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 established safety in humans through its prior use, CBLC102 was 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. CBLI launched a Phase II study with CBLC102 in January 2007 to provide proof of safety and of anti-neoplastic activity in cancer patients and establish a foundation for clinical trials of CBLI’s new proprietary Curaxin molecules, which have been designed and optimized for maximum anticancer effects, as well as for additional treatment regimens based on ongoing research into the precise molecular mechanisms of action of Curaxins.

Thirty-one patients were enrolled in a Phase II study of CBLC102 as a monotherapy in late stage, hormone-refractory taxane-resistant prostate cancer. All patients had previously received hormonal treatment for advanced prostate cancer and 28 of the 31 had also previously received chemotherapy. One patient had a partial response, while 50% of the patients exhibited a decrease or stabilization in PSA velocity, a measure of the speed of prostate cancer progression. CBLC102 was well tolerated and there were no serious adverse events attributed to the drug.

This clinical evidence indicates several opportunities for extending development of CBLC102 into other cancer types, dose escalation or use in combination with existing therapies. The Company will be evaluating these opportunities, while moving more aggressively forward with a new generation of more powerful, proprietary Curaxin molecules with similar mechanisms of action, which offer improved patent protection.

Next Generation Curaxins
CBLI has successfully completed a comprehensive hit-to-lead optimization program directed towards development of new proprietary Curaxin molecules simultaneously targeting p53 and NF-kB. Working in partnership with ChemBridge Corporation, a chemical libraries manufacturer and CBLI co-founder, the Company has developed CBLC137; which is a drug candidate with proprietary composition of matter intellectual property protection belonging to CBLI’s next generation of highly improved Curaxins.

CBLC137 has demonstrated reliable anti-tumor effects in animal models of colon, breast, renal and prostate cancers. CBLC137 has favorable pharmacological characteristics, is suitable for oral administration and demonstrates a complete lack of genotoxicity. It shares all of the positive aspects of CBLC102, but significantly exceeds the former compound’s activity and efficacy in preclinical tumor models. CBLC137 is currently undergoing manufacturing and preclinical toxicology studies in preparation for clinic trials in early 2010.

Development Status of Next generation Curaxins: CBLC137 is currently undergoing manufacturing and preclinical toxicology studies in preparation for clinic trials in early 2010.