In the early 70's, Dr. Judah Folkman described a new paradigm for the treatment of cancer. This concept, anti-angiogenesis, aimed to inhibit the formation of tumor specific vasculature with the resulting starvation and ultimate death of malignant neoplasms. In the last 30 + years, a literal cottage industry formed to understand angiogenesis and to create drugs that would inhibit tumor cell initiated angiogenesis. Much of the early work revolved around inhibiting single cytokines, notably vascular endothelial growth factor (VEGF). One of the first of such inhibitors was Sugen's SU5416, a small molecule drug tyrosine kinase inhibitor of VEGF signalling. It later became clear that angiogenesis could be initiated by not one but many angiogenic cytokines. Work then began in earnest to broaden the activity of a single cytokine approach by creating other drugs that could inhibit two or more angiogenic cytokines. However, as cancer cells have been shown to secrete over 30 angiogenic cytokines (as cancer progresses, the multitude of angiogenic cytokines secreted by cancer cells increases over time) it has been difficult to come up with cytokine neutralizing agents or tyrosine kinase pathway inhibitors to inhibit such a wide variety of angiogenic cytokines. For this reason, pharmaceutical companies have been searching for anti-angiogenic agents that are safe yet broadly inhibit cancer. Unfortunately, even if such an agent was identified and angiogenesis was completely inhibited, one would still not be able to kill cancer since the periphery of the cancer is fed by normal vessels. To completely destroy cancer one would need to kill both the central tumor region and the tumor rim.
Conventional cancer therapy, chemo or radiation, is not particularly successful at targeting the central core of cancer since it is difficult to get chemotherapeutic agents into the central areas of the tumor. With radiation, since the cancer core is hypoxic, lack of oxygen impedes the effect of radiation therapy. Radiation induced oxidative cell damage requires the presence of oxygen. It is the belief of the Company that the mechanism of action of the Palomids may bridge the gap between broad angiogenic activity and direct anti-tumor activity, yet be safe.
The Palomids display activity that could be considered as ideal for an anti-cancer agent. P529 has been shown to inhibit the transcription factor hypoxia inducible factor 1 alpha (HIF-1α) through dissociation of TORC1 of the PI3K/Akt/mTOR pathway. HIF-1α is the primary inducer of the synthesis and secretion of a wide variety of tumor derived angiogenic cytokines. Hence, inhibiting HIF-1α will broadly inhibit angiogenesis without the need to directly inhibit or neutralize specific angiogenic cytokines. It has also been shown that Palomid 529 stimulates tumor cell apoptosis as shown by the accumulation of histone-associated DNA fragments in endothelial cells. Furthermore, Palomid 529 inhibits the activation (phosphorylation) of Akt through dissociation of TORC2. Inhibition of Akt resulting in inhibiting the PI3K/Akt/mTOR signal transduction pathway, a key regulator of cell growth and proliferation, which will broadly inhibit angiogenesis directly as it is downstream of many of the receptors known to activate angiogenesis. This mechanism of action would not only broadly stop tumor vessel formation but reduce cancer growth via inhibition of tumor cell proliferation and induction of apoptosis. By inhibiting tumor vessels, one would kill the tumor from the inside out and by inhibiting tumor cell growth and stimulating apoptosis, one would kill the tumor from the outside in. Hence, the mechanism of activity of Palomid 529 is consistent with the ability to induce cancer cures and regressions. Of particular interest, this mechanism of action would be expected to have activity over a wide range of tumor types. The National Cancer Institute (NCI) has shown P529 to be active in inhibiting proliferation of all tumors examined in their in vitro 60 cell screen (non-small cell lung, leukemia, colon, breast, melanoma, ovarian, CNS, prostate and renal cell cancers). Furthermore, the NCI and a variety of independent academic groups have shown P529 to be activity in inhibiting tumor growth in animal models of cancer both subcutaneous (thigh of mouse) and orthotopic (actual physiological location of tumor type) as well as showing synergy with radiation and conventional chemotherapeutic agents.