer cell using an antibody or receptor ligand tethered to a chemotherapeutic drug. Prostate cancer cells express the gonadotropin releasing hormone receptor (GnRH-R) and the bombesin receptor 2 (BB2), which are not expressed in healthy prostate tissue. Both GnRH-R and BB2 targeted antagonists inhibit mitotic progression of prostate cancer. Moreover, both GnHR-R and BB2 agonist-doxorubicin conjugates prevent cancer progression in mouse xenograft models of human prostate cancer. GnRH-doxorubicin conjugates have effectively induced regression in 17% of patients and stabilized the cancer in 56% of patients in Phase II clinical trials. The use of a toxin that targets mitosis, doxorubicin, in these directed therapies is a result of a lack of cancer specific targets, illustrating the first limitation of targeted therapeutics. Ligand directed therapies are also limited by receptor-mediated internalization via endocytosis. Endocytosis is a process by which the cell membrane folds in on itself to form a membrane bubble that is taken into the cell. Thus, toxins internalized through endocytosis remain sequestered from the cytosol and are subject to degradation as the endosome is acidified. In this grant application, we propose a novel therapeutic strategy that would prevent sequestration of internalized toxins, while enhancing specificity to allow for cytotoxic chemotherapeutics. Both GnRH-R and BB2 signaling affect the progression of human prostate cancer. GnRH-R expression in healthy tissue is limited to pituitary gonadotropes and hypothalamic GnRH neurons. BB2 is expressed in the pancreas, stomach, adrenal cortex, and brain (source). Importantly, there is no overlap of BB2 and GnRH-R in healthy tissue. However, prostate cancer expresses both GnHR-R and BB2. By developing a therapy in which a toxin and endosome disruptor are simultaneously and differentially targeted to either the GnRH-R or BB2, we can induce co-internalization of a toxin and endosome disruptor. This allow for internalized toxins to escape the endosome and reach their site of action specifically in cells that express both receptors. This strategy exploits endosomal sequestration and degradation to enhance specificity, encouraging the use of cytotoxic chemotherapeutics that are sensitive to endosomal degradation. Moreover, this strategy decreases the efficacious in vitro dose of GnRH-RIP conjugates 100 million times. Rather than lament the endosomal degradation of targeted toxins, this innovative strategy uses endosome degradation of toxins to improve specificity and encourage efficacy at the targeted cancer cells. The work proposed in this grant has the potential to immediately impact the efficacy of a treatment (GnRH-doxorubicin) that is currently in Phase II clinical trials,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710398
Entities
People
- Josef Vagner
Organizations
- United States Army
- University of Arizona