DFMO Effects On Cancer Thwarted. Prior attempts at exploiting the higher polyamine requirements of cancer cells have not been successful because these living cells can compensate for the loss of one source of these metabolites (biosynthesis) by increasing their uptake from the other remaining source (bloodstream). The FDA-approved drug DFMO inhibits the rate-limiting biosynthesis enzyme, ODC, that produces the polyamines through biosynthesis. In a tour-de-force demonstration of modern scientists’ ability to design a molecule that specifically inhibits only this enzyme, great hope surrounded this drug’s description in 1978. Despite many attempts to demonstrate its effectiveness against various human cancer indications, it never lived up to its promise in the oncology clinic.

Subsequent scientific exploration showed, maybe not too surprisingly, that cancer cells can respond to a block in their biosynthesis of polyamines by increasing their importation of these metabolites from external sources via their blood supply. Plenty of polyamines are obtained through the diet and from gut microorganisms. Through a series of animal experiments, we now know that we need to block both known sources of cellular polyamines (biosynthesis and transport) to effectively deplete tumor polyamine levels.

Aminex Therapeutics, Inc.’s optimized lead compound, AMXT 1501 was designed to block polyamine uptake into cancers cells and does so in an extremely potent manner.¹ This potency is in the low nanomolar (10 parts per billion) level and Aminex has demonstrated the effectiveness of its PBT approach against fifteen different tumor cell lines grown in culture; including breast, prostate, melanoma and ovarian cancer lines. Furthermore, combination of these two drugs (designated as our new drug entity PBT) has demonstrated efficacy in breast² and prostate³ xenograft mouse tumor models.

Subsequently, using an advanced immuno-competent mouse model we observed an immune stimulation against the tumor. We believe that only by testing in the ‘whole’ biological system represented by this immuno-competent animal model, could the true promise of our PBT therapy be recognized. An equally dramatic observation was made when treatment was stopped, the tumors did not reappear! Positive results were recently obtained when treating spontaneous oral tumors in house cats with PBT therapy. The results from this Phase I/II veterinarian study have been accepted for publication⁴ and form the basis of our sub-license of our PBT technology to MBF Therapeutics, Inc. of Philadelphia, PA, developing it for use in the veterinarian field.

The elimination of established tumors in our experimental animal model, together with the durable effect against tumor reoccurrences clearly point to the most promising features of PBT therapy. A major advantage of PBT’s potential ability to induce an adaptive immune response would be its long-lived benefit. Drugs or antibodies target one cell at a time and then disappear…you have to give enough to kill every tumor cell. In contrast, with PBT’s adaptive mechanism, the amount of drug needed is multiplied by the catalytic power of the immune system to destroy the tumor. Importantly, with more recently approved targeted drug therapy, the ability of the tumor to overcome the drug’s block of a specific pathway is facilitated. With PBT, multiple immunological mechanisms of cancer cell killing are engaged at once. The chance that the tumor will be able to evade such a powerful onslaught is greatly minimized.

PBT represents a first-in-class therapeutic approach that promises to enable development of a small molecule drug with potentially broad applicability against numerous cancer indications. It differs from many previous attempts at exploiting polyamine metabolism in cancer cells because of its cytostatic instead of cytotoxic mechanism of action. In fact, by returning the levels of polyamines to their normal, non-cancerous levels, removal of the commonly observed tumor immunosuppression is accomplished. This allows the body’s natural immune system to perform its normal function; elimination of the transformed cancerous cells and tissue in a highly specific and far less damaging manner compared to standard cancer chemotherapy. We expect to not only significantly lower the side-effect profile with our therapy compared with standard care, but also to allow continued, long-term immuno-surveillance against metathesis and therefore guard against the re-occurrences of cancer. By developing PBT for human clinical use, we truly stand to change the way cancer is treated.

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 cancer targets including Prostate Cancer, Colon Cancer and Non-Hodgkin Lymphoma. 

Biological Summary:  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.

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.

1) Burns, M.R.; Graminski; G.F.; Weeks, R.S.; O’Brien T.G. Lipophilic lysine-spermine conjugates are potent polyamine transport inhibitors for use in combination with the polyamine biosynthesis inhibitor DFMO. J. Med. Chem. 2009, 52 (7), 1983-1993.

2) Skorupski, K.A.; O'Brien, T.G.; Guerrero, T.; Rodriguez, C.O.; Burns, M.R. Phase I/II clinical trial of 2-Difluoromethylornithine (DFMO) and a novel polyamine transport inhibitor for feline oral squamous cell carcinoma. Vet. Comp. Oncol. 2011, 9, published online March 8, 2011.

3) Weeks, R. S., Vanderwerf, S. M., Carlson, C. L., Burns, M. R., O'Day, C. L., Cai, F., Devens, B. H., and Webb, H. K. (2000) Novel lysine-spermine conjugate inhibits polyamine transport and inhibits cell growth when given with DFMO, Experimental cell research 261, 293-302.

4) Devens, B. H., Weeks, R. S., Burns, M. R., Carlson, C. L., and Brawer, M. K. (2000) Polyamine depletion therapy in prostate cancer, Prostate cancer and prostatic diseases 3, 275-279.