Lixte Biotech (OTC: LIXT.OB): A Combination Cancer Killer in Development

The Company has two lead programs of anti-cancer compound categories in preclinical development, including the LB-100 series (targeting serine / threonine phosphatase inhibitors which are involved in the regulation of cell signaling pathways associated with the cell cycle / DNA replication process) and the LB-200 series (targeting enzymes involved with the DNA backbone / structure known as histone deacetylases or HDACs). Lixte has a highly efficient, outsource-based drug development model that includes acquiring the intellectual property rights to promising compounds in preclinical stages and leveraging upon the facilities / scientists at NIH labs and other key scientific, drug development / formulation, and advisory collaborations.

The Company’s LB-100 series compounds are potent (200X more potent than phosphatase) selective inhibitors of protein phosphatase 2A with a mode of action that suggests beneficial combination with DNA-targeting, cytotoxic chemotherapeutic agents such as temozolomide and doxorubicin. Preclinical toxicology studies indicate a good therapeutic index (i.e. the lead compound in this series is effective at safe doses). In addition, a synthetic process is in place to make the drug in a stable form as a powder and solution.

Lixte’s LB-200 series of HDAC inhibitors includes a lead compound which has demonstrated promising activity against GBM in preclinical studies, in addition to having a good safety profile and stable synthetic process for both dry powder and solution formulations. This class of HDAC inhibitors has also demonstrated promising preclinical results in non-cancer indications such as anti-fungal effects and neural cell protective effects against chemical stress factors.

An abstract of the characterization of the neuroprotective effects of two lead compounds from the LB-200 series in standard assays of injury to normal embryonic mouse neurons supporting their continued development for the possible treatment of chronic neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease have been submitted for presentation at the annual meeting of the Society for Neuroscience in November 2009.

Lixte does not have any full-time employees with John S. Kovach, M.D., serving as the Company's sole administrative officer and founder. Dr. Kovach is a part-time Professor in the Department of Preventive Medicine at the State University of New York and has not received any compensation from Lixte since its inception in August 2005. Dr. Kovach is a world-leading figure in the cancer drug discovery community and is recognized for his previous leadership roles at the Mayo Clinic and City of Hope (which are NCI-designated comprehensive cancer care centers) in addition to inclusion in over 100 peer-reviewed publications related to cancer and drug discovery.

In early July, Lixte announced that the results of studies characterizing the novel and potent anti-cancer activity and mechanism of action of its lead compound (LB-1.2) both alone and in combination with standard chemotherapy drugs were published in a leading scientific journal, the Proceedings of the National Academy of Sciences.  The primary conclusion was that one of the Company's lead compounds appears to inhibit cancer cells by stimulating cancer cells to attempt to grow in the presence of a standard cancer drug and interferes with cancer cell defense mechanisms, with the end result being much greater damage to the cancer than occurs when treatment is limited to the standard anti-cancer drug.

The authors of this study concluded that treatment with the Company's compound LB-1.2 may be a general method for enhancing the therapeutic benefit of a number of standard cancer regimens, not limited to the original targets of brain tumors of adults and children. Based on the positive preclinical results for LB-1.2, Lixte believes its lead compounds have the potential to be used in combination with Temodar (for a similar commercial market opportunity) since nearly all patients with GBM relapse regardless of current treatments and the published study results offer a possible explanation for a synergistic mode of action that must be proven in human clinical trials

The authors concluded that treatment with the Company's compound LB-1.2 may be a general method for enhancing the therapeutic benefit of a number of standard cancer regimens, not limited to the original targets of brain tumors of adults and children. Each year about 19,000 people in the United States are diagnosed with primary brain cancers, according to NCI/NIH statistics. The estimated market for the treatment of GBM is about $800M annually based on the current use and pricing of an existing drug for the condition called Temodar (temozolomide or TMZ is classified as a DNA-methylating chemotherapy drug).  Temozolomide is given to nearly every patient with a diagnosis of GBM, including about 40,000 people in the U.S. and Europe each year.

In collaboration with NIH scientists, Dr. Kovach / Lixte have a new publication (Cell Cycle 8:20, 1-4; October 15, 2009) which is entitled, “Enhancement of cancer chemotherapy by simultaneously altering cell cycle progression and DNA-damage defenses through global modification of the serine/threonine phospho-proteome.” To summarize, Lixte’s lead compound has demonstrated positive preclinical results and has the potential to greatly enhance the cancer killing effects as part of combination treatment with chemotherapy drugs that target DNA as their mode of action such as temozolomide and doxorubicin. Lixte’s lead compound has a counter-intuitive mode of action that involves speeding up the cell cycle / DNA replication process of cancer cells despite the presence of chemo-induced DNA damage.

These cancer cells would otherwise lie dormant and repair the DNA damage caused by drugs such as Temodar, but in combination with Lixte’s compound, the cancer cells speed through the cell cycle / replication process to their demise. The authors of this article conclude that (1) the absence of toxicity in preclinical / animal model studies suggests that specific mutations in the signaling pathways regulating the cell cycle in cancer cells make them more vulnerable to this mode of action as compared to normal cells and (2) the mode of action of Lixte’s compound (global modulation of the serine-threonine phospho-proteome) may represent a general method of enhancing the anti-cancer effects of cytotoxic chemotherapy drugs by exploiting molecular defects in cell cycle regulation for targeted killing of cancer cells.

One lead compound (LB-1) is the most advanced in the process and Lixte plans to be ready for IND submission in mid-2010. The other lead compound (LB-2.5), which inhibits cancer cells by a different mode of action compared to LB-1, is anticipated to complete its evaluation by the end of 2010. If the Company is able to achieve a strategic partnership and funding from an established pharmaceutical company to co-develop its compounds, the development process is expected to occur more quickly since these two lead compounds are well characterized with regards to their activity and mechanism of action.

The encouraging preclinical results for Lixte’s lead compound as an add-on treatment for brain cancer, the unmet medical needs for effective brain and pancreatic cancer treatments, the pending patents for Lixte’s lead compound, and the growing body of scientific / preclinical evidence should help to increase the awareness of Dr. Kovach and the Company’s research efforts and result in funding to expedite the process of proceeding to a Phase I / II clinical trial for the treatment of GBM, which is an urgent unmet medical need due to the poor prognosis and aggressive nature of this most common type of brain cancer.

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