New Approach to inhibiting cancer
Traditional chemotherapy can kill cancer cells but is also toxic to normal cells, causing severe side effects on normal organs. Targeted therapies aim at specific signaling pathways that control cancer cell proliferation and survival limiting side effects. However, many targeted cancer therapies fail due to complex signaling loops that compensate for the inhibition of a particular signaling pathway.
It was our hypothesis that blocking survival at different levels of signaling would induce active proliferation-related death of cancer cells. We came to this understanding by observing that blocking proliferation of cancer cells induces stasis but does not kill them. To kill cancer cells one needs to inhibit multiple survival pathways. If survival pathways are blocked, the intrinsic properties deregulating the cell cycle in response to damage will kill them. By a combination of drugs, we are able to block survival signaling at multiple levels, induce mitosis-related cell death in proliferating cells and block mitotic entry in healthy cells leaving them unaffected.
The science behind it
The PI3K/AKT/mTOR pathway is critical for cancer cell proliferation and survival. Inhibition of this pathway has been clinically proven to be effective in cancer therapy. For example, the inhibitor of mTOR rapamycin has been approved by FDA for renal cancer therapy and Everolimus, a rapamycin homologue, has recently been approved by FDA for metastatic breast cancer therapy. A number of inhibitors of this pathway have been developed by a number of companies and are currently in phase I and phase II clinical trials for cancer therapy.
Although these inhibitors are expected to improve the outcomes of cancer patients, the therapeutic effect will be very limited. The reason is that inhibition of this pathway will cause feedback activation of other oncogenic pathways, which will in turn drive cell proliferation and survival. One example of this is the failure of rapamycin in randomized clinical trials for cancer because of feedback activation of PI3K/AKT. Scientific studies have also shown that inhibition of PI3K/AKT caused feedback activation of ErbB3 and IGF1R, leading to dampened therapeutic effect.
The peptidase inhibitors we have identified block multiple signaling pathways, including PI3K/AKT. The inhibitors block the PI3K/AKT pathway by inducing degradation of insulin receptor substrate (IRS) proteins (IRS-1-3). IRS proteins are essential regulators of PI3K/AKT downstream of receptor tyrosine kinases for cell proliferation and survival. The inhibitors, by degradation of IRS proteins, are very potent inducers of cancer cell death. More importantly, the inhibitors completely blocked rapamycin-induced feedback activation of PI3K/AKT. Their combination with rapamycin synergistically killed cancer cells and inhibited tumor growth in animal models.