We can turn potentially deadly forms of cancer into manageable conditions.
We believe that we can specifically target Cyr61 (CCN1) to develop therapeutic agents that would theoretically reduce the lethality of tumor-based cancer to a chronic but comfortably manageable condition. The approach that our therapeutic agent uses is the suppression of angiogenesis (the growth of blood vessels). This is the same approach used by blockbuster drugs such as Avastin and Herceptin. However, where the current market’s anti-angiogenesis drugs have limited efficacy in most cases, we have strong evidence to believe that our target will produce an anti-angiogenesis drug that has long lasting efficacy.
Anti-angiogenesis approach to treating cancer
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The theory behind this approach to treat cancer is to suppress angiogenesis to inhibit cancer cell growth. By limiting blood flow to the tumor cells, normal essential nutrient needs of the body would not be compromised, and the nutrient-starved tumors would remain too small to interfere with any vital organ functions, thus reducing their lethality to a chronic but easily manageable condition.
Since tumor-specific vasculature is approximately 1,000-fold less stable than normal (non-tumor) vasculature, it must be constantly replenished through tumor-induced angiogenesis to sustain the ever-increasing blood flow needed to support unabated tumor growth. This vulnerability of tumor-specific vasculature provides the opportunity to limit tumor cell growth by the deployment of angiogenesis suppressing reagents. Because angiogenesis suppressing agents need not be mutagenic, their use would not hasten the emergence of drug-resistant (and usually lethal) forms of cancer, or engender problematic side effects such as immune system loss, toxic death, nausea & hair-loss, etc., and thus have major advantages over the conventional mutagenic cytotoxic anti-cancer therapies. |
The nutrient-starved tumors would remain too small to interfere with any vital organ functions |
Current anti-angiogenesis therapeutic limitations
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Initially, clinical administration of existing therapeutics (such as Avastin) to the appropriate cancer patients quickly resulted in effective suppression of tumor angiogenesis and tumor growth, leading to tumor shrinkage. This observation provided firm clinical support for the therapeutic approach of using tumor angiogenesis suppression to suppress cancer growth. However, it is now established that Avastin can prolong the lives of the treated cancer patients by only a few months on average, whereas Herceptin can only be used to treat Her2 over-producing cancer cells, which are found in only a minor subset (around 20%) of only breast cancer cases, and can also become ineffective over time.
Two recent detailed surveys of the long-term effectiveness of these drugs revealed that these biologics would abruptly cease to suppress tumor angiogenesis a few months after the treated patients had initiated using the therapeutics. Curiously, when tumor angiogenesis resumes pursuant to the loss of efficacy of the therapeutics, the new tumor vasculature formed is considerably more robust and stable than the tumor vasculature that formed prior to the use of these therapeutics. |
Since angiogenesis suppressing agents are designed to stifle tumor cell growth by nutritional starvation instead of directly killing tumor cells through the intra-cellular accumulation of cytotoxic chemicals like classical chemotherapeutic agents, this observed sudden loss of efficacy in Avastin and Herceptin cannot arise from the selected appearance of classical drug-resistance mutations in the tumor cell efflux pump systems.
Mainstream tumor angiogenesis experts in the industry were, in fact, unable to come up with a cogent theoretical explanation for the observed sudden loss of efficacy in these angiogenesis suppressing biologic agents.
Nevertheless, despite these limitations, the combined annual global revenues generated from the sale of Herceptin and Avastin remains consistently in excess of CHF$10 billion from the sale of these two therapeutics for the past several years, because there are simply no better currently available alternatives for these patients.
Mainstream tumor angiogenesis experts in the industry were, in fact, unable to come up with a cogent theoretical explanation for the observed sudden loss of efficacy in these angiogenesis suppressing biologic agents.
Nevertheless, despite these limitations, the combined annual global revenues generated from the sale of Herceptin and Avastin remains consistently in excess of CHF$10 billion from the sale of these two therapeutics for the past several years, because there are simply no better currently available alternatives for these patients.
Cyr61 (CCN1) protein’s role as the key downstream convergent junction molecule in the angiogenesis process
Our published and unpublished data as well as a vast amount of data accumulated in the past decade from multiple research groups has now provided firm support that Cyr61 is a key downstream convergent junction signaling molecule that directly implements the tumor-angiogenesis process initiated by multiple proven upstream tumor growth-promoting angiogenic factors (refer to Figure below). This conclusion that Cyr61 is induced by, and is a common downstream angiogenic effecter of the activities of multiple important tumor growth-promoting angiogenic factors including VEGF, FGF (Fibroblast Growth Factor) and PDGF (Platelet-Derived Growth Factor), etc. is one of the most overlooked aspects of Cyr61’s significance in angiogenesis suppression research. This key role that Cyr61 plays in tumor-angiogenesis has been best demonstrated in all forms and stages of breast cancers, especially in those that are the most aggressive and treatment-resistant.
Cyr61 expression is induced by tumor-growth/angiogenesis factor VEGF (and other angiogenic growth factors [GFs]) and further functionally enhances and induces the expression of VEGF (and other GFs) through the activation of alpha6beta1 integrin receptors of neighboring fibroblasts to establish a closed-circuit “VEGF/GF/Cyr61 signal amplification loop”. This signal amplification process would allow for the formation and radiating transmission of an angiogenesis signaling gradient that can direct new blood vessel growth towards the tumor-secreted and immobilized Cyr61 (refer to the red arrow in Figure). Consequently, blocking Cyr61 activity alone can (and does) suppress the angiogenic activity of an upstream angiogenic growth factor/receptor that acts through Cyr61.
Cyr61 expression is induced by tumor-growth/angiogenesis factor VEGF (and other angiogenic growth factors [GFs]) and further functionally enhances and induces the expression of VEGF (and other GFs) through the activation of alpha6beta1 integrin receptors of neighboring fibroblasts to establish a closed-circuit “VEGF/GF/Cyr61 signal amplification loop”. This signal amplification process would allow for the formation and radiating transmission of an angiogenesis signaling gradient that can direct new blood vessel growth towards the tumor-secreted and immobilized Cyr61 (refer to the red arrow in Figure). Consequently, blocking Cyr61 activity alone can (and does) suppress the angiogenic activity of an upstream angiogenic growth factor/receptor that acts through Cyr61.
To date, the accumulated published evidence gleaned from hundreds of articles in the scientific literature provides firm support that Cyr61 possesses all the characteristic properties expected of the elusive tumor-secreted effecter protein that directly induces tumor-angiogenesis, and is a proven angiogenesis effecter protein secreted by all late stage breast cancer tumors. In addition, Cyr61 is in fact a required molecule for the pre-natal developmental establishment of a stable mammalian cardio-vascular system.
A scientific explanation for why current anti-angiogenesis drugs lose efficacy
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It is now known that rapidly dividing mammalian cells (including tumor cells) starved for blood supply (which would happen to tumor cells treated with anti-angiogenesis therapeutics) would become hypoxic (lacking oxygen) and would automatically activate a defensive gene expression program to direct the building of stable vessels towards the distressed hypoxic cells. This genetic signaling program is initiated by the default production of Hypoxia Inducing Factors (HIFs) in the hypoxic cells. These HIFs have now been shown to directly activate growth-factor independent expression of Cyr61 in the hypoxic cells. Since Cyr61 is also the proven effecter protein that activates tumor-angiogenesis, its secretion would lead to the resumption of the tumor-angiogenesis program despite the presence of either Avastin or Herceptin and bring blood supplied relief to the oxygen-starved cells.
These recent reports thus provide a scientific explanation for why anti-angiogenesis agents such as Avastin and Herceptin would cease to have anti-angiogenic effects once they succeeded in starving the targeted tumor cells into a hypoxic state, at which time the hypoxic cells would begin producing HIFs to activate Cyr61 production and reinitiate the suppressed tumor-angiogenesis. Because Cyr61 is a proven angiogenesis inducing effecter, it stands to reason that any attempts to suppress tumor angiogenesis using agents that induce hypoxia would be doomed to fail within a few months, as with the case of Avastin and Herceptin, if the problem posed by hypoxia induced Cyr61 expression is not addressed. |
These recent reports provide a scientific explanation for why anti-angiogenesis agents would cease to have anti-angiogenic effects once they succeeded in starving the targeted tumor cells. |
Challenging current cancer treatment drugs: Why our treatment will work where others have not
For these reasons, cancer cells treated with effective anti-Cyr61 therapeutics should be a preferred approach to suppress cancer cell growth through angiogenesis suppression, because tumors thus treated would be unable to bypass this anti-angiogenesis treatment by switching on either:
Moreover, there is now also mounting evidence that Cyr61 is actually directly responsible for starting the metastasis process itself, and that suppression of Cyr61 expression would sensitize tumor cells to cytotoxic chemotherapeutic agents such as Taxol. Studies on breast cancer has demonstrated that Cyr61 overexpression is tightly linked to breast cancer cells becoming resistant to standard cytotoxic chemotherapeutic agents like Taxol and that suppressing Cyr61 expression significantly enhances the efficacy of Taxol in treating advanced breast cancer.
Therefore Cyr61 must now be considered the clinical target of choice for developing a truly effective broad-spectrum anti-angiogenesis anti-cancer therapeutic.
- an alternative parallel angiogenic growth factor induced Cyr61-mediated signaling pathway; or,
- a direct expression of Cyr61, independent of any upstream growth factor signaling pathways, which can occur in rapidly dividing hypoxic cells that will arise from any anti-angiogenesis anti-cancer treatment.
Moreover, there is now also mounting evidence that Cyr61 is actually directly responsible for starting the metastasis process itself, and that suppression of Cyr61 expression would sensitize tumor cells to cytotoxic chemotherapeutic agents such as Taxol. Studies on breast cancer has demonstrated that Cyr61 overexpression is tightly linked to breast cancer cells becoming resistant to standard cytotoxic chemotherapeutic agents like Taxol and that suppressing Cyr61 expression significantly enhances the efficacy of Taxol in treating advanced breast cancer.
Therefore Cyr61 must now be considered the clinical target of choice for developing a truly effective broad-spectrum anti-angiogenesis anti-cancer therapeutic.