Basis for the Clinical Use of TPA to Treat Hodgkins Lymphoma. In general, cure rates for Hodgkins disease are high but long term side-effects of treatment remain an important issue. A major goal is to find less-toxic treatments that do not have serious long-term side effects yet cure as many patients as possible. As a result, new chemo drugs and drug combinations used to treat other cancers are being studied in patients with Hodgkins disease. Also, targeted therapy drugs such as the histone deacetylase inhibitors have shown some early promise, and new studies are being planned for a series of monoclonal antibodies. Newer drugs are being sought that better target the Hodgkins disease cells. In general, efforts to find new and more effective treatments of Hodgkins Lymphoma is a major goal. In view of the critical need to develop better therapeutics for the treatment of Hodgkins, Rich Pharmaceuticals was formed to pursue the development of a molecule that has demonstrated some ability to reduce tumor size in a Hodgkins patient. This proprietary molecule (TPA) caused this effect in a Phase 1 study conducted at the Robert Wood Johnson Medical School at the University of Medicine and Dentistry at New Brunswick, New Jersey under the direction of a leading oncologist, Roger Strair MD (See Cancer Chemotherapy 57: 789 2006 A Phase I clinical trial with 12-O-tetradecanoylphorbol-13-acetate for patients with relapsed refractory malignancies). The early results of the Phase 1 study indicate that TPA administration results in short term/reversible toxicity at doses that can induce phenotypic alterations of malignant cells and result in biological and clinical effects. A Phase 2 study will be conducted by Rich Pharmaceuticals to confirm and extend the tumor reducing action of TPA in Hodgkins. With appropriate funding it is expected that this clinical study will be initiated before the end of 2015.
Properties of TPA. TPA is a phorbol ester that induces induction and differentiation and/or apoptosis in multiple cell lines. TPA has been demonstrated to modulate the growth, differentiation, survival, function and metabolism of other primary cells and cell lines. The broad range of these phorbol-mediated biological effects suggests a role for this drug in the modulation of a variety of cellular processes including those that affect the development, progression and therapy of human malignancies. It has been shown to activate protein kinase C (PKC) and modulates the activity of multiple downstream signaling pathways including mitogen activated protein kinase (MAPK) pathways. By inducing PKC it causes the formation of NF Kappa leading to the formation of NF Kappa B which has the ability to regulate cellular responses by entering the nucleus of the cell. NF-Kappa B binds to the DNA thereby inducing differentiation, proliferation, cytokine induction and/or apoptosis (see figure).
Intellectual Property Protection for TPA. A patent application for the use of TPA in Hodgkins Lymphoma has been filed under the title “Compositions and Methods of Use of Phorbol Esters for the Treatment of Hodgkins’s Lymphioma” by the inventor Richard L. Chang. The patent application and all intellectual property concerning the use of TPA to treat Hodgkin’s Lymphoma has been assigned to RBS for the clinical development of this molecule. The use of TPA to treat Hodgkin’s Lymphoma qualifies for Fast Track and Orphan Drug designation.
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