Cancer Treatment

One of the major applications of CBLI’s apoptosis-modulating technology is for cancer treatment. Most human tumors acquire defects that make them resistant to apoptosis such as constitutive activation of the anti-apoptotic factor NF-kappaB and /or inactivation of the pro-apoptotic factor p53. Pharmacological restoration of apoptotic pathways could result in direct tumor cell killing or sensitization of tumor cells to the effects of traditional cancer therapies. CBLI has discovered several classes of proprietary small molecule compounds, called Curaxins, that simultaneously inactivate NF-kappaB signaling and restore p53 signaling, effectively reversing the death-resistant tumor phenotype. Given the significant incidence of cancer worldwide and the lack of effective treatments for many types of malignant disease, Curaxins have the potential to make an important impact on a large oncology market.
Background and Rationale
The initial focus of CBLI’s anti-cancer drug development program was one of the most treatment-resistant types of cancer, a highly fatal form of kidney cancer called renal cell carcinoma (RCC). A drug discovery program was initiated to identify small molecules that selectively destroy tumor cells by restoring normal activity to the wild type, but functionally impaired, p53 expressed in RCC. This program yielded a number of molecules with the desired properties, which were named Curaxins.

Curaxins have a unique mechanism of action that involves simultaneous activation of p53 and inhibition of NF-kappaB, thus reversing two of the conditions frequently associated with tumor onset and maintenance. Strategies targeting p53 or NF-kappaB independently have been validated as cancer therapies; however, Curaxins are the only compounds currently known to CBLI that simultaneously target both pathways.

Since NF-kappaB induces expression of numerous genes with anti-apoptotic, cell growth-inducing and pro-inflammatory functions, the constitutive NF-kappaB activity typical of tumor cells renders them resistant to apoptosis and supports tumor cell proliferation, motility, metastasis and angiogenesis. Importantly, Curaxins inhibit the function of both basal and activated NF-kappaB by “reprogramming” NF-kappaB-containing protein complexes from transcription activators to transcription repressors. Thus, Curaxins are most effective in tumor cells since they contain increased levels of total NF-kappaB protein as compared to normal cells. This suggests that Curaxins might be useful in sensitizing tumor cells to traditional therapies that otherwise impair their own anti-cancer activity by inducing NF-kappaB.

The p53 tumor suppressor gene is frequently mutated or deleted in human cancers. Moreover, p53 is functionally compromised in about 50% of tumors that retain the wild type p53 gene. Curaxins restore functionality to the wild type p53 protein in such tumor cells. Importantly, unlike traditional chemotherapeutic agents, activation of p53 by Curaxins does not involve induction of DNA damage.

Discovery of the mechanism of action of Curaxins allowed CBLI to predict and later experimentally verify that Curaxins could be used for treatment of multiple forms of cancers, including RCC, hormone-refractory prostate cancer, hepatocellular carcinoma, multiple myeloma, acute lymphocytic leukemia, acute myeloid leukemia, soft-tissue sarcoma and others. While Curaxins are most effective in inducing death of tumor cells retaining wild type p53, they also display significant toxicity towards p53-deficient tumor cells, suggesting that inactivation of NF-kappaB on its own can be sufficient to achieve the desired therapeutic effect. This greatly broadens the potential use of Curaxins in patients regardless of the p53 status of their tumor.

CBLI’s lead product candidate for cancer treatment is Curaxin CBL102, which is currently in Phase II clinical trials. Other Curaxins are being validated in preclinical studies.

Lead Compounds
Curaxin CBLC102
One of CBLI’s first generation Curaxins with a 9-aminoacridine-related structure (CBLC102) is the well-known compound Quinacrine. Quinacrine has been used in humans for over 60 years to treat malaria, osteoarthritis, autoimmune disorders and other conditions. However, its ability to destroy tumors through inactivation of NF-kappaB signaling and restoration of p53 signaling is a novel discovery made by CBLI.

CBLI’s development of Quinacrine for the novel application of cancer treatment has benefited from its long history of human use. The compound has well-established toxicity and pharmacokinetics profiles and is characterized as a safe, non-carcinogenic and orally available drug.

CBLI has demonstrated that CBLC102 (Quinacrine) displays significant cytotoxic activity against human malignant cell lines of multiple origins, including renal cell, prostate, colon, lung, and hepatocellular carcinoma, sarcoma, multiple myeloma and leukemia. At the same time, CBLC102 shows minimal in vitro cytotoxicity towards prototype normal cells. While CBLC102 is most potent against tumor cells expressing wild type p53, the compound also displays significant toxicity against p53-negative cancers. Notably, cell lines that are resistant to standard chemotherapy (for example, doxorubicin) were found to be sensitive to CBLC102. In vivo experiments using human tumor xenografts in mice confirmed the anti-cancer activity of CBLC102.

Development Status of CBLC102: Due to its prior use establishing safety in humans, CBLC102 is eligible for expedited development (fast track to Phase II) as a novel anti-cancer agent with a unique mechanism of action. CBLI has an agreement with Regis Technologies, Inc., a cGMP manufacturer, to produce CBLC102 according to the established process used when the drug was in common use. In May 2006, CBLI filed an IND application with the FDA to begin Phase II clinical trials in patients with advanced hormone-refractory (androgen-independent) prostate cancer (HRPC). Information on the ongoing HRPC trial is available at www.clinicaltrials.gov (using Cleveland BioLabs in the search tool). Ongoing and planned clinical trials for CBLC102 are listed at Clinical Trials.

CBLI has applied for U.S. and international patents covering the use of Curaxin CBLC102 as an anticancer agent based upon a newly-discovered mechanism of action, and is also planning to seek orphan drug status from the FDA for the use of Curaxin CBLC102 to treat various cancers. The orphan drug provisions of the Federal Food, Drug, and Cosmetic Act provide incentives to drug and biologic manufacturers to develop drugs for the treatment of rare diseases, currently defined as affecting fewer than 200,000 individuals in the U.S. Under these provisions, a manufacturer of a designated orphan drug can seek tax benefits, and the holder of the first orphan drug designation approved by the FDA will be granted a seven-year period of marketing exclusivity for that drug.

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Other Curaxins
In addition to developing CBLC102, CBLI is also focused on discovery of additional Curaxin compounds. Active chemical core structures have been identified through chemical library screening and extensively analyzed for structure-function relationships. This work has been performed in collaboration with medicinal and synthetic chemists at Chembridge Corporation (www.chembridge.com). Using proprietary computational chemistry approaches, CBLI has generated a number of second generation Curaxin molecules that display p53-activating, NF-kappaB-inactivating, and cytotoxic properties that are qualitatively identical to those of CBLC102. However, these compounds have chemical structures that are distinct from CBLC102 and typically display greatly improved efficacy in comparison to CBLC102. Some of these advanced Curaxin compounds have already been tested in vivo in mouse xenograft cancer models and have demonstrated potent antitumor activity.
Development Status of Other Curaxins: Pre-clinical studies in animal model systems are ongoing. It is expected that a second generation of Curaxins will enter formal development in 2008.

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