Aminex Therapeutics, Inc.
Aminex Therapeutics, Inc.’s goal is to develop PBT for human clinical oncology practice and thereby become a leader in the development of the next generation of cancer chemotherapeutic products.
Background: Humanity’s ability to use chemotherapeutic agents to interrupt cellular metabolic processes constitutes a significant achievement and has supported much advancement in medical treatment over the last half century. As one of the first rationally designed chemotherapeutics, difluoromethylornithine (DFMO) once held great promise in the fight against cancer. Despite early results achieved against cancer cells grown in tissue culture, the use of this mechanism-based inhibitor of the first step in the biosynthesis of polyamines failed to translate into the oncology clinic. Nevertheless, DFMO (also known as eflornithine) has found use against the parasite that causes trypanosomiasis, also called African sleeping sickness. Dr. Henry Laelman cured a woman from a deeply comatose state using DFMO and named the drug "the resurrection drug" for its curative activity in late-stage African sleeping sickness. Technology Summary: Cancer cells can overcome the ability of drugs such as a-difluoromethylornithine (DFMO), based on inhibition of polyamine biosynthesis, from completely depleting their internal polyamines by the importation of these molecules from external sources. The company has developed a group of lipophilic polyamine analogs that potently inhibit this polyamine uptake system and greatly increase the effectiveness of polyamine depletion when used in combination with DFMO, even in the presence of extracellular polyamine. The company has produced and patented additional series of analogs with several orders of magnitude higher potency against a variety of cultured cancer cell types. The resulting novel two-drug combination therapy targets cellular polyamine metabolism and has shown exceptional efficacy against cutaneous squamous cell carcinomas (SCCs) in a transgenic ornithine decarboxylase (ODC) mouse model of skin cancer. A majority (88%) of large, aggressive SCCs exhibited complete or near-complete responses to this combination therapy, while responses to each agent singly were poor. The availability of a potent polyamine transport inhibitor allows, for the first time, for a real test of the hypothesis that starving cells of polyamines will lead to an objective clinical response. The biological association between increased polyamine concentration and tumor growth is well established. Numerous multidisciplinary studies have shown that intracellular concentrations of polyamines are highly regulated at many steps in their biosynthesis, catabolism and transport. The fact that the cell contains such a complex apparatus for the tight control of the levels of these molecules indicates that specific concentrations are required depending on the dynamics of cell growth, differentiation and cycling. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, catalyzes the conversion of ornithine to putrescine; which is then converted to the tri- and tetra-amines spermidine and spermine. An increase in the activity of ODC has been associated with tumor growth. Inhibition of polyamine biosynthesis in cells in culture by a-difluoromethylornithine (DFMO), a well-studied mechanism-based inhibitor of ODC, causes a substantial depletion of intracellular putrescine and spermidine with resultant cell growth inhibition. Upon supplementing the culture media with exogenous polyamines, this depletion causes transport activity to rise several-fold, allowing the cells to return to their original hyperproliferative rate of growth.
Head and Neck Squamous Cell Carcinoma (HNSCC) is the fifth most common cancer in men with an incidence of about 780,000 new cases per year worldwide and a poor rate of survival. The majority of tumors (95%) that arise in the head and neck region are squamous cell carcinomas and the progressive local growth of these tumors impinge on the highly critical functions of speech, swallowing and respiration. Clinical trials pursing this $400 million annual market opportunity include several ongoing trials by Roche, Lilly and GSK for the 40,000 patients annually diagnosed with HNSCC in the U.S. The company’s positive animal data in mice and house cats with HNSCC supports PBT therapy’s use against additional cancer targets including melanoma and colon cancer (68,720 and 146,970 new cases in the U.S. expected in 2009).
Aminex Therapeutics has licensed a group of lipophilic polyamine analogs that potently inhibit the mammalian polyamine uptake system and greatly increase the effectiveness of polyamine depletion when used in combination with DFMO. The resulting novel two-drug combination therapy targets cellular polyamine metabolism and has shown great effectiveness against a variety of cancer cells grown in culture together with two animal models of cancer. Extensive research now points to the fact that proliferating cells treated with DFMO can overcome this metabolic blockage by importing their required polyamines from extracellular sources. By compensating for the loss of one avenue for obtaining polyamines, the cell utilizes an alternative biochemical mechanism to obtain the molecules necessary for survival and continue to proliferate. Aminex Therapeutics’ Polyamine-Based Therapy (PBT) approach blocks both these routes for obtaining polyamines.
The Company expects to dramatically shorten the time-frame for product development by leveraging discovery work already performed. These initial discovery, optimization and animal proof-of-concept stages have already been accomplished at MediQuest Therapeutics, Inc. Furthermore, the Company expects a substantial portion of the remaining pre-clinical development work to be performed by the National Cancer Institute through an already awarded Rapid Access to Interventional Development (RAID) grant. Overall, the Company is well-positioned to rapidly advance these novel discoveries for the benefit of cancer patients.
Company Goals and Objectives: The company’s goal is develop PBT (polyamine-based therapy) for introduction into clinical practice and thereby become a leader in the development of the next generation of cancer chemotherapeutic products. Our molecularly targeted approach should be useful against many hyperproliferative disease states, yet due to the strong animal efficacy data in hand, it is the strategy of the company to pursue its use for Head and Neck Squamous Cell Carcinoma (HNSCC) as its first cancer indication. Substantial animal proof of concept data supports PBT therapy’s use against additional skin cancer targets including melanoma and colon cancer.
Aminex - It's what's Next!
