Media.Player

A Cure from within: promoting Self Destruction of Cancer Cells (Carmel)

Summary

A rapidly growing section in the pharmaceutical market is searching for drugs that specifically trigger the cell-death-apoptotic process in cancer cells. We are developing therapies based on smart proteins that restore the ability of cancer cells to commit suicide apoptosis). Particularly, we are using drugs based on ARTS, a proprietary powerful pro-apoptotic protein
Great Interest in Apoptosis and IAP Antagonists as targets for cancer therapies All the cells in our body have the ability to self-destruct by activating an intrinsic cell suicide program termed Apoptosis, which greatly limits the accumulation of damaged and potentially dangerous cells. Cancer cells, however, can acquire resistance to cell death by deactivating cell suicide pathways. Today, nearly all anti-cancer therapies such as chemotherapy and radiation act through activation of the apoptosis pathways in cancer cells.

Apoptosis (programmed cell death) is essential in the development and survival of multicellular organisms. Aberrations in this process play a key role in the pathogenesis of many human diseases, ranging from degenerative disorders to autoimmunity and are the hallmark of most if not all types of cancer.

The IAP (Inhibitors of Apoptosis Proteins) family is an important family of anti-apoptotic proteins. IAPs are up-regulated in many cancers, conferring upon cancer cells a resistance to apoptosis. This allows cancer cells to expand unlimitedly at the expense of normal cells. Furthermore, cells that over-express IAPs are more resistant to traditional cancer treatments such as chemotherapy and radiation, which act by inducing apoptosis. Not surprisingly, recent years have shown a growing interest in drugs that trigger the apoptotic process in cancer cells. Many companies and academic institutes are currently conducting R&D programs focusing specifically on IAP antagonists as potential anti cancer drugs.




ARTS is a proprietary IAP antagonist which is a key regulator of apoptosis

ARTS, discovered by Dr. Larisch, is a mitochondrial protein that acts downstream in the apoptotic pathway as a potent IAP antagonist. ARTS activation in the cell is one of the last stages in the cascade that irreversibly promotes the cell destruction process. In fact, ARTS is localized at the "no-return point" which initiates the irreversible stage in the apoptotic cascade.

ARTS is expressed in all normal tissues that have been tested. In many types of cancer, on the other hand, its levels are highly reduced. By losing the ARTS protein, cancer cells gain a selective advantage which allows them to escape apoptosis and multiply. An ARTS based drug would be effective in restoring apoptosis to a wide range of target cancer types, including cancers which lost the ARTS protein specifically, as well as cancer types which exhibit high levels of IAPs. These cancers include Breast, Ovarian, colorectal, bladder and prostate Carcinoma, leukemia (AML), multiple myeloma, hepatocellular carcinoma and melanoma. Importantly, as only tumor cells lack ARTS expression, or express IAPs at high levels, these cancer cells will be more sensitive to ARTS-anti-IAP therapy than normal cells. An ARTS-based drug would restore ARTS levels in cancer cells which lost ARTS, and/or would reduce IAP levels in cancer cells over expressing IAPs. The result in both cases would be selective killing of these tumor cells

Technology Benefits

In contrast to traditional anti-cancer treatments, over-expression of ARTS specifically kills cancer cells and not healthy cells. In fact, experiments conducted in our lab have shown that normal lymphocytes from healthy donors were not affected by doses of ARTS five times higher than those needed to effectively kill cancer cells.

While ARTS may ultimately replace current cancer treatments, it may also be used to enhance their efficacy. Cells which exhibit loss of ARTS protein, or even reduced levels of ARTS, show increased resistance to chemotherapy-induced apoptosis. Treatment of these non responsive cells with ARTS can cause them to regain their responsiveness to chemotherapy.

ARTS’ mode of action as an IAP antagonist is unique, and so far it is the only IAP antagonist found to function as a tumor suppressor protein.

ARTS contains a unique binding motif to IAPs which is not found in any other protein or any other IAP-antagonist.

ARTS binds directly and specifically to XIAP, which is considered the most potent inhibitor of caspases. ARTS induces apoptosis through binding and induction of proteosome-mediated degradation of XIAP.

Since ARTS does not bind to IAPs through the same binding motif as other IAP antagonists (Smac/Diablo), ARTS could be used in combination with other IAP antagonists for achieving a complementary potentially more effective pro-apoptotic effect.

Inhibiting the apoptotic process in neurodegenerative and auto immune diseases Neurodegenerative and auto-immune diseases are characterized by excessive cell death. As opposed to cancer treatment, in these pathologies inhibition of the apoptotic process is desired. This can be achieved using ARTS-agonists, which compete with endogenous ARTS and other IAP antagonists and thereby disrupt and prevent the unwanted apoptotic process

Patent Information

The technology is protected by six patent applications in different stages of examination. These patents protect our rights to use ARTS and its derivatives as drug candidates in cells that do not express ARTS or contain it in low amounts, and specifically to use ARTS and its derivatives as drug candidates in Leukemia. They protect our rights to use complexes containing ARTS and IAP as well as ARTS-mimetic compounds for treating various diseases. The last patent relates specifically to the use of a smaller derivative of ARTS developed as a drug candidate

Others

Future Opportunities:

The interest in Apoptosis based therapy is rising specifically in developing anti-cancer drugs based on IAP-anatgonists. There are currently more than 50 companies that have reported developing apoptosis based therapies, and at least eight major companies which specifically develop IAP targeted therapy. Companies currently working on developing IAP-antagonists (based on SMAC (SMAC mimetics). Novartis, Abbot, Genentech, Bristol Meyers Squib (MBS), Aegera (Canada), Ascenta, Tetralogics , Joyant Pharmaceutical. San-Diego. Ca. Importantly, all current IAP-antagonists developed as anti-cancer drugs are based on the specific IAP-Binding Motif (IBM) found in SMAC. ARTS contains a novel, unique binding motif, which serves as the basis for developing ARTS-based IAP-antagonist anti-cancer drug. However to date, ARTS is the only IAP antagonist shown to have a tumor suppressing effect, and to degrade XIAP rather than cIAP1. Of interest, a few years ago, California based Idun Pharmaceuticals was purchased by Pfizer for an estimated $300 million. IDUN targets key proteins within the apoptosis pathway, and was the flagship company in apoptosis related research, being the first company founded which was focused solely on apoptosis based therapies.

The Business Model:

Our long term goal is to develop a variety of ARTS based therapies. We intend to focus initially on developing a small ARTS–mimetic molecule for the treatment of selected cancer types. Once reaching late development stages, we will seek collaborations with major pharmaceutical companies. Such collaboration will help us bear the development costs, while enabling it to retain partial marketing rights in selected countries. Upon entering clinical trials with LEAD candidates for treatment of selected cancers, we will consider joint programs for the development of ARTS based therapy for other types of cancers and will also seek to out license the technology for treatment of neurodegenerative diseases (i.e. Parkinson and Alzheimer), where the apoptotic process needs to be halted.

Milestones and Needed Investment:

We are currently focusing on optimizing ARTS–based peptide-mimetics to ARTS-based small- molecule drugs. We currently have small (5-9 amino acids) ARTS derived peptides which will be tested for binding and neutralizing IAPs as well as for their selective apoptotic activity. Once the shortest peptide is identified and tested, we will focus on the identification of a small molecule, which could become the therapeutic LEAD molecule. The optimized small ARTS-based-molecules will be tested in specific cancer animal models followed by pre-clinical studies later on. We are currently seeking a $2 million investment which will enable us to complete optimization of lead compound, and animal pre clinical studies within the next three years

Country/Region

Israel