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A Personalized Approach for the Treatment of Metastatic Breast Cancer
The vast majority of anticancer drugs are general cytotoxins that arrest all rapidly dividing cell types. Most of these drugs can be classified as either S-phase arrestors or M-phase arrestors. Although the use of these compounds has been very successful for the treatment of certain cancer types, for many solid tumors and for most metastatic disease chemotherapeutic treatments have limited effectiveness. It is now recognized that a hallmark of cancer is its resistance to apoptosis. Cancer cells have mutations in or altered expression levels of a variety of proteins in the apoptotic cascade. Classic examples of alterations in the apoptotic cascade include mutation of p53, elevated levels of Bcl-2, reduced expression of death receptors, among many others. These changes are effectively "breaks" in the apoptotic circuitry, and prevent the proapoptotic signal from being transmitted to activate procaspse-3 to caspase-3. Caspase-3 is the key "executioner" caspase and has >100 substrates in the cell; cleavage of these substrates executes the death program. In cancer cells procaspase-3 is still intact and functional, but because of upstream alterations in the apoptotic cascade it is not activated. It is now know that levels of procaspse-3 are actually elevated in many cancer cell types. Procaspase-3 is elevated in colon cancer, lung cancer, melanaoma, and many others. Importantly, several papers have presented convincing evidence indicating that procaspase-3 levels are significantly elevated in breast cancer. In exciting recent work, we have discovered a small molecule, called PAC-1, that binds to procaspase-3 and induces its autoactivation to active caspase-3. Direct activation of procaspase-3 allows PAC-1 to bypass the damaged apoptotic pathway; thus PAC-1 is powerfully proapoptotic even in cancer cell lines that are highly resistant to apoptosis due to multiple alterations in their apoptotic proteins. We have also shown that in cells isolated from primary colon tumors the potency of PAC-1 tracks directly with the level of the procaspse-3 target. Given the elevated levels of procaspase-3 in breast cancer, there is a real opportunity for the development of PAC-1 as a personalized treatment for breast cancer, whereby a patient would be treated with a procaspase-3 activator if the level of procaspase-3 in their tumor cells was above a certain threshold. The goals of this proposed research are to (1) synthesize and identify derivatives of PAC-1 that are highly potent procaspase-3 activators, and (2) determine which of these derivatives are most effective in mouse models of cancer, including a metastatic model. Thus the potential outcomes for this research are the validation of procaspase-3 activation as a viable strategy for the treatment of breast cancer, and the discovery of potent procaspase-3 activators to be moved forward toward Investigation New Drug status and Phase I clinical trials at the end of the two year funding cycle.
Patients with metastatic breast cancer have a poor prognosis and limited therapeutic options. They are typically treated with anticancer drugs that are general cytotoxins, meaning they kill all rapidly dividing cell types. Such compounds have toxicity that limits their dosing and makes them largely ineffective against metastatic disease. We aim to develop a novel class of therapeutic agents for the treatment of breast cancer. Cells have an elaborate pathway that they use to kill themselves when they are no longer needed or when they are damaged. At the end of this pathway a key enzyme is converted from its inactive form (called procaspase-3) to its active form (caspase-3). Caspase-3 then kills the cell by degrading many other proteins. Unfortunately, in cancerous cells this pathway is damaged and the cell cannot convert procaspase-3 to caspase-3, thus it cannot kill itself and the cancer grows uncontrolled. It is known that procaspase-3 levels are elevated in breast cancer cells. However, because of the damaged cell death pathway, in cancer cells procaspase-3 is not naturally converted to caspase-3. In exciting recent results we have discovered a compound, called PAC-1, which directly converts procaspase-3 to caspase-3 thus tricking the cell into turning ?on? this key protein for cell death. We have also shown that PAC-1 is highly effective at killing cancerous cells that have elevated levels of procaspase-3. In the proposed work we aim to: (1) optimize the potency of PAC-1 and, (2) gather animal data such that within two years this compound can be utilized in a Phase I clinical trial with late-stage breast cancer patients. To optimize the potency of PAC-1, we will synthesize 900 different compounds that have a chemical structure that is similar to PAC-1. We will then test these PAC-1 derivatives for their ability to activate procaspase-3 and selectively induce death in cancer cells. The best 5-10 derivatives will then be tested in several mouse models of breast cancer. Importantly, we will use mouse models that mimic metastatic breast cancer. Compounds that show the greatest efficacy in these experiments will be moved forward toward Investigational New Drug status and a Phase I clinical trial. Using a drug to directly activate procaspase-3 to caspase-3 is a completely novel anti-cancer strategy. As procaspase-3 levels are known to be highly elevated in breast cancer cells, this strategy has enormous potential for the treatment of breast cancer, including the difficult-to-treat metastatic breast cancer. Thus the potential outcome of this research is the development of a novel drug and novel approach for the treatment of breast cancer.