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Vascular normalization by anti-angiogenic agents in breast cancer
The recognition of angiogenic vasculature as a target for intervention in cancers has led to the development of anti-angiogenic therapies. Originally intended to destroy blood vessels and reverse tumor growth, anti-angiogenic therapies such as vascular endothelial growth factor (VEGF) blocking antibodies and receptor tyrosine kinase inhibitors are rapidly entering the clinic. However, as in the case of VEGF-blocking antibody for patients with locally recurrent or metastatic breast cancer, treatment with the VEGF-blocking antibody does not starve the tumor, but rather sensitizes it to cytotoxic therapies. These results have raised fundamental questions about how an anti-angiogenic agent can be used in the clinic to 1) destroy tumor blood vessels and 2) enhance the outcome of cytotoxic therapy that require blood vessels for the delivery of drugs. Our laboratory has proposed that these drugs normalize the abnormal structure and function of the blood vessels, rendering them more efficient for the delivery of therapeutic agents. The goal of this proposal is to test the “normalization hypothesis” and apply it to further improve the design of treatment regimens that combine anti-angiogenic and cytotoxic therapies. The first aim of our study is to compare the vascular normalization potential of three different anti-angiogenic agents: an anti-VEGF antibody, B20-4.1; and receptor tyrosine kinase inhibitors AZD2171 and PTK787. Our second aim focuses on studying whether the three different anti-angiogenic agents have differential effects on interstitial fluid pressure, drug delivery and cytotoxic therapy. We will use intravital microscopy and histological techniques to determine the effect of the anti-angiogenic agents on vessel density, vessel pericyte coverage, and tissue oxygenation in an orthotopic breast cancer model in mice. We will also measure tumor interstitial fluid pressures and quantify delivery of molecules to tumors during anti-angiogenic treatment. Finally, we will assess improvement in tumor growth delay with administration of chemotherapy during vessel normalization, combining each of the three anti-angiogenic agents with paclitaxel in the orthotopic breast cancer model. If successful, the proposed research will offer the first comprehensive data comparing the vascular normalization potential of these anti-angiogenic agents (currently in clinical trials) in an orthotopic model of breast cancer. This will provide us with detailed information about the timing and duration of the normalization window in breast cancer as well as a direct measure of the improved effect of chemotherapy during vessel normalization. This will allow for the improved design of more effective treatment regimens for patients with breast cancer.
The development of a new class of cancer therapies, called anti-angiogenic therapies, stems from the realization that tumors can actively recruit new blood vessels in order to sustain their growth. These newly formed blood vessels supply tumors with oxygen and nutrients that allow them to grow and spread to distant sites. Anti-angiogenic therapies are supposed cut off this supply and starve tumors, preventing their growth and spread. However, as in the case of patients with breast cancer treated with a combination of anti-angiogenic and chemotherapeutic agents, the anti-angiogenic therapy does not starve the tumor, but rather makes it more sensitive to chemotherapy. This surprising finding has lead to a deeper investigation into how anti-angiogenic drugs may be working in patients. Our laboratory has proposed a novel hypothesis called “vascular normalization”, to describe a unique period of time during the anti-angiogenic therapy when the existing tumor vasculature, which is normally faulty in its structure and function, behaves more like vasculature of normal tissues. This normalization facilitates the delivery of oxygen and nutrients as well as chemotherapeutic agents into the tumor, explaining the findings of recent clinical and pre-clinical studies. The aim of my proposal is to study the vascular normalization potential of several of the anti-angiogenic agents that are currently in clinical trials. Using a mouse model of breast cancer, I propose to perform a series of studies to determine how and when breast tumor blood vessels start to function more like normal blood vessels after initiation of anti-angiogenic therapy. I will also determine the optimal window of time in which to combine chemotherapeutic agents with the anti-angiogenic treatment, in order to establish the best possible treatment for breast cancer. With these objectives in mind, I propose to study the arrival of chemotherapeutic drugs in breast tumors during anti-angiogenic treatment alons with a variety of structural and physiological parameters to gain a full understanding of these processes. The overall effect will be judged by the effect on tumor growth when combining the different anti-angiogenic agents with chemotherapy. Although anti-angiogenic agents are being pushed forward in clinical trials, it is not understood how these drugs work to improve cancer survival. Opportunities to improve therapy or hazards to patients may be missed without this knowledge. The proposed study will greatly improve our knowledge of combining anti-angiogenic agents and chemotherapy, and allow the design of more effective treatment regimens for patients with breast cancer.